Archive for the ‘Life Extension Foundation’ Category

FDA outlawing injectable vitamin C to further destroy health of Americans

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Posted 08 Jan 2011 — by James Street
Category Antioxidants, Complementary Therapy, Finance and Politics of cancer research and treatment, Life Extension Foundation, Natural Therapies, Nutrition and Cancer, Prevention, Vitamins and Supplements

by Mike Adams, the Health Ranger, NaturalNews Editor

(NaturalNews) Not content to kill 100,000 Americans each year with deadly Big Pharma drugs while censoring the truth about the healing effects of herbs, nutritional supplements and natural medicines, the FDA has now set out to deny Americans access to yet another lifesaving medicine known simply as vitamin C.

As reported by the Alliance for Natural Health, the FDA has notified a manufacturer of injectable vitamin C that it will be criminally prosecuted if it continues to manufacture this lifesaving nutritional therapy. (http://www.anh-usa.org/action-alert…)

Why injectable vitamin C saves lives

In an age where tens of millions of Americans are already vitamin C deficient and suffer from colds and other infections that can be prevented with vitamins, the FDA appears to be acting on what can only be called a death wish for the American people. But really, it’s more likely a targeted attack at the alternative cancer industry that frequently uses injectable vitamin C to help patients eliminate cancer tumors and heal from various cancers.

If there’s one thing that the health authorities in the United States absolutely cannot tolerate, it’s natural cures for cancer. That’s why (nearly) all the natural cancer treatment clinics have been chased out of the country, leaving only toxic chemotherapy centers (poison clinics) in their place. And that’s probably why the FDA is going after vitamin C right now as well. Take away enough natural cures and the people will be forced into accepting conventional medicine, regardless of whether it works or not.

Injectable vitamin C has many other uses besides cancer, too. As the ANH reports, “The government, instead of banning intravenous vitamin C, should instead be supporting research into it. Even though IV C is being used in burn units around the world, including in the US, and has been adopted by the military for this purpose, the National Institutes of Health (NIH) refuses to fund any studies using intravenous C in patients. There are privately funded studies currently underway, but of course these cannot continue if the FDA bans the substance.”

Take action now to protect your access to vitamin C

Please take a moment to take action with both of the following petitions:

The Alliance for Natural Health has posted an online action item that sends a letter to Dr Margaret Hamburg, the commissioner of the FDA:

https://secure3.convio.net/aahf/site/Advocacy?cmd=display&page=UserAction&id=648

The Natural Solutions Foundation has also posted an action item, this one going out to various FDA and government officials:
http://salsa.democracyinaction.org/…

Of course, sending these letters to FDA bureaucrats assumes that they give a damn about human health in the first place, and after observing the FDA’s behavior over the last several years, I can confidently state that the FDA’s own actions betray its real agenda: To protect the profits of the drug companies by eliminating competing products such as vitamin C.

As Dr Rima Laibow says about this issue, “When injectible Vitamin C goes, the rest will soon go, and the natural Docs WILL be criminalized a la the infamous Flexner report. Codex standards effectively criminalize accurate speech on nutrition. This IS the other shoe; I do not believe we are being alarmist.”

The rise of tyranny

The larger issue here, however, is not this isolated decision by the FDA but rather the question: Why do unelected regulatory bureaucrats have such power in the first place?

While we may elect lawmakers in America today, those lawmakers have long since delegated the real “laws of the land” to bureaucratic agencies like the FDA which are run by unelected politicians who simply write their own laws and regulations without the approval of Congress. This situation is described by attorney Jonathan Emord as The Rise of Tyranny, which also happens to be the name of his book on the topic (http://www.amazon.com/Rise-Tyranny-…)

This book, which I consider a “must read” on the subject of health freedom, explains how the delegation of powers to rogue federal agencies (FDA, DEA, DHS, TSA, etc.) results in the nation being ruled by tyrannical bureaucrats who operate outside the authority of Congress. Under this power structure, for example, the FDA could simply announce one day that “all vitamins are illegal,” without Congressional approval and without any new laws being debated or signed into law. The delegation of powers to agencies like the FDA is the granting of dictatorial police state powers over entire sectors of our society.

The FCC, for example, may simply decide to seize control over the internet at any time. The TSA could simply announce it’s going to perform body cavity searches on all air travelers starting this Saturday. The DEA could announce it’s going to arrest operators of websites that even discuss marijuana. The FDA, likewise, could announce that “all herbalists are criminals” and proceed to have them all arrested.

Think this couldn’t happen? It’s happening right now, one step at a time. Last year it was cherries and walnuts (http://www.naturalnews.com/029698_c…). Today it’s injectable vitamin C. Tomorrow it could be all vitamin D supplements, or raw cacao, or medicinal herbs. The point is that the FDA could take away our access to supplements virtually overnight with no debate, no scientific scrutiny, and no Congressional oversight. The FDA is, itself, a tyrannical police state branch of the federal government that is now proceeding to take away Americans’ access to lifesaving supplements one by one.

Senator Rand Paul hopes to put a stop to this bureaucratic madness by introducing legislation that would require Congressional approval for such regulatory actions by any federal agency. That would strip the power out of the hands of these rogue agencies and put it back into the hands of lawmakers who are elected. While this may not be a perfect solution (because most lawmakers are still largely just corporate whores, to state it matter-of-factly), it would certainly be an improvement over the current situation where unelected bureaucrats rule over the American people as if they were dictators.

You know why the TSA is reaching down your pants? For the same reason the FDA is banning injectable vitamin C — because this nation is run by tyrants, not the legislators who are elected by the People. And as long as the tyrants are in charge, freedom can never be fully expressed.

Stop begging the King and just pick up your pitchforks

That’s why opposing the FDA on this decision by appealing to the FDA itself is sort of like begging the King to change his mind. It’s a slave-mentality action. Sure, it may be useful at some level, and that’s why we support these petitions, but let’s not kid ourselves on the fact that this is a slave-mentality appeal to a group of tyrants who act as if they were the King.

The real solution here is not to appeal to the King as peons, but rather to pick up our pitchforks, storm the castle, tie a rope around the neck of the King and hang him from a high castle wall (metaphorically speaking, of course) to send a message to all other would-be tyrants that messing with the freedom of the people will have consequences.

The way to accomplish that in our modern world would be to arrest FDA commissioner Margaret Hamburg for her crimes against humanity, prosecute her in a fair and open trial, and watch her serve time in prison while firing all the other bureaucrats at the FDA and dismantling the agency. No good can come out of the FDA. It is beyond repair. It is effectively working against the interests of the American people, making it as dangerous as a foreign enemy organization such as a terrorist group.

With the FDA, we are past the point of being able to negotiate with rational human beings who have ethics and souls. What we are dealing with at the FDA and other agencies are real-life incarnations of evil who are pursuing an agenda to spread death and suffering across our lands while they increase their power and control. And remember, the Congress just put the FDA in charge of the national food supply, too. Oh yippee. I can’t wait to see them ban broccoli because broccoli contains anti-cancer medicine, too.

I have a feeling that I will have a very exciting future as a broccoli smuggler. That’s my dream. To be the Han Solo of vegetables, fighting the Evil Empire with the power of garden vegetables.

Hold on a sec… somebody already did that! You can watch the hilarious video here: http://naturalnews.tv/v.asp?v=D86C3…

The Organic Rebellion is fighting back!

Cancer Adjuvant Therapy

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Posted 25 Sep 2010 — by James Street
Category Alternative Therapies, Antioxidants, Complementary Therapy, Life Extension Foundation, Natural Therapies, Nutrition and Cancer
Life Extension
Cancer Adjuvant Therapy

The good news is that many of the 4 million people being treated for cancer in America will survive the disease and go on to live full and productive lives.

While the numbers that survive are far too low (about 44%), many of the more than 1500 daily cancer deaths occur because patients and their families are unaware of the depth of the resources currently available. Unfortunately, some die avowing they would never resort to natural medicine, while others are interested but lack the expertise to implement the program to their best advantage. Regrettably, some turn to alternative care fairly late in the course of the disease process, weakening the probability of recovery.

Mainstream medicine (relying upon surgery, chemotherapy, and radiation) may initially appear successful, but the indications of the disease process are less often addressed. Conventional cancer treatments are not for those individuals who are frail in body or spirit. For the past 30 years, cancer therapies have experienced tremendous setbacks because of an associated toxic response, resulting in significant numbers of treatment-induced deaths rather than disease-induced fatalities. Awareness regarding historic numbers of unsuccessful outcomes has forced patients to look for alternatives to bolster survival odds. Many who use alternative therapies report doing so without their oncologist’s knowledge, fearful of criticism or rejection by a physician (Richardson et al. 2000).

The University of Texas M.D. Anderson Cancer Center (Houston) found that 99.3% of patients had heard of complementary medicine, and 68.7% of patients reported having used at least one unconventional therapy (Richardson et al. 2000). About 75% of the patients surveyed, however, yearned for more information concerning complementary medicine and about one-half of those participating in the survey wanted the information to come from their physician.

Until most recently, major medical schools granted only a few hours to nutritional education out of the hundreds of academic hours required to complete medical school. The exclusion began when Abraham Flexner (commissioned to correct inequities occurring in medical schools) penned the Flexner Report of 1910. His contribution, entitled Medical Education in the United States and Canada, closed smaller medical schools and forced those that survived to adopt a uniform curriculum that excluded nutritional courses. Thus, some physicians emerged from medical schools, scoffing at the concept of nutrition influencing health or overcoming disease.

Sir William Osler (1849-1919), chief physician at Johns Hopkins’s School of Medicine, drilled into students that medical research must be validated and replicated to be good medicine. This led to controlled experiments (as randomized, controlled trials) that became the backbone of mainstream medicine. Nutritional protocols often used multiple nutrients, a difficult model to apply in clinical trials. Testing a single nutraceutical denied the patient full support of nutritional pharmacology, an injustice when treating a seriously ill patient. In addition, trials are expensive to conduct and early natural healers (by and large) did not represent an affluent subset of society.

But, ever so slowly, the medical scene is being revolutionized. According to the American College for Advancement in Medicine, physicians (in many cases) are showing eagerness to learn more about natural medicine and how to best implement it into their practice (Corbin-Winslow et al. 2002). Scientists, teaching at nutritional seminars, report attendees are often medical doctors, a vast departure from years past.


PREVENTING AND CONTROLLING CANCER

While some individuals will be reading this protocol looking for help managing a malignancy, others will be focusing upon prevention and recurrence. The alphabetical list that follows provides quick guidelines for structuring a program, highlighting major nutrients in the prevention and treatment of cancer.

These recommendations should not be implemented individually in aggressive cancers without careful consultation of the remainder of the material. Cancer patients (and physicians) should be deliberate about reading the entirety of this protocol in order to avoid missing information that could prove to be lifesaving. Note: It is important that the reader also consult the protocols entitled Cancer Treatment: The Critical Factors and Cancer: Should Patients Take Dietary Supplements?

The dosages required for treating cancer (which are considerably larger than those required for prevention) can change the effects that a nutrient has on the body. The risk is multidirectional. Overdosing or underdosing, as well as a lack of patient awareness regarding the full potential of natural pharmaceuticals, hampers recovery.


THE CRITICAL IMPORTANCE OF SCHEDULED BLOOD TESTS

It is important to measure the successes or losses in regard to treatment-associated tumor response. Evaluating tumor markers in the blood or tumor imagery provides a basis for calculating regression of the disease. In addition, tumor markers provide direction for introducing other therapies if failures are evidenced.

Table 1: Type of Cancers and the Tumor Marker Used for Assessment
Type of Cancer Tumor Marker Blood Test
Ovarian cancer CA 125, CK-BB
Prostate cancer PSA, PAP, prolactin, testosterone
Breast cancer CA 27.29, CEA, alkaline phosphatase, and prolactin (or CA 15-3 rather than the CA 27.29)
Colon, rectum, liver, stomach, and other organ cancers CEA, CA 19-9, AFP, TPS, and GGTP
Pancreatic cancer CA 19.9, CEA, and GGTP
Leukemia, lymphoma, and Hodgkin’s disease LDH, CBC with differential, immune cell differentiation and leukemia profile

It is also important to evaluate the effectiveness of immune-boosting therapies and guard against anemia and therapeutic toxicities. At a minimum, a monthly complete blood chemistry (CBC) test that includes assessment of hematocrit, hemoglobin, and liver and kidney function should be done in all cancer patients undergoing treatment.

An immune cell test should be performed bimonthly, measuring total blood count, CD4 (T-helper), CD4/CD8 (T-helper-to-T-suppressor) ratio, and NK (natural killer) cell activity. Also consider tests measuring cortisol levels (Cortisol am and pm) and HCG (human chorionic gonadotropin), a hormone that may be elevated 10-12 years prior to a diagnosis of cancer. For information regarding test availability call (800) 208-3444.


COMPLEMENTARY THERAPIES

When describing the various complementary cancer therapies, it is not possible to endorse one supplement, hormone, or drug over another. We have provided as much evidence as space allows so that patients and their physicians can evaluate what approach may be suited for the individual situation.

A great deal of effort has been made to identify therapies that are substantiated in published scientific literature or that provide a cancer patient with the opportunity to experiment with cutting-edge treatment strategies. The focus of our effort has been to identify potentially lifesaving therapies that have been overlooked by mainstream oncology. We also attempt to discuss both positive and negative studies when applicable.

The Life Extension Foundation can assume no responsibility for outcome, apart from a self-assigned duty to stay abreast of the most promising of therapies and to share the data with members. No warranties (expressed or implied) accompany the material; neither is the information intended to replace medical advice. As always, each reader is urged to consult professional help for medical problems, especially those involving cancer. All supplements, drugs, and hormones are listed alphabetically and not in order of importance.


Alpha-Lipoic Acid–is a powerful antioxidant that regulates gene expression and preserves hearing during cisplatin therapy
Lester Packer, Ph.D. (scientist and professor at the Berkeley Laboratory of the University of California), refers to lipoic acid as the most powerful of all the antioxidants; in fact, Packer says that if he were to invent an ideal antioxidant, it would closely resemble lipoic acid (Packer et al. 1999). Alpha-lipoic acid claims anticarcinogenic credits because it independently scavenges free radicals, including the hydroxyl radical (a free radical involved in all stages of the cancer process and linked to an increase in the likelihood of metastasis).

Lipoic acid increases the efficacy of other antioxidants, regenerating vitamins C and E, coenzyme Q10, and glutathione for continued service. In fact, lipoic acid boosts the levels of glutathione by 30-70%, particularly in the lungs, liver, and kidney cells of laboratory animals injected with the antioxidant. In addition, glutathione tempers the synthesis of damaging cytokines and adhesion molecules by influencing the activity of nuclear factor kappa B (NF-kB), a transcription factor (Exner et al. 2000). Note: A great deal of material relating to NF-kB is presented in the protocol Cancer Treatment: The Critical Factors.

Lipoic acid can down-regulate genes that accelerate cancer without inducing toxicity. So responsive are cancer cells that laboratory-induced cancers literally soak up lipoic acid, a saturation that increased the lifespan of rats with aggressive cancer by 25% (Karpov et al. 1977).

Alpha-lipoic acid was preferentially toxic to leukemia cells lines (Jurkat and CCRF-CEM cells). The selective toxicity of lipoic acid to Jurkat cells was credited (in part) to the antioxidant’s ability to induce apoptosis. Lipoic acid activated (by nearly 100%) an enzyme (caspase) that kills leukemia cells (Pack et al. 2002). Other researchers showed that lipoic acid acted as a potentiator, amplifying the anti-leukemic effects of vitamin D. It is speculated that lipoic acid delivers much of its advantage by inhibiting NF-kB and the appearance of damaging cytokines (Sokoloski et al. 1997; Zhang et al. 2001). Finding that lipoic acid can differentiate between normal and leukemic cells charts new courses in treatment strategies to slow or overcome the disease (Packer et al. 1999).

As with all antioxidants, the appropriateness of using lipoic acid with chemotherapy arises. Animal studies indicate that alpha-lipoic acid decreased side effects associated with cyclophosphamide and vincristine (chemotherapeutic agents) but did not hamper drug effectiveness (Berger et al. 1983). More recently, a combination of alpha-lipoic acid and doxorubicin resulted in a marginally significant increase in survival of leukemic mice (Dovinova et al. 1999). Nonetheless, the definitive answer regarding coupling antioxidants with conventional cancer therapy is complex. Factors, such as type of malignancy, as well as the nature of the cytotoxic chemical and even the time of day the agents are administered, appear to influence outcome (please consult the protocol Cancer: Should Patients Take Dietary Supplements to learn more about the advisability of antioxidant therapy during conventional treatments).

To its credit, lipoic acid appears able to counter the hearing loss and deafness that often accompanies cisplatin therapy. Depreciated hearing occurs as free radicals, produced as a result of treatment, plunder the inner ear; lipoic acid preserves glutathione levels and thus prevents deafness in rats (Rybak et al. 1999).

A suggested lipoic acid dosage for healthy individuals is from 150-300 mg a day. Degenerative diseases usually require larger dosages (sometimes as much as 500 mg 3 times a day).


Arginine
Various scientists have attempted to describe the complex role of arginine in cancer biology and treatment. L-arginine is the common substrate for two enzymes, arginase and nitric oxide synthase. Arginase converts L-arginine to L-ornithine, a pathway that can increase cell proliferation. Nitric oxide synthase converts L-arginine to nitric oxide, a conversion process with uncertain effects regarding cancer.

A positive study conducted by a team of German researchers showed that arginine contributed significantly to immune function by increasing levels of white blood cells. Scottish scientists added that dietary supplementation with arginine in breast cancer patients enhanced NK cell activity and lymphokine cytotoxicity (Brittenden et al. 1994). (Lymphokines are chemical factors produced and released by T-lymphocytes that attract macrophages to a site of infection or inflammation in preparation for attack.) Various researchers have shown that increasing arginine increases neutrophils (white blood cells that remove bacteria, cellular debris, and solid particles), significantly upgrading host defense (Muhling et al. 2002).

Apart from enhancing immune function, arginine increases a number of amino acids, creating the possibility of an amino acid imbalance. Oversupplying some amino acids while undersupplying others is thought to destabilize the tumor. All cells, both healthy and diseased, have amino acid requirements; if not met, the cell is significantly disabled (Muhling et al. 2002). Amino acid manipulation has been applied in oncology for decades with varying degrees of success.

Interesting studies have emerged regarding arginine or arginine analogs in cancer treatment. For example, infusions of arginine significantly reduced the incidence of liver and lung metastasis in laboratory mice. Earlier research found that supplemental arginine altered the number of tumor-infiltrating lymphocytes in human colorectal cancer, offering important implications for new strategies in cancer treatment (Heys et al. 1997). Though many factors are involved (including appropriate dosages), Japanese researchers found that arginine induced apoptosis in pancreatic (AR4-2J) cells, inhibiting cell proliferation (Motoo et al. 2000).

The two faces of arginine, however, cloud dosing with confidence. The role of nitric oxide (NO), a molecule synthesized from arginine, remains controversial and poorly understood. While a few reports indicate that the presence of NO in tumor cells or their microenvironment is detrimental to tumor-cell survival, and subsequently their metastatic potential, a large body of data suggests that NO actually promotes tumor progression. Illustrative of its fickleness, NO was recently identified as a downstream regulator of prolactin, an inhibitor of apoptosis. However, arginine stimulated proliferation of prolactin-dependent Nb2 lymphoma cells in laboratory rats (Dodd et al. 2000). In addition, NO production (by murine mammary adenocarcinoma cells) promoted tumorcell invasiveness. Whereas, introducing NO inhibitors resulted in an antitumor, antimetastatic profile (Orucevic et al. 1999).

Ambiguity and nonconformity reduce arginine’s role at the present time to adjunctive support with either traditional cancer treatment or fish oil supplementation. A heartening report regarding arginine, fish oil, and doxorubicin therapy appears in this protocol in the section devoted to Essential Fatty Acids (Ogilvie et al. 2000). Nonetheless, the diverse biological properties of L-arginine demand further careful studies, clarifying chemopreventive advantages and endangerments (Szende et al. 2000).
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Cancer Adjuvant Therapy


Carotenoids–have antioxidant activity, inhibit cellular proliferation, and offer protection against numerous types of malignancies
Carotenoids, acting as immune enhancers and free-radical scavengers, are important substances in oncology. When using carotenoids for antioxidant and cancer protection, it appears wise to use mixed carotenoids, that is, alpha-carotene, lycopene, zeaxanthin, canthaxanthin, beta-crytoxanthine, and lutein rather than emphasizing only beta-carotene.

The following are illustrative of the worth of mixed carotenoids:

  • Lycopene offers targeted protection against cancers arising in the prostate (Kucuk et al. 2001), pancreas (Burney et al. 1989), digestive tract (De Stefani 2000), and colon (Nair et al. 2001).
  • The American Journal of Clinical Nutrition added that individuals seeking broad-spectrum colon protection should also include lutein-rich foods in their diet (spinach, broccoli, lettuce, tomatoes, oranges, carrots, celery, and greens) (Slattery et al. 2000).
  • Canthaxanthin, a less well-known carotenoid, was shown to induce apoptosis and inhibit cell growth in both WiDR colon adenocarcinoma and SK-MEL-2 melanoma cells (Palozza et al. 1998).
  • Researchers showed that the risk of breast cancer approximately doubled (2.21-fold) among subjects with blood levels of beta-carotene in the lowest quartile, compared with those in the highest quartile. The risk of breast cancer associated with low levels of other carotenoids was similar, that is, a 2.08-fold increased risk if lutein is deficient and a 1.68-fold greater risk if beta-cryptoxanthin is lacking (Toniolo et al. 2001). A Swedish study found that menopausal status has an impact on the protection delivered by carotenoids. Analysis showed that lycopene was associated with decreased breast cancer risk in postmenopausal women, but in premenopausal women, lutein offered greater protection (Hulten et al. 2001).
  • Leukoplakia (an often precancerous condition marked by white thickened patches on the mucous membranes of the cheeks, gums, or tongue) is responsive to spirulina, a source of proteins, carotenoids, and other micronutrients (Sankaranarayanan et al. 1995). An inverse relationship between beta-carotene and thyroid carcinoma was observed in both papillary and follicular carcinomas (D’Avanzo et al. 1997). A high dietary intake of beta-carotene appears a protective (though modest) factor for the development of ovarian cancer (Huncharek et al. 2001).
  • Lastly, Japanese researchers showed that all the carotenoids inhibited hepatic (liver) invasion, probably through antioxidant properties (Kozuki et al. 2000).

Men who consume 10 or more servings of tomato products per week reduce their risk of prostate cancer by about 35%. The American Chemical Society in August 2001 reported that 32 (largely African-American) patients diagnosed with prostate cancer and awaiting radical prostatectomy were placed on diets that included tomato sauce, providing 30 mg a day of lycopene. After 3 weeks, mean serum prostate specific antigen (PSA) concentrations fell by 17.5%, oxidative burden by 21.3%, DNA damage by 40%, while programmed cell death increased threefold in cancer cells (Holzman 2002). Part of lycopene’s protection involves the ability of carotenoids to counteract the proliferation of cancer cells induced by insulin-like growth factors (Agarwal et al. 2000a).

Beta-carotene exhibited a radio-protective effect among 709 children exposed to radiation inflicted by the Chernobyl nuclear accident. For example, the Chernobyl accident showed that irradiation increases the susceptibility of lipids to oxidative damage and that natural beta-carotene may act as an in vivo lipophilic antioxidant or radio-protective agent (Ben-Amotz et al. 1998). Therefore, using beta-carotene following radiotherapy may reduce the tissue damage caused during treatment.

Beta-carotene, perhaps the most controversial of the family of carotenoids, has come under attack several times in the past few years. For example, smokers who received synthetic beta-carotene (as a prophylactic) in the CARET study had a higher rate of lung cancer and death than smokers not supplemented. In fact, the study was terminated by the National Cancer Institute (NCI) because of the widespread discrepancy between the two groups. The CARET study is not new, but because it still concerns beta-carotene users, we will attempt to explain the unexpected results of the study.

Dr. Packer described the subjects as “walking time bombs.” Many were victims of asbestos exposure or heavy smoking. The form of beta-carotene selected for the study (synthetic versus natural) was also cited as another possible explanation for the negative outcome.

Dr. Leo Galland, M.D. (practitioner and director of the Foundation of Integrated Medicine, New York City), also explains that high-dose beta-carotene (25,000 IU a day) administered to smokers results in a particular pattern of metabolism (Galland 2000). The process is orchestrated as cytochrome p450 enzymes (Phase I detoxification system) are summoned into action by tars in cigarette smoke. As beta-carotene is acted on by cytochrome p450, oxidized end products are formed, as well as toxic derivatives.

Simultaneously, vitamins C and A, as well as glutathione, are depleted, severing antioxidant protection. This sequence can damage DNA and increase the likelihood of lung cancer, particularly in an environment with initially high oxidative stress, a profile common to smokers. Without full spectrum antioxidant support, the single dose of beta-carotene produces an oxidative environment rather than one of protection. (Comment: As one free radical is neutralized by an antioxidant, another oxidant may be formed. It is well established that vitamin C can serve as a pro-oxidant through the formation of ascorbyl radicals. It is also known that this radical is quenched by vitamin E to yield a tocopheryl radical, which in turn is reduced by the conversion of glutathione to glutathione disulfide. Thus, the full spectrum of antioxidants is preferable, rather than emphasizing single antioxidants.)

Beta-carotene is largely considered nontoxic even at high doses; for example, some nonconventional cancer therapies recommend large amounts of carrot juice. One large glass of carrot juice can contain 100,000-200,000 IU of provitamin A or carotene. The problem with carrot juice is that it is loaded with fructose (sugar). Cancer cells feed on sugar, and drinking carrot juice may induce an insulin spike that could potentially fuel cancer cell propagation.

Cancer patients should consider natural beta-carotene supplements in lieu of carrot juice. Suggested phytonutrient dosages are from 9-20 mg of sulphoraphane, 10-30 mg a day of lycopene, and 15-40 mg of lutein, along with a mixed carotenoid blend that includes alpha- and beta-carotene. A product called PhytoFood Powder provides potent amounts of sulphoraphane, while carotenoid extracts are available in a variety of encapsulated preparations. Note: What Should the Cancer Patient Eat, appearing later in this protocol, contains a discussion regarding the value of sulphoraphanes in the diet.


Cimetidine (Tagamet)
Histamine (H2) receptor antagonists (such as cimetidine) became popular in the late 1970s to treat gastrointestinal ulcers and other benign conditions of the stomach, esophagus, and duodenum. In 1985, the Life Extension Foundation announced that cimetidine had merit as a cancer adjunct. Since then, many studies have been published encouraging the use of cimetidine as a means of disabling tumors and expanding survival rates (Tonnesen et al.1988; Yoshimatsuk et al. 2003).

Ways through which cimetidine impacts cancer involves a three-pronged mechanism including (1) inhibition of cancer cell proliferation, (2) stimulation of lymphocyte activity by inhibition of T-cell suppressor function, and (3) inhibition of histamine’s activity as a growth factor (Siegers et al. 1999).

In a Japanese study, a total of 64 colorectal cancer patients (who had earlier undergone surgery) were evaluated for the effects of cimetidine on survival and disease recurrence. The cimetidine arm of the study received 800 mg a day of cimetidine along with 200 mg a day of the chemotherapy drug 5-fluorouracil (5-FU); the control group received only 5-FU. The treatment was initiated 2 weeks following surgery and terminated 1 year later. Strikingly beneficial effects were noted: The 10-year survival rate for patients treated with cimetidine/5-FU was 84.6%, whereas that of the control group (5-FU alone) was only 49.8% (Matsumoto et al. 2002).

The effect of cimetidine on a particularly aggressive form of colon cancer (Dukes grade C) was investigated. The cumulative 10-year survival rate of the cimetidine-treated group was consistently 84.6%, whereas that of the control group was only 23.1%. (Less virulent cancers (Dukes A or B) responded less well to cimetidine treatment) (Matsumoto et al. 2002).

Cimetidine treatment is particularly effective in patients whose tumors express higher levels of Lewis A and Lewis X antigens (i.e., breast and pancreatic cancers, as well as about 70% of colon cancers). Lewis A and Lewis X antigens are cell surface ligands that adhere to a molecule in the blood vessels called E-selectin. (Ligand comes from the Latin word ligare, meaning that which binds.)

The adhesion of the cancer cell to vascular endothelial cells expressing E-selectin is a key step in invasion and metastasis. Cimetidine improved patient outcome presumably by inhibiting the expression of E-selectin, thus abolishing the binding site for continued cancer growth and metastasis. The 10-year cumulative survival rate of the cimetidine group displaying Lewis antigens was 95.5%, whereas the control group was only 35.1% (Matsumoto et al. 2002). Comment: Patients are well-advised to undergo Lewis antigen determinations for optimal therapy and a more favorable outcome. Contact Impath Laboratories at 521 West 57 Street, New York, NY 10019, Telephone: (800) 447-8881, for information regarding testing.

Researchers recently unearthed another mechanism through which cimetidine offers cancer protection. Cimetidine enhanced cell-mediated immunity by improving suppressed dendritic cell function (Kubota et al. 2002). Dendritic cells capture foreign invaders and carry the antigen to lymph nodes and spleen. The “hand-delivered” antigen shows the immune system exactly what it has to fight. A more in-depth explanation regarding dendritic cells appears in a separate protocol entitled Cancer Vaccines.

The growth inhibitory effects of cimetidine were assessed on five cell lines derived from human brain tumors of different tissue types and grades of malignancy. Each cell line was treated with cimetidine 24 hours before analysis. Cimetidine significantly inhibited cell proliferation in three of five cell lines, which indicates the apparent dependence of these cells on histamine stimulation (Finn et al. 1996).

Because we do not wish the reader to interpret positive material as a universal ameliorant for all cancers, the following findings are noted:

  • Fred Hutchinson Cancer Research Center researchers explored whether cimetidine exerted a cancer-preventive effect on prostate and breast cancers by tracking 48,512 individuals from 1977-1995. Unfortunately, the study concluded that cimetidine did not influence the risk of female breast cancers; in addition, the researchers concluded that there was little evidence to support the previously hypothesized preventive effect of cimetidine on the risk of prostate cancers (Rossing et al. 2000).
  • In multiple myeloma patients, cimetidine reduced by about 30% the bioavailability of melphalan (Alkeran), the standard treatment for the disease (Sviland et al. 1987).
  • A total of 132 male rats were evaluated for immune status after ingesting cimetidine to forestall a diagnosis of gastric cancer. In the cimetidine-fed group, 19 of 48 developed cancer, versus 12 of 43 in the control group. The Norwegian researchers concluded that cimetidine had no significant immune-modulating effects on the development of gastric cancer in rodents (Hortemo et al. 1999).

While cimetidine is not efficacious in cancer prevention, it shows efficacy in treating certain cancers. A suggested cimetidine dosage for cancer patients is 800 mg (taken at night). Do not supplement with cimetidine without physician awareness; the drug can interact with several medications (such as digoxin, theophylline, phenytoin, warfarin, and lidocaine), increasing or decreasing drug potency.


Clodronate–is a bisphosphonate that inhibits cell proliferation and the threat of metastasis
Clodronate reduced the incidence and number of metastasis in bone and viscera (organs enclosed in the abdominal, thoracic, or pelvic cavity) in high-risk breast cancer patients by 50% (Diel et al. 1998; also see Journal Club on the Web).

Between 1990 and 1995, 302 patients (median age 51 years) with primary breast cancer and tumor cells in the bone marrow (the presence of which is a risk factor for the development of distant metastasis) were randomly assigned to receive 1600 mg a day of oral clodronate for 2 years or standard follow-up without clodronate supplementation (Diel et al. 1998).

At the conclusion of the trial, bone metastases were detected in 12 (8%) of the clodronate group versus 25 (17%) of the control group. The mean number of bony metastases per patient was 3.1 in the clodronate group versus 6.3 in the nontreated group. Visceral metastasis was observed in 13 (8%) versus 27 (19%) of controls; 6 patients (4%) died in the clodronate group, compared to 22 (15%) in the untreated group. Researchers concluded that clodronate opposed metastasis by altering the binding capacities of adhesion molecules on tumors and bone cells. Women with existing metastatic breast cancer (who added bisphosphonates to their regimen) reported less bone pain and fewer fractures with treatment.

The bisphosphonates (particularly zoledronic acid) appear to be effective against the skeletal complications of multiple myeloma, reducing vertebral fractures and pain. In the early phase of metastasis to bone, tumor cells activate osteoclasts, cells that break down and resorb bony tissue. This favors tumor growth, as growth factors are released when bone is degraded. Bisphosphonates inhibit the development of monocytes into osteoclasts (cells that digest and remove bone) and promote osteoclast death.

In addition, bisphosphonates restrain the production of bone-resorbing cytokines such as interleukin-6, an inflammatory marker for myeloma prognosis. Lastly, bisphosphonates directly affect myeloma by inducing apoptosis of malignant plasma cells. The biochemical effects of zoledronic acid continued for as long as 8 weeks after a single administration (Berenson 2001), but myeloma mortality was not decreased by bisphosphonates (Djulbegovic et al. 2001; Fromique et al. 2000). Typically, a synergism (a cooperative effort) exists between bisphosphonates and cytotoxic agents, increasing chemotherapy’s effectiveness.

The standard dose for treating cancer is 800 mg of clodronate taken twice daily, although double this dosage has been used safely. Breast cancer patients may consider a 3- to 5-year regimen of clodronate or other bisphosphonate therapy. Blood tests to measure serum calcium levels and kidney function are required 10 days after beginning clodronate and every 1-2 months thereafter. Persons who are pregnant or who have severe renal insufficiency requiring dialysis should avoid clodronate.

Note: Newer bisphosphonate drugs such as Zometa, Actonel, Fosamax, and Aredia, more potent than clodronate, are now FDA approved and readily available in the United States and covered by most health insurance plans. Prophylactic bisphosphonate therapy is highly recommended for cancers with a propensity to metastasize to bone, such as prostate and breast cancers. Most cancer patients should be on bisphosphonate therapy since any amount of bone breakdown releases growth factors that fuel cancer cell growth. Refer to Cancer Treatment: The Critical Factors for more information about bisphosphonate drugs approved in the United States.


Coenzyme Q10 and Statin Drugs
Statins, a class of cholesterol-lowering drugs, have been shown to inhibit the activity of ras oncogenes. ras oncogenes are involved in the regulation of cell growth, modulating the signals that govern the cancer cell cycle. Mutations in genes encoding Ras proteins have been closely associated with unregulated cell proliferation, a hallmark of cancer (refer to the protocol Cancer Treatment: The Critical Factors to read more about Ras oncogenes).

A number of studies have shown the value of statin drugs in a cancer regimen, and the benefit escalates when a statin is combined with a nonsteroidal anti-inflammatory drug (NSAID). People who regularly used NSAIDs lowered their risk of colon cancer by as much as 50%; when lovastatin was added to a cyclo-oxygenase 2 (COX-2) inhibitor, the rate of cell death of three colon cancer cell lines increased up to five-fold (Agarwal et al. 1999).

The statin’s mode of operation, however, raises concern. Statin drugs reduce cholesterol synthesis in the liver by inhibiting the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. HMG-CoA reductase is required for the conversion of HMG-CoA to mevalonic acid, a step in cholesterol synthesis (Folkers et al. 1990). Inhibiting HMG-CoA reductase results in lower amounts of cholesterol being produced. Disruption of the cascade also interferes with the synthesis of coenzyme Q10 (CoQ10), creating a potential tradeoff regarding advantages and disadvantages gathered from statin usage (Folkers et al 1990; Hattersley 1994).

The impact upon CoQ10 levels when taking statin drugs can be significant. For example, patients taking CoQ10, who later started lovastatin, lowered their CoQ10 levels by 44-75%. The problems associated with drug-related suppression of CoQ10 escalate when age-associated decline in serum CoQ10 levels are also present. A CoQ10 deficiency of 25% is linked with illness in animals and a deficit of 75% with death (Hattersley 1996; Bliznakov et al. 1988). Administering adequate amounts of CoQ10 with a statin drug allows the cancer patient the value of the drug without the risks imposed by depletion of the coenzyme.
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Cancer Adjuvant Therapy

In 1997 the Life Extension Foundation suggested that cancer patients ask their oncologist to consider lovastatin (80 mg a day) as adjunct therapy. The recommendation was based on scientific studies indicating lovastatin interfered with the cancer cell cycle and appeared to encourage cell death (apoptosis) (Dimitroulakos et al. 2001). Lovastatin, sold under the name Mevacor, is a fat-soluble statin drug, as are Zocor and Lipitor. Water-soluble statin drugs such as Pravachol may not work as effectively against cancer as the fat-soluble varieties, although one study showed Pravachol induced significant benefits to a group of primary liver cancer patients (Wang et al. 2000).

One of the concerns associated with low levels of CoQ10 is an increased risk of developing cancer. CoQ10 has been reported to be effective in inhibiting the progression of cancers and metastasis, even in patients for whom all conventional treatment failed (Folkers et al. 1993; Lockwood et al. 1995). CoQ10, acting as a nonspecific stimulant to the immune system, increases blood levels of T-lymphocytes and improves the T4-T8 lymphocyte ratio (Folkers et al. 1991). Contrast this with the energy loss and immune suppression associated with conventional cancer therapies.

Dr. Karl Folkers, a pioneer in CoQ10 exploration, reported that in a study of blood levels of CoQ10 in 116 breast cancer patients, 23.1% had blood levels of CoQ10 below 0.5 mcg/mL. The incidence of breast cancer cases with levels below 0.6 mcg/mL was 38.5%, higher percentages than observed in healthy women. A subsequent study reported in the Journal of Clinical Pharmacology and Therapeutics showed a statistically significant relationship between the level of CoQ10 deficiency and breast cancer prognosis (Folkers et al. 1997; Joliet et al. 1998).

Molecular Aspects of Medicine reported the results of an 18-month study conducted in Denmark involving 32 breast cancer patients (Lockwood et al. 1994). The patients had complicated medical profiles, that is, some had involvement in axillary lymph nodes and others had distant metastasis. The patients all received antioxidant therapy, consisting of vitamins C, E, and beta-carotene, select minerals and trace minerals, along with essential fatty acids, and 90 mg of CoQ10 a day. Their treatment was an integrated approach that also included surgery, radiation therapy, and chemotherapy. The survival rate during the 18-month study was 100%; a follow-up evaluation at the 24-month interval indicated all participants were still alive, although the expected deaths were four at 18 months and six at 24 months. All 32 of the enrollees in the study reported improvement in quality of life, stabilization of weight, a withdrawal from pain medications, and no signs of further distant metastases; six of the 32 patients showed apparent partial remissions.

Patients (n = 15) with myeloma showed a mean CoQ10 blood level of 0.67 ± 0.17 mcg/mL. The incidence of a CoQ10 blood level below 0.7 mcg/dL was 53.3%, which is higher than the 24.5% found among a group of nonmyeloma patients (Folkers et al. 1997). Individuals with bloodborne tumors are often saddened with the scarcity of nutritional material relevant to their type of cancer. When links are found, patients and physicians should take special note. The full clinical implication of this finding remains to be explored.

Patients, with and without cancer, report a decrease in the incidence of infection while taking CoQ10 (Bliznakov et al. 1970). This is particularly important to the cancer patient, who often faces additional challenges because of a suppressed immune system. Another extremely important characteristic of CoQ10 is its antioxidant potential, stabilizing cell membranes and preserving cellular integrity (Ernster et al. 1993).

One of the most potent chemicals used in cancer chemotherapy treatment is Adriamycin (doxorubicin). A significant consequence of this drug is cardiac damage, especially in older patients with established heart disease. Italian researcher Dr. Mario Ghione discovered a depletion of CoQ10 in the diseased hearts of animals after long-term Adriamycin administration. When CoQ10 was given to a group of mice before Adriamycin therapy, 80-86% survived; a control group (receiving Adriamycin but without CoQ10) had only a 36-42% survival rate (Bertazzaoli et al. 1977; Cortes et al. 1978).

Dosage suggestions are 90-390 mg a day of CoQ10, taken with some fat to enhance absorption. The American Journal of Health-System Pharmacy reported that liver enzymes could become elevated when taking 300 mg of CoQ10 a day for extended periods of time (Pepping 1999). Also, Folia Microbiologica reported that mice injected with human small cell lung cancer cells and then given high doses of CoQ10 had a diminished response to radiation therapy compared to the non-supplemented group (Lund et al. 1998). Note: Refer to the Cancer Chemotherapy and/or Cancer Radiation protocols along with Cancer: Should Patients Take Dietary Supplements to read about the appropriateness of supplementing with CoQ10 during chemotherapy or radiation therapy.Food sources of CoQ10 include mackerel, salmon, and sardines along with beef, peanuts, and spinach.


Conjugated Linoleic Acid (CLA)–is a trace fatty acid that inhibits tumor formation and metastasis, suppresses arachidonic acid, and encourages apoptosis
Researchers at the Roswell Park Cancer Institute (Buffalo, NY) showed that CLA, derived mainly from dairy products, reduced the incidence of breast cancer (Ip et al. 1999). Animal experiments showed that only 50% of rats feeding on CLA butter developed mammary tumors when exposed to high doses of known carcinogens, compared to 93% of the rats deprived CLA. This research demonstrated for the first time that CLA in foods is biologically active and that a food can offer significant protection against cancer (Cornell News 1999).

Anticancer Research published supporting data that CLA (in both test tube and animal models) demonstrates strong antitumor activity. Particularly gratifying effects were observed regarding inhibition of growth and metastatic spread of transplantable mammary tumors in severely immune deficient mice. The mice were fed CLA for 2 weeks prior to inoculation with human breast adenocarcinoma cells (107 MDA-MB468) and throughout the trial. CLA completely abolished the spread of breast cancer cells to the lungs, blood, and bone marrow. These results indicate that CLA blocks the local growth and spread of human breast cancer via mechanisms independent of the immune system (Visonneau et al. 1997; Banni et al. 1999; Ipet al. 1999).

The effects of CLA and beta-carotene were assessed on white blood cell (lymphocyte) and macrophage function. CLA alone increased lymphocyte numbers and their cell killing ability. Conversely, CLA inhibited interleukin-2 production (a desirable cytokine) and suppressed the ability of macrophages to destroy foreign material. When given together, CLA and beta-carotene interacted in an additive manner to increase lymphocyte production and their cytotoxicity. In addition, beta-carotene was able to overcome the inhibitory action of CLA on the phagocytic activity of macrophages (Chew et al. 1997).

Note: The Melanoma Center at the University of Pittsburgh Cancer Institute showed a potential role for histamine in cancer immunotherapy. A Phase II trial of IL-2 versus IL-2 and histamine in patients with metastatic melanoma demonstrated a trend toward a superior survival benefit from IL-2 and histamine for all patients enrolled and a statistically significant survival benefit for patients with hepatic metastasis (Agarwala et al. 2001).

The effect of three different diets on the local growth and metastatic potential of human prostatic carcinoma cells (DU-145) in severely immune-deficient mice was studied. Animals were fed either a standard diet or diets supplemented with 1% linoleic acid (LA) or 1% CLA for 2 weeks prior to inoculation with cancer cells and throughout the 14-week study. Mice receiving the LA-supplemented diet displayed significantly higher body weight, lower food intake, and increased local tumor load as compared to the other two groups of mice. Mice fed the CLA-supplemented diet exhibited not only smaller local tumors, but also a significant reduction in lung metastasis (Cesano et al. 1998). It was estimated that CLA inhibited the formation of premalignant lesions by approximately 50%, while increasing apoptosis in diseased cells (Ip et al. 2000).

CLA, in a dose-related fashion, has an ability to suppress arachidonic acid (AA). Since AA produces inflammatory mediators that can promote cancer at initiation and progression, CLA’s ability to stifle AA elevates its status as a chemopreventive (Miller et al. 2001; Urquhart et al. 2002).

In 1996, the Life Extension Foundation was in the forefront, recommendingCLA; after evaluating the results of numerous studies, the Foundation presented the promising anticarcinogenic nature of CLA to members. Relatively small doses (3-4 grams of CLA) are effective. For example, young female rats (still maturing) fed 0.8% of their diet from CLA achieved long-term protection against breast cancer. The dose of 0.8% correlates positively to the recommended daily dosage of 3-4 grams endorsed by the Foundation. A dose of six 1000-mg CLA capsules (76%) each day is suggested for cancer patients, pregnant and lactating women should avoid CLA.


Cyclooxygenase-2 (COX-2) Inhibitors (Naturally Occurring)
Note: The following compendium drawn (in part) from Beyond Aspirin (Newmark et al. 2000) underscores herbs that inhibit COX-2, an enzyme intricately involved in the cancer process. Natural compounds usually have many mechanisms of action; thus, the protective mechanisms common to the herb often extend beyond enzyme inhibition and are described herein. Because of the synergism of herbs, combinations are often of greater value than a single herb. The COX-2-cancer connection is thoroughly discussed in the protocol Cancer Treatment: The Critical Factors.


Berberine–Containing Herbs (Goldenseal, Barberry, Goldthread, and Oregon Grape)
Berberine, strong and bitter in taste and found in various herbs, delivers anti-inflammatory properties via COX-2 inhibition (Fukuda et al. 1999). Kaempferol, a constituent of berberine, is a strikingly active inhibitor of COX-2 activity (Chen et al. 1999; Newmark et al. 2000). Berberine is unique, having the ability to inhibit COX-2 activity without involving the beneficial COX-1 enzyme. Berberine, perhaps by impacting the production of cyclooxygenase, influences the development of cancers at various sites:

  • Berberine is effective against bladder cancers (Chung et al. 1999).
  • Berberine suppressed colon carcinogenesis and inhibited COX-2 without COX-1 inhibition. The COX-2 enzyme is abundantly expressed in colon cancer cells and plays a role in tumorigenesis. The berberine-COX-2 connection appears to best explain the mechanism of berberine’s anti-inflammatory and antitumor-promoting effects (Fukuda et al. 1999, Newmark et al. 2000).
  • Berberine-induced apoptosis in human leukemia cells (Kuo et al. 1995).
  • Berberine inhibited the development of skin tumors (Kitagawa et al. 1986).
  • Berberine has potent antitumor activity against human and rat malignant brain tumors (Zhang et al. 1990). Studies using goldenseal, which contains the alkaloid berberine, showed average cancer kill rate of 91% in rats, over twice that seen in BCNU (a standard chemotherapy agent for brain tumors). Rat studies used 10 mg/kg of berberine.

A suggested dose is three 250-mg capsules of goldenseal each day. The preparation should be standardized to provide 5% hydrastine. Various respected herbalists suggest that goldenseal should be cycled (rotated with other herbals) rather than routinely administered. Goldenseal contains the alkaloids berberine, hydrastine, and canadine.


Feverfew (Tanacetum parthenium)
The anti-inflammatory traits of Feverfew have an ability to inhibit the COX-2 enzyme (Hwang et al. 1996). According to Newmark et al. (2000), feverfew contains a lactone, or chemical compound called parthenolide. Parthenolide, in turn, contains a variant of methylene-gamma-lactone (MGL) that interacts with macrophages. The white blood cell-lactone interaction suppresses a critical protein process, a repression that ultimately inhibits the COX-2 enzyme. In addition, feverfew contains apigenin (a flavonoid) and melatonin, both COX-2 inhibitors (Murch et al. 1997).

Researchers at Children’s Hospital Medical Center (Cincinnati, Ohio) explained another of parthenolide’s anti-inflammatory traits: its ability to inhibit NF-kB, the predecessor of a number of potentially damaging cytokines (Sheehan et al. 2002). Recall that as inflammation is reduced the risks of many degenerative diseases decrease as well (turn to the protocol entitled Cancer Treatment: The Critical Factors to read about the cytokine/cancer connection).

In addition, feverfew inhibits 5-lipoxygenase, an enzyme that metabolizes AA. A byproduct of this metabolism (hydroxy-eicosatetraenoic acid or HETE) feeds cancer cells and promotes angiogenesis, the development of new blood vessels. Agents that inhibit the production of lipoxygenase should be of particular interest to individuals taking COX-2 inhibitors; as the COX-2 enzyme is inhibited, 5-lipoxygenase enzymes become activated (Pizzorno 2001).

A suggested dosage is 1-2 capsules of feverfew a day, standardized to contain 600 mcg of parthenolide. Pregnant and lactating women should avoid feverfew, as well as those showing allergic sensitivities.


Ginger (Zingiber officinalis)
From the scores of biologically active components contained in ginger, some are specific for inhibiting COX-2 and others for inhibiting 5-lipoxygenase, enzymes responsible for the formation of pro-inflammatory agents (prostaglandin E2 and leukotriene B4) from AA. Ginger safely modulates COX-2 activity but also brings balance to COX-1 (an enzyme responsible for gastric mucosal integrity) in a manner vastly superior to synthetic NSAIDs (Newmark et al. 2000; Reiter et al. 2001).

As COX-2 and 5-lipoxygenase are repressed, two distinct metabolic pathways are inhibited, one leading to the synthesis of prostaglandins and the other leading to the production of HETEs. Prostaglandin E2 (PGE2) (produced from COX-2-arachidonic acid interactions) promotes cellular proliferation, and 5-HETE is considered indispensable fuel for tumor growth (prostate in particular).

It has been speculated that therapeutic dosages of ginger inhibit PGE2 by up to 56%. As ginger slows down 5-lipoxygenase and 5-HETE production, cell death is stimulated in both hormone responsive and nonresponsive human prostate cancer cells (Suekawa et al. 1986; Ghosh et al. 1998). Leukotrienes, produced by lipoxygenase, are considered 1000 times more reactive than histamine. Ginger has more 5-lipoxygenase inhibitors than any other botanical source (Newmark et al. 2000).

Ginger may also be useful in overcoming nausea that accompanies chemotherapy and toxicity associated with the breakdown products of cancerous tissue. James Duke, Ph.D., distinguished botanist and author, has high regard for ginger, adding that it has a major advantage over other antiemetics because of its safety profile. Ginger’s antioxidant activity adds another plus to a booming list of anticancer credits. A suggested dosage is 2 grams of ginger a day.


Green Tea
Salicylic acid, the main anti-inflammatory component of aspirin, is a naturally occurring compound found in green tea, having COX-2 inhibiting qualities. The polyphenols and flavonoids contained in green tea are also COX-2 inhibitors (Noreen et al. 1998).

Mayo Clinic researchers showed that green tea consumption inhibited cancer growth (Paschka et al. 1998). They identified the green tea polyphenol EGCG (epigallocatechin gallate) as the most potent inhibitor of cancer cell proliferation. Japanese researchers pinpointed the types of cancer most responsive to green tea (breast, esophageal, liver, lung, skin, and stomach) by surveying cancer-free individuals who consumed 4-6 cups of green tea a day.

The odds ratio of stomach cancer decreased to 0.69 with a high intake of green tea (7 cups or more a day) (Inoue et al. 1998). Another study conducted in Yangzhong (a region in China with a high incidence of chronic gastritis and gastric cancer) showed the amount and duration of green tea consumption governed the rate of stomach cancer. Frequent long-term green tea drinkers had approximately 50% less risk of developing gastric cancer compared to individuals consuming little or no tea (Setiawan et al. 2001). Green tea reduces the damaging effects of nitrites in the acidic environment of the stomach with greater efficiency than vitamin C.

The growth of non-Hodgkin’s lymphoma cells, transplanted in mice, was reduced by 50% when green tea was a part of the animal’s diet. Cyclophosphamide, a chemotherapeutic drug, administered at the maximum tolerable dose, was unable to replicate similar benefits (Bertolini et al. 2000). Part of green tea’s anticancer profile includes an antimutagenic factor that helps DNA replicate accurately (Uhlenbruck et al. 1998).

PGE2 is thought to stimulate tumor promotion in precancerous and cancerous cells (August et al. 1999; Bertolini et al. 2000). Of 14 subjects, 10 (71%) demonstrated a response to green tea, as evidenced by at least a 50% inhibition of PGE2 in rectal mucosa.

EGCG appears to normalize the cell growth cycle and prompt apoptosis in cancer cells by inhibiting NF-kB, a growth vehicle cancer cells use to escape cell regulatory control (Ahmad et al. 2000). EGCG strongly and directly inhibits telomerase, an enzyme (normally dormant from birth) that delivers immortal status to cancer cells (Naasani et al. 1998).

Cigarette smokers who drink green tea have a 45% lower risk of lung cancer compared to non-tea drinkers. Even though Japan has one of the highest numbers of smokers in the world, they have one of the lowest rates of lung cancer of any developed nation, a protection thought to be delivered by green tea.

The number of anticarcinogens, antioxidants, and anti-proliferative agents found in green tea (carotenoids, chlorophyll, polysaccharides, vitamins C and E, and numerous flavonoids) explains why some researchers advocate using a broad-spectrum extract, replicating the plant’s total constituents. Considering the vastness of green tea’s anti-cancer effects, incorporating green tea into the diet 5-10 cups a day (or five 350-mg capsules three times a day of a 95% polyphenol extract) would appear to be wise for individuals concerned with cancer.
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Cancer Adjuvant Therapy


Curcumin
Worldwide clinical trials have chiseled out a definite place for curcumin in oncology. Among them are New York Presbyterian Hospital and the Weill Medical College, which reported that curcumin, a curcuminoid found in turmeric, directly inhibited the COX-2 enzyme (Zhang et al. 1999). So excited are various oncologists regarding curcumin that the potent anti-inflammatory has been classed as a potential third generation cancer chemopreventive agent.

Curcumin inhibited thromboxane A2 (TxA2), a highly unstable, biologically active compound created by COX from AA (Shah et al. 1999; Newmark et al. 2000). Unless controlled, TxA2 promotes tumor endothelial cell migration (metastasis) and angiogenesis. By inhibiting TxA2, curcumin reduces the tumor’s blood supply and lessens the threat of metastasis (Arbiser et al. 1998; Nie et al. 2000). Curcumin is effective at inhibiting 5-lipoxygenase and subsequently HETE, a survival factor for prostate, breast, and pancreatic cancers (Ghosh et al. 1998; Ding et al. 1999; Newmark et al. 2000; Li et al. 2001).

The following list illustrates the depth of curcumin’s defenses against cancer:

  • Colon: Curcumin inhibited chemically induced carcinogenesis in the colon when administered at different stages of the cancer process. Laboratory rats, administered curcumin during either initiation or late in the premalignant phase, had a lesser incidence and fewer numbers of invasive malignant colon tumors (Kawamori et al. 1999). Also, by inhibiting COX-2-arachidonic acid interactions, curcumin suppresses prostaglandins responsible for inflammatory processes (Plummer et al. 1999). Chronic inflammation has for decades been regarded as a cause of colon cancer (Konig et al. 1976).
  • Antioxidant activity: Curcumin inhibits or possibly even reverses oxidative damage by scavenging and neutralizing free radicals. By defusing the hydroxyl and superoxide radicals and breaking oxidative chain reactions, curcumin protects DNA with greater efficiency than lipoic acid, vitamin E, or beta-carotene (Ruby et al. 1995; Ahsan et al. 1999; Li et al. 2001).
  • Breast cancer: Curcumin inhibits the growth of multiple breast cancer cell lines (Inano et al. 1999), particularly those that result from exposure to environmental estrogens such as chemicals and pesticides (Verma et al. 1998). Also, curcumin, estrogen, and estrogen mimickers gain entry into the cell through the aryl hydrocarbon receptor. Because curcumin competes for entry, it can crowd out damaging materials (Ciolino et al. 1998). According to researchers, curcumin blends well with other cancer inhibitors. For example, a curcumin-isoflavonoid combination suppressed the growth of estrogen receptor-positive cancer cells up to 95% (Verma et al. 1998).
  • Oral tumors: Curcumin inhibits oral squamous cell carcinoma more effectively than either genistein or quercetin (Ellatar et al. 2000). Only cisplatin, a platinum-based chemotherapy drug, was more effective.
  • Skin tumors: Curcumin inhibits skin tumors. When applied topically, curcumin reduces skin inflammation and inhibits local swelling (Huang et al. 1997).
  • Prostate cancer: Curcumin was able to decrease the proliferative potential of androgen-independent prostate cancer cells–and cells of other androgen-dependent cancers–largely by encouraging apoptosis. Moreover, a significant decrease in microvessel density, the sustaining blood supply of a tumor, was also observed (Dorai et al. 2001).
  • Leukemia: Curcumin-induced apoptotic cell death in promyelocytic leukemia HL-60 cells at concentrations as low as 3.5 mcg/mL (Kuo et al. 1996).
  • Protein kinase C (PKC) and epidermal growth factors (EGF): Curcumin was proclaimed “potentially useful” in developing anti-proliferative strategies to control tumor growth by suppressing the activity of protein kinase C (PKC) (Korutla et al. 1995). As the activity of PKC is slowed down, tumor proliferation is halted (Lin et al. 1997). PKC transmits signals from the epidermal growth factor receptor (EGF-R), a cycle that ultimately encourages the growth of tumors. Conversely, cancers awaiting EGF stimulation are dealt a severe blow if this pathway is severed. Curcumin blocked the activation of EGF by 90%.
  • p53 potentiator: Curcumin increases expression of healthy nuclear p53 protein in human basal cell carcinomas, hepatomas, and leukemia cell lines (Jee et al. 1998). Turn to the protocol Cancer: Gene Therapies, Stem Cells, Telomeres, and Cytokines to read more about tumor suppressor genes.
  • Tumor necrosis factor-alpha (TNF-alpha): Researchers at the University of Kentucky showed that TNF-alpha acts as a catalyst in cytokine production, stimulating interleukin-6 (IL-6) and -8 (IL-8) and activating NF-kB (Blanchard et al. 2001). Curcumin inhibits TNF-alpha, thus blocking TNF-alpha, NF-kB pathways, and the emergence of pro-inflammatory cytokines (Xu et al. 1997-1998; Li et al. 2001; Literat et al. 2001). To read more about proinflammatory cytokines, turn to the protocol Cancer: Gene Therapies, Stem Cells, Telomeres and Cytokines.
  • Helicobactor pylori: Exposure of gastric epithelial cells to the ulcer-causing bacterium H. pylori (considered a potential gastric and pancreatic carcinogen) induces secretion of IL-8. IL-8 plays a pivotal role in the development of cancer. The more virulent H. pylori, the greater the production of IL-8. H. pylori strains that fail to induce IL-8 secretion do not activate NF-kB, while all IL-8 inducing strains activate the transcription factor. Curcumin is capable of inhibiting NF-kB and completely suppressing IL-8. By restraining essential players in the development of H. pylori, curcumin diminishes the risks of both gastric and pancreatic cancer (Munzenmaier et al. 1997; Stolzenberg-Solomon et al. 2001).

Although the benefits of curcumin are impressive, curcumin is poorly assimilated. This means that while the digestive tract and liver profit, the remainder of the body may be denied benefit. Administering 2000 mg of curcumin showed that very little reached the bloodstream. This dilemma is amendable by adding a small amount of piperine (a component of black pepper) to curcumin, increasing bioavailability by 2000% (Shoba et al. 1998). However, it is possible that piperine in combination with prescription drugs could increase the bioavailability of the drug. Therefore, it is recommended that curcumin (containing piperine) be taken 2 hours apart from prescription medications.

Super Curcumin dosage: Healthy people typically take 900 mg of curcumin each day. Cancer patients often take as much as four 900-mg capsules 3 times a day for a 6- to 12-month period, reducing the dosage thereafter. Individuals with biliary tract obstruction should avoid curcumin because it enhances biliary flow from the liver. High doses of curcumin should not be taken on an empty stomach to protect against gastric irritation.

Note: The question ultimately arises as to whether curcumin is appropriate during chemotherapy. A recent study from the University of North Carolina (Chapel Hill) showed that curcumin reduced the effectiveness of chemotherapy in breast cancer patients by inhibiting reactive oxygen species (Somasundaram et al. 2002). Please refer to the protocols Cancer: Should Patients Take Dietary Supplements? and Cancer Chemotherapy to read more about this study and the advisability of taking curcumin during conventional treatment.


Dimethyl Sulfoxide (DMSO)
In August 1995, Dr. Julian Whitaker, M.D., relayed his own experience with DMSO, when a basal cell carcinoma (about the size of a dime) appeared on his ear. A dermatologist recommended surgical removal of the cancerous portion and a skin graft replacement. Instead, Dr. Whitaker made a paste from shark cartilage, vitamin C, and DMSO and applied the mixture to the lesion daily. Within 3.5 weeks, the basal cell had completely disappeared. Stanley Jacob, M.D., professor at the Oregon Health Sciences University (Portland) suspected DMSO was the hero, although Dr. Whitaker has confidence in the full formula (Whitaker 1995).

The Sealy Center for Molecular Sciences reported that DMSO, administered either before or 15 minutes after TNF-alpha, blocked 80% of NF-kB. By suppressing TNF-alpha and NF-kB, DMSO broke an inflammatory cascade that otherwise terminates in an onslaught of potentially damaging cytokines (Vlahopoulos et al. 1999).

DMSO is an excellent transporter of other therapies into cancerous cells. In fact, many offshore cancer clinics consider it the standard for all patients who are undergoing various therapies.


Essential Fatty Acids (EFAs)–
block arachidonic acid, inhibit COX-2 enzyme, regulate cell division and inhibit adhesion, prevent cachexia, potentiate traditional cancer therapies, and suppress the activity of pro-inflammatory cytokines
As a result of the current fat phobia, over 80% of Americans consume inadequate amounts of essential fatty acids (especially omega-3 fatty acids). Physicians report that this scarcity is contributing to epidemic proportions of degenerative diseases, including cancer (Murray et al. 1996). The omega-6 to omega-3 fatty acid ratio typically seen may be as high as 20:1, whereas the optimal ratio may be nearer 1:1 (Mercola 2002a). EFAs, although not manufactured by the body, perform vital functions that prevent and control cancer.

  • As enzymes metabolize AA, the byproducts of the metabolism fuel the cancer process (Comprehensive Cancer Care 2001). Oxidized AA is, in fact, considered a primary initiator of cancer (Newmark et al. 2000). One gram of omega-3 fatty acids blocks 10 grams of AA (Pizzorno 2001).
  • The COX-2 enzyme (interacting with AA) can cause excess production of PGE2, promoting cancer cell growth. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (derived from alpha-linolenic acid or fish oil) are effective COX-2 inhibitors (Ringbom et al. 2001).
  • Fish oil is the most documented supplement to suppress (up to 90%) a cascade of damaging cytokines, including TNF-alpha and IL-1 (James et al. 2000). It should be noted that psychological stress induces the production of pro-inflammatory cytokines, such as TNF-alpha, IL-6, and IL-10. Increasing omega-3 fatty acids lessened the pro-inflammatory response to psychological stress (Maes et al. 2000). For information regarding a blood test to obtain a cytokine profile, call (800) 208-3444.
  • Women with high levels of alpha-linolenic acid in breast tissue have a 60% lower risk of breast cancer compared to women with low levels (Klein et al. 2000; Maillard et al. 2002). Jeffrey Bland, esteemed scientist and teacher, reported a supportive study involving 500 (C3H) mice prone to breast cancer. The mice were divided into 10 groups of 50 animals and evaluated regarding the impact of various dietary oils on the occurrence of cancer. One-tenth of the animals received standard chow and served as a control group; another group received standard chow plus benzanthracene, a carcinogen. The other eight groups received isocaloric diets along with the cancer inducer; the variable was the type of fat (not the amount) fed in conjunction with the chow. Eight oils were evaluated: tallow, fish, corn, primrose, safflower, linseed oils, and two others. At the conclusion of the study, eight of the 10 groups (400 animals) were dead with mammary cancer. The 100 survivors were animals fed omega-3 rich oils. The study was repeated using different types of oils and varying amounts of the cancer inducer. The end results werethe same. Researchers postulated that the advantage of omega-3 fatty acid was the oil’s ability to reduce inflammatory mediators, those signaling tumor progression and metastasis (Cameron et al. 1989).
  • Epidemiologic and experimental studies suggest that oils rich in omega-3 fatty acids lessen the risk of colon cancer. A relatively small fraction of alpha-linolenic-rich perilla oil (25% of total dietary fat) provided an appreciable beneficial effect in reducing cancer risk (Narisawa et al. 1994).
  • Low EFA status results in a lack of oncogene control with a shift toward cell proliferation (Pizzorno 2001). EFAs also regulate the adhesiveness of cancer cells, including cell-cell and cell-matrix adhesions (Jiang 1998).
  • Fatty acids, particularly EPA, inhibited the growth of three human pancreatic cancer cell lines (MIA PaCA-2, PANC-1, and CFPAC), suggesting therapeutic benefit to pancreatic cancer patients (Falconer et al. 1994).
  • Omega-3 fatty acids prevent cachexia (the muscle wasting and weight loss that occurs in some cancer patients irrespective of proper nutritional intake). Controlling the symptoms common to cachexia (anorexia, abnormal macronutrient metabolism, and fatigue) improves quality of life and extends periods of remission (Bruera 2003).
  • Researchers found DHA and EPA cytotoxic to myeloma cells in vitro (Sravan et al. 1997). Individuals who regularly consume fish and cruciferous vegetables appear to lessen their risk of developing multiple myeloma (Brown et al. 2001).

Thirty-two dogs with Stage III lymphoma and their response to a dietary and chemotherapeutic regime were evaluated. All of the animals were fed identical diets, but they received varying types of oils. For example, one group received menhaden fish oil (rich in omega-3 fatty acid) and arginine, while the control group received soybean oil (Ogilvie et al. 2000). The animals also received doxorubicin every 3 weeks.

As DHA and EPA levels increased in the test group, the animals experienced longer disease-free intervals and subsequently increased survival time. Dogs receiving the supplemented diet lived about 700 days; animals receiving the soybean oil lived only about 400 days. The time until relapse was also significant: 425 days in the treatment group versus 275 days in the control group. Note: Since fish oil increases the effectiveness of chemotherapeutic agents, the animals receiving the menhaden oil realized an additional advantage over the soybean-treated animals (Hardman et al. 2001).

Suggested dosages for various EFAs: Take six 1000-mg capsules a day of perilla oil, which provide 550-620 mg of alpha-linolenic. Flaxseed oil, 1000-mg softgels, is a rich source of omega-3 fatty acids. Take 7 softgels a day. A preventive dose of a fish oil concentrate called Mega EPA is 4 capsules a day (2800 mg of EPA/DHA). Cancer patients often use 8-12 Mega EPA softgels daily along with 4 Mega GLA softgels to balance the high amount of omega-3 being consumed in the fish oil. Another option for cancer patients is 8 capsules a day of Super GLA/DHA, providing a highly concentrated amount of DHA, GLA, and a moderate amount of EPA. Higher dosages should be physician supervised.


Garlic (Allium sativum)–is inhibitory to a number of malignancies, minimizes damage imposed by known carcinogens, and boosts the immune system
No plant has the medicinal history, spanning as many cultures, of garlic. Garlic, in fact, appears to be the quintessential medicine/food, having influence on simplistic diseases from common colds to degenerative diseases. For centuries the Chinese have used garlic-containing herbal formulas to treat tumors, but scientists were challenged to find the mechanism that rendered it efficacious.

Among those dedicated to validating garlic is Dr. Benjamin Lau, M.D., Ph.D. Dr. Lau, focusing upon cancer biology and immunology, was motivated by an epidemiological study reported by the People’s Republic of China. The study compared two large populations in the Shandong Province: Cangshan Country and Qixia Country (Mei et al. 1982). Residents of Cangshan County experienced the lowest death rate due to stomach cancer (three per 100,000), regularly consuming about 20 grams of garlic a day; the people of Qixia had a 13-fold higher stomach cancer death rate, eating garlic only rarely. It appears that lowering nitrite concentrations may be the protective mechanism resulting in fewer numbers of gastric cancers. Jhinzou Liu, Ph.D., a Chinese biochemist, found garlic “much more effective than vitamin C” in keeping nitrosamines, potentially carcinogenic compounds, from forming.

Garlic’s anticarcinogenic effects are not restricted to gastric malignances.

  • Garlic (administered intralesionally to mice) was significantly more effective than BCG (bacillus Calmette-Guerin), a weakened form of the tuberculosis bacilli, in treating bladder cancer (Lau et al. 1986).
  • Garlic extract reduced the incidence of breast cancer (in mice) by 70-90% (Langer 1991).
  • Diallyl disulfide, a sulfur compound, induced cell death (apoptosis) in non small cell lung cancer cells (Hong et al. 2000); Diallyl sulfide, a component of garlic oil, inhibited liver carcinogenicity following carcinogenic exposure (Hayes et al. 1987); S-allyl cysteine, (a derivative of aged garlic extract), inhibited human neuroblastoma cell growth in vitro (Welch et al. 1992); allixin, one of the compounds of aged garlic extract, inhibited the development of skin cancer (Nishino et al. 1990). Diallyl sulfide was highly inhibitory during the initiation phase of esophageal cancer (Wargovich et al. 1992).
  • S-allyl cysteine (SAC) inhibited proliferation and cell growth of nine human and murine melanoma cell lines, producing positive results without side effects (Takeyama et al. 1993). Of equal importance, garlic modulated major cell differentiation markers of melanoma. As the cell shows distinguishable characteristics (differentiation), it eventually loses its uncontrollable propensity to divide.
  • S-allyl cysteine and diallyl sulfide reduced colonic damage and the incidence and frequency of colon tumors if administered 3 hours prior to each carcinogenic injection. Colonic damage was inhibited by 36% and 47% respectively (Sumiyoshi et al. 1990). Michael Wargovish, M.D. (Houston), claims that diallyl sulfide is one of the most active chemopreventive agents known.

S-allyl cysteine (SAC) appears to be able to overcome the adverse side effects (heart and liver damage) associated with the chemotherapeutic agent doxorubicin. Doxorubicin resulted in a 58% mortality rate among laboratory mice; SAC reduced doxorubicin-induced mortality to 30% (Mostafa et al. 2000). Weight loss, typical with doxorubicin, was reduced from 13% to 9% with SAC.

Certain garlic constituents possess antioxidant properties, while other constituents act as oxidants. The latter case is strikingly demonstrated when human hemoglobin is mixed with extracts from fresh garlic and from dried raw garlic powder products. The hemoglobin-garlic extract mixtures turn dark, and their spectra reveal the oxidation of hemoglobin to methemoglobin. Contrarily, extracts from aged garlic do not cause oxidative changes.
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Cancer Adjuvant Therapy

When t-butylhydroperoxide, a free-radical generator and oxidant, is used to oxidize red blood cells, it results in rupturing of the cells and darkening of the hemoglobin. An extract of aged garlic, added to the red blood cell suspension prior to the addition of the oxidant, minimized oxidation and cell rupture (Lin 1989). Since many cancer therapies produce free radicals in an attempt to kill cancer cells, researchers concluded that garlic could offer significant protection against treatment-induced tissue damage. Comment: Please consult the protocol Cancer: Should Patients Take Dietary Supplements to read about the appropriateness of antioxidant therapy during conventional cancer treatment.

Another benefit of garlic to the cancer patients is its effect on enhancing immune function. Here are a few of the numerous studies relating to garlic’s effect on immune cells:

  • Garlic stimulates proliferation of lymphocytes, those cells comprising 25% of total white blood cells that carry out the principal responsibilities of the immune system (Colic et al. 2000).
  • Garlic quickens macrophage phagocytosis, a process by which microorganisms and cellular debris are engulfed and destroyed (Lau et al. 1991).
  • Fraction 4 (F4), a protein isolated from aged garlic extract, enhanced the cytotoxicity of human lymphocytes. Although F4 alone increased cytotoxicity, the effect was amplified when F4 was combined with suboptimal doses of interleukin-2. F4 is an efficient immune potentiator and may be used for immune therapy (Morioka et al. 1993).

T-helper/T-suppressor ratios converted to normal among a small group of AIDS patients supplementing with garlic. Thrombocytopenia (a reduction in platelet count) is often therapy-resistant in individuals with AIDS. Yet, platelet numbers have been reported to increase, sometimes greater than 100,000, during 4 months of garlic supplementation. Although AIDS is not cancer, this feared disease has forced researchers and clinicians to look closely at the immune system (Abdullah et al. 1989).

Research suggests that garlic preparations are not equal in pharmacologic value. While raw garlic juice, heated garlic juice, dehydrated garlic powder, and aged garlic extract all significantly enhanced natural killer cell numbers and activity, only aged garlic extract and heated garlic juice inhibited the growth of tumor cells in mice (Kasuga et al. 2001).

Dr. Abdullah evaluated the percentage of tumor kill using raw and aged (Kyolic brand) garlic. Raw garlic killed 139% of tumor cells compared to an untreated group, while Kyolic killed 159% (Abdullah et al. 1988). Note: Defining the most efficacious type of garlic is confounding. Some physicians and clinicians report greater gains from odorous garlic supplementation. If garlic is part of your nutritional program, experiment with different varieties, assessing both subjective and objective improvements. It is highly possible that different metabolic types respond differently to various forms of garlic.

A good source of supplemental garlic is PureGar Caps. PureGar Caps contain the highest available potency (9 mg) of the active allicin compound, deemed by some as the yardstick for measuring the worth of garlic. Use 4 capsules, 2-4 times daily, with meals. If Kyolic aged garlic is the selection, use one 1000-mg caplet daily with meals. PureGar can cause a temporary gastric burning and pungent odor, whereas Kyolic aged garlic extract is free of these effects. No serious side effects have been reported.

Evaluating hundreds of garlic users, however, it should be noted that garlic thins the blood, and for some individuals (particularly those using anticoagulants) it is essential to abstain from or to watchfully monitor supplementation coagulation status.

Therapeutic factors contained in garlic include magnesium, selenium, 17 amino acids, 33 sulfur compounds, and vitamins B1, A, and C, as well as germanium. Germanium has been shown to induce production of interferon, enhance natural killer cell activity, and activate macrophage activity in experimental animals (Aso 1985).


Glutamine–increases NK cell activity, decreases PGE2 synthesis, inhibits tumor growth, stabilizes weight loss, and reduces incidence of stomatitis and infection
Tumors typically have high concentrations of glutamine; thus, physicians have been reluctant to add supplemental glutamine to a cancer protocol. However, oral glutamine (1 gram per kg of body weight a day administered to rats) upregulated tissue glutathione (a powerful antioxidant) by 25% and increased natural killer cell activity 2.5-fold. PGE2 synthesis (a pro-inflammatory prostaglandin that fuels tumor growth) decreased and tumors were inhibited by 40% (Klimberg et al. 1996a).

When glutamine accompanied either chemotherapy or radiotherapy, it protected the host and actually increased the selectivity of therapy for the tumor. This was evidenced among a group of rats (receiving either methotrexate, cyclophosphamide, or cisplatin) whose tumor reduction nearly doubled with glutamine supplementation (Klimberg et al. 1992, 1996b).

Researchers also observed that glutamine decreased progression of tumor formation in rats implanted with mammary tumors, suggesting oral glutamine may be useful as a chemopreventive in breast cancer (Feng et al. 1997). Oral glutamine maintained lymphocyte numbers and protected the gut of esophageal cancer patients during radio/chemotherapies (Yoshida et al. 1998).

Glutamine typically stabilizes weight loss by preserving intestinal function and allowing better nutrient absorption. Subsequently, glutamine prolongs survival by slowing down catabolicwasting, a disorder characterized by weight loss, diminished muscle mass, and loss of body fat. Fewer incidences of stomatitis (a generalized inflammation of the oral mucosa) and bouts of infection help reduce the number of days spent in a hospital (Anderson et al. 1998). Harvard University research showed that glutamine supplementation decreased medical expenses of leukemia patients undergoing bone marrow transplants by $21,095 per patient (MacBurney et al. 1994). (The retail cost of glutamine is $10.00 per day.)

A suggested glutamine dosage is 2 or more grams a day taken on an empty stomach. Glutamine is regarded as nontoxic, but cancer patients contemplating higher dosages should do so only after consulting with a health care provider.


Inositol hexaphosphate (IP-6)–activates natural killer cells, promotes differentiation, supports p53 activity, and normalizes the cell cycle by modifying signal transduction pathways
IP-6, a promising anticancer compound sold as a nutritional supplement, is a combination of inositol (a B vitamin) and phytic acid, also known as inositol hexaphosphate. According to Dr. A. Shamsuddin, M.D., Ph.D., who introduced IP-6 after more than 15 years of research, it works by enhancing the body’s ability to defend itself against cancer, making it of equal importance as either a cancer preventive or therapeutic agent.

Inositol hexaphosphate is a sugar, very much like glucose, except it has six phosphates attached to its molecules. Every animal and plant species tested had varying levels of IP-6, but the highest amounts were found in rice, about 2% by weight: 100 grams of rice provide approximately 2 grams of IP-6, but even that amount is not readily available. Since the body is dependent upon digestive enzymes to break it down, only a meager amount is actually absorbed from foodstuffs. Thus, IP-6 in encapsulated or bulk forms should be of special interest to cancer patients and those desiring protection against cancer.

The following chemotherapeutic properties are assigned to the immune modulator:

  • IP-6 activates natural killer cells, cells that work without antibody participation (Baten et al. 1989).
  • IP-6 decreases cellular proliferation (Sakamoto et al. 1993; Shamsuddin et al. 1989b). Illustrative of its potential, IP-6 reduced large intestinal cancer (by regulating cell proliferation) in F344 rats even when the treatment was begun 5 months after carcinogenic induction (Shamsuddin et al. 1989a).
  • IP-6 promotes differentiation (“normalization”) of cancer cells, that is, an unspecialized, atypical cell structure assumes the likeness of the tissue of origin, indicating the virulence of the malignancy is waning (Yang et al. 1995). IP-6 was shown to inhibit growth and induce differentiation in HT-29 human colon cancer cells, making it valuable as an adjunctive treatment in colon cancer. IP-6 also strongly inhibited growth and induced differentiation in human prostate cancer cells (PC-3) in both in vitro and in vivo studies (Shamsuddin et al. 1995).
  • IP-6 has been effective against every cancer cell tested (Shamsuddin et al. 1997; Grases et al. 2002).
  • After inducing cancer in laboratory animals, IP-6 administered either orally or by injection at the site of the tumor, or intraperitoneally, resulted in tumors two-thirds smaller than the controls. As tumors reduced in size, survival rate increased (Shamsuddin et al. 1989a).
  • IP-6 increases expression of the tumor suppressor gene p53 by up to 17-fold. p53 acts on cells under stress, such as those with DNA damage, reducing proliferation and encouraging apoptosis. When cancer arises, a mutation in p53 is commonly involved. Lastly, since loss of p53 function increases cancer cells’ resistance to chemotherapeutic agents, the stimulating action of IP-6 on p53 makes it an attractive adjuvant chemotherapeutic agent (Shamsuddin et al. 1997; Saied et al. 1998).

Toxicity studies (dating back to 1958) showed that a daily dose of 9 grams of IP-6 for 3 years resulted in side effects, including lesser incidences of kidney stones and fatty liver, as well as lower cholesterol levels. It is important to note that IP-6 does not kill cancer cells, as most anticancer agents do; thus, hair loss and immune suppression do not occur. A suggested dosage of 1-3 grams a day is adequate for most individuals. For those requiring larger doses, a powder is available (1 scoop twice daily is equivalent to 16 capsules, supplying about 6.4 grams of IP-6).


Lactoferrin–is immunoregulatory, inhibits angiogenesis, and binds iron
Perhaps one of the most promising therapeutic uses of lactoferrin, a milk protein with bacteriostatic properties, may be as a nontoxic, anticancer agent. Lactoferrin, a minor fraction of whey, results in a significant reduction in the incidence of esophageal, lung, bladder, and colon cancer in laboratory rats (Ushida et al. 1999; Masuda et al. 2000; Tsuda et al. 2002).

Since evidence indicates milk products protect against colon cancer, researchers speculate that bovine lactoferrin, a natural ingredient in milk, may be the chemoprotective agent (Tsuda et al. 2000b). Rats treated with a carcinogen and supplemented with 2% bovine lactoferrin for 36 weeks had a reduced incidence of colon cancer (27% of that observed in a control group; rats receiving 0.2% bovine lactoferrin reduced incidence to 46%). A remarkable 43% reduction in spontaneous lung metastasis (compared to controls) occurred after implanting colon carcinoma 26 (Co 26 Lu) in lactoferrin-treated laboratory animals (Tsuda et al. 2000a).

In addition to inhibiting angiogenesis (the vascular network that sustains the tumor), lactoferrin maintains the integrity of the immune system (Yoo et al. 1997; Tsuda et al. 2002). Typically, bovine lactoferrin prompts an increase in the number of natural killer cells, as well as the cytotoxicity of white blood cells (Tsuda et al. 2000a). The antibiotic, anti-inflammatory, and immune-modulating properties of lactoferrin appear active against the gastritis-, ulcer-, and cancer-inducing bacterium Helicobacter pylori (Dial et al. 2002).

Lactoferrin, a natural iron-binding protein, scavenges free radicals in fluids and inflamed areas, suppressing free radical mediated damage. It decreases the availability of iron in neoplastic cells, depriving them of an iron supply (Khan et al. 2001; Weinberg 2001).

The suggested dosage is 300-900 mg a day of the superior apolactoferrin (iron-depleted) form of lactoferrin. Lactoferrin is a natural component of cows’ and human mothers’ milk, but is also found in the milk of sheep, goats, and pigs.


Melatonin–is an immune modulator that increases the survival time of most cancer patients
Some cancer patients are now taking melatonin, an immune-modulating neurohormone, as part of a comprehensive, nontoxic cancer treatment. The cone-shaped pineal body, a small but crucial gland located in the brain, produces melatonin, a hormone that influences sexual maturation but also appears to play an important role in cancer.

Melatonin supplementation appears to restore circadian rhythms, which diminish or disappear with age. When melatonin’s circadian rhythm is abolished, the aging process is accelerated, life span is shortened, and an increase in spontaneous tumors occurs (Maestroni 1999). It has been shown that when the defense system is compromised due to disrupted rhythms, tumors grow two to three times faster (Filipski et al. 2002).

Melatonin also protects and restores normal blood-cell production caused by the toxicity of conventional treatments; a profile shared with the FDA-approved drugs Neupogen, a granulocyte colony-stimulating factor (G-CSF), and Leukine, a granulocyte-macrophage colony-stimulating factor (GM-CSF). A combination of melatonin and low-dose interleukin 2 (IL-2) neutralizes treatment-induced lymphocytopenia, a decrease in the numbers of lymphocytes in the peripheral circulation of cancer patients (Lissoni et al. 1993).

Researchers found the best way to amplify the antitumoral activity of low dose IL-2 is by not coadministering another cytokine but rather cosupplementing with the immune-modulating neurohormone melatonin (Lissoni et al. 1994a). This is hopeful news for a subset of cancer patients, because melatonin has been shown to cause tumor regression in neoplasms nonresponsive to IL-2 (Maestroni 1999).

The Division of Radiation Oncology of the San Gerardo Hospital (Milan) developed the following protocol for 80 patients with advanced metastatic tumors (Lissoni et al. 1994a). The patients were randomized to receive 3 million IU of IL-2, 6 days a week, for 4 weeks or IL-2 plus 40 mg a day of melatonin. A complete response was achieved in 3 of 41 patients treated with IL-2 plus melatonin and in none of the patients receiving only IL-2. A partial response occurred in 8 of 41 patients treated with IL-2 plus melatonin and in 1 of 39 patients treated with IL-2. Tumor regression rate was significantly higher in patients using IL-2 and melatonin compared to those receiving IL-2 (11/41 versus 1/39). The survival rate at 1 year was higher in patients treated with IL-2 and melatonin than in the IL-2 group (19/41 versus 6/39). Lymphocytic populations were consistently higher when melatonin accompanied the treatment and thrombocytopenia (a decrease in the number of circulating platelets) occurred less frequently.

For patients with bloodborne cancers, an IL-2/melatonin combination is also promising. Twelve patients (nonresponsive to standard therapies) evaluated the efficacy and tolerability of a combination of low-dose IL-2 plus melatonin in advanced malignancies of the blood, including non-Hodgkin’s lymphoma, Hodgkin’s disease, acute myelogenous leukemia, multiple myeloma, and chronic myelomonocytic leukemia. IL-2 was given 6 days a week for 4 weeks, along with oral melatonin (20 mg a day). Cancer was stabilized and did not progress in 8 of 12 (67%) participants for an average duration of 21 months. An additional benefit accrued as the melatonin/IL-2 therapy was well-tolerated (Lissoni et al. 2000).

Nonresectable brain metastasis remains an untreatable disease. Because of melatonin’s cytostatic action (the ability to suppress the growth of cells) and its anticonvulsant activity, the pineal hormone may prove effective in the treatment of brain metastasis. In a study to test the theory, 50 patients with inoperable brain metastasis were given supportive care or supportive care plus 20 mg of melatonin nightly. Freedom from brain tumor progression and survival rates at 1 year were higher in patients who were treated with melatonin compared to those who received only supportive care (Lissoni et al. 1994b, 1996). Even when melatonin was unable to stop the progression of advanced, metastatic disease, it improved the performance status of patients (see Table 2).

Low melatonin levels play a role in escalating rates of breast cancer. As melatonin levels decrease, the secretion of estrogen increases. Nighttime production of melatonin inhibits the body’s secretion of estrogen and decreases the proliferation of human breast cancer cells. Conversely, exposure to light during the night decreases melatonin production and increases cumulative lifetime estrogen levels, a sequence that may increase the risk of breast cancer.

In fact, two current studies show that women who work night shifts may increase their risk of breast cancer up to 60%. Blind women have a significantly lower risk (36% less) of breast cancer than normally sighted women because of consistently higher levels of melatonin (Kliukiene et al. 2001). Women, who are classed as only visually impaired, realize no protective effects in regard to breast cancer.

Table 2: Summary of Studies Using Melatonin (Lissoni’s Phase II Randomized Clinical Trial Results)
1-Year Survival
Tumor Type Patient Number Basic Therapy Melatonin Dose Melatonin Placebo Level of Significance
Metastatic non-small cell lung 63 Supportive care only 10 mg 26% under 1% <0.05
Glioblastoma 30 Conventional radiotherapy 10 mg 43% under 1% <0.05
Metastatic breast 40 Tamoxifen 20 mg 63% 24% <0.01
Brain metastases 50 Conventional radiotherapy 20 mg 38% 12% <0.05
Metastatic colorectal 50 IL-2 40 mg 36% 12% <0.05
Metastatic nonsmall cell lung 60 IL-2 40 mg 45% 19% <0.05
Compiled by Cancer Treatment Centers of America and published in the March 2002 issue of Life Extension Magazine.
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Cancer Adjuvant Therapy

It appears that melatonin may also reduce the number of estrogen receptors on breast cancer cells. Since estrogen effectively feeds the growth of hormone-responsive breast tumors, reducing the receptors might slow tumor growth. Science News reported that the amount of melatonin required to inhibit breast cell proliferation appears no greater than the amount commonly present in human blood at night (Science News 93; Moss 1995).

Electromagnetic fields (EMFs) are another inhibitor of melatonin production. There is evidence that ELF (extremely low frequency) magnetic fields can act at the cellular levels to enhance breast cancer cell proliferation by blocking melatonin’s natural oncostatic action. The mechanism(s) of action is unknown and may involve modulation of signal transduction events associated with melatonin’s regulation of cell growth (Liburdy et al. 1993)

Melatonin delivers another anticancer perk through its antioxidant values. Physicians who once credited glutathione and vitamin E as being antioxidants of choice have now given special honor to melatonin. The neurohormone appears to protect against tumors by shielding molecules (especially DNA) from oxidative stress. Melatonin exerts its antioxidant properties by detoxifying the highly reactive hydroxyl radical, as well as singlet oxygen, hydrogen peroxide, and peroxynitrite anions (Kim et al. 2000).

A typical dose for a healthy individual is 300 mcg-6 mg each night. Cancer patients often take between 3-20 mg each night.


Modified Citrus Pectin (MCP)–retards cancer growth and metastasis
Modified citrus pectin (MCP), also known as fractionated pectin, is a complex polysaccharide obtained from the peel and pulp of citrus fruits. Through pH and temperature modifications, the pectin is broken down into shorter, nonbranched, galactose-rich, carbohydrate chains. The shorter chains dissolve more readily in water, making them better absorbed than ordinary, long-chain pectin. The short polysaccharide units afford MCP its ability to access and bind tightly to galactose-binding lectins (galectins) on the surface of certain types of cancers. By binding to lectins, MCP is able to powerfully address the threat of metastasis (Strum et al. 1999).

In order for metastasis to occur, cancerous cells must first bind or clump together; galectin is thought responsible for much of cancer’s metastatic potential by providing the binding site (Raz et al. 1987; Guess et al. 2003; Pienta et al. 1995). MCP appears small enough to access and bind tightly with galectins, inhibiting (or blocking) aggregation of tumor cells and adhesion to surrounding tissue (Kidd 1996). Deprived of the capacity to adhere, cancer cells fail to metastasize.

Men with prostate cancer who took 15 grams of MCP a day had a slowdown in the doubling time of their PSA levels. (Lengthening of doubling time represents a decrease in the rate of cancer growth.) Interestingly, rats injected with prostate adenocarcinoma and given MCP (in drinking water) showed a significant reduction in metastasis (compared to control animals), although the primary tumor was unaffected. According to Dr. Kenneth Pienta (leader of the Michigan Cancer Foundation), MCP may be the first oral method of preventing spontaneous prostate cancer metastasis (Pienta et al. 1995; Guess et al. 2003).

As with prostate adenocarcinoma, research shows that metastasis of breast cancer cell lines requires aggregation and adhesion of the cancerous cells to tissue endothelium in order for it to invade neighboring structures (Glinsky et al. 2000). To test the anti-adhesive properties of MCP, researchers evaluated (in an in vitro model) breast carcinoma cell lines MCF-7 and T-47D. The study concluded that MCP countered the adhesion of malignant cells to blood vessel endothelium and subsequently inhibited metastasis (Naik et al. 1995). MCP decreased metastasis of melanoma to the lung by more than 90% in laboratory animals (Platt et al. 1992).

Because MCP is a soluble fiber, no pattern of adverse reaction has been recorded in the scientific literature, apart from a self-limiting loose stool at high doses. MCP dosages are usually expressed in grams, with a typical adult dose ranging from 6-30 grams divided throughout the day. MCP’s apparent safety and proven antimetastatic action, and the lack of other proven therapies against metastasis appear to justify its inclusion in a comprehensive orthomolecular anticancer regimen (Kidd 1996). Pecta-Sol is the brand name of the original modified citrus pectin (MCP. The dosage for Pecta-Sol is about 15 grams a day.


N-acetyl-cysteine (NAC)–is an anticarcinogenic and antimutagenic agent; it inhibits IL-6 as well as invasion and metastasis of malignant cells
N-acetyl-cysteine (NAC) is the acetylated precursor of the amino acids L-cysteine and reduced glutathione. Historically, it is used as a mucolytic agent in respiratory illnesses as well as an antidote for acetaminophen hepatotoxicity, but more recently its credits have grown. Animal and human studies have shown it to be a powerful antioxidant and a potential therapeutic agent in the treatment of cancer (Bongers et al. 1995; van Zandwijk 1995).

The biological value of NAC is attributed to its sulfhydryl group, while its acetyl-substituted amino group offers protection against oxidative and metabolic processes (Bonanomi et al. 1980; Sjodin et al. 1989). In vitro studies showed NAC to be directly antimutagenic and anticarcinogenic; in vivo, NAC inhibited mutagenicity of a number of mutagenic materials (De Flora et al. 1986, 1992).

NAC has both chemopreventive and therapeutic potential in malignancies arising in the lung, skin, breast, liver, head, and neck (van Zandwijk 1995; Izzotti 1998). NAC is effective in inhibiting tumor cell growth in melanoma, prostate cells, and astrocytoma cell lines (the latter is a primary tumor in the brain) (Albini et al. 1995; Arora-Kuruganti et al. 1999; Chiao et al. 2000). Neovascularization (new blood vessel growth) is crucial for tumor mass expansion and metastasis. NAC inhibited invasion and metastasis of malignant cells by up to 80% by preventing angiogenesis (De Flora et al. 1996).

A number of cancers express IL-6 and other potentially dangerous cytokines. NAC inhibited (in a dose-dependent manner) the synthesis of IL-6 by alveolar macrophage (Munoz et al. 1996; Gosset et al. 1999).

Peak plasma levels of NAC occur approximately 1 hour after an oral dose; 12 hours after dosing, it is undetectable. Despite a relatively low bioavailability (4-10%), research has shown NAC to be clinically effective (Borgstrom et al. 1986). A suggested NAC therapeutic dosage is usually in the range of 600 mg per day.


Resveratrol–influences cancer at initiation, promotion, and progression stages
Resveratrol is one of a group of compounds (called phytoalexins) that are produced in plants during times of environmental stress, such as adverse weather or insect, animal, or pathogenic attack. Resveratrol has been identified in more than 70 species of plants, including mulberries and peanuts, and the skins of red grapes, which are a particularly rich source (Jang et al. 1999). According to Pezzuto, “Of all the plants we’ve tested for cancer chemopreventive activity, this one [resveratrol] has the greatest promise” (Pezzuto 1997).

Resveratrol was effective against cancer during all three phases of the cancer process: initiation, promotion, and progression. For example, resveratrol displayed antimutagenic and antioxidant activity, providing greater protection against DNA damage than vitamins C, E, or beta-carotene. Resveratrol restored glutathione levels, considered by some as the most essential of antioxidants (Jang et al. 1999). It increased levels of a Phase II detoxifying enzyme (quinone reductase), an enzyme responsible for metabolically disassembling carcinogens.

Resveratrol inhibited the activity of cyclooxygenase-2 (COX-2), reducing the inflammatory response in human epithelial cells (Subbaramaiah et al. 1999). Upregulation of COX-2 is associated with the physical manifestations of various human cancers, as well as other inflammatory disorders. Since inflammation is closely linked to tumor promotion, substances with potent anti-inflammatory activities are thought to exert chemopreventive effects, particularly in the promotion stage of the disease.

Resveratrol prompted differentiation of human promyelocytic leukemia cells. The development of preneoplastic lesions in mouse mammary glands was inhibited by resveratrol (Kang et al. 2003; Asou et al 2002; Tsan et al. 2002).

The following studies illustrate the many pathways resveratrol employs to inhibit cancer:

  • Italian researchers recently determined that resveratrol exhibited a protective role against colon carcinogenesis, with the defense attributed to changes occurring in Bax protein, which encourages cell death (apoptosis), and p21 expression (Tessitore et al. 2000). Reduced Bax activity is associated with resistance to cytotoxic therapy (Bosanquet et al. 2002). p21 is able to arrest the cell cycle at the G1 phase by inhibiting DNA replication (Aaltomaa et al. 1999). Suppressing the growth cycle allows for a critical phase in cellular development referred to as differentiation, that is, an abnormal cell becomes more normal.
  • Resveratrol appears a promising anticancer agent for both hormone-dependent and hormone-independent breast cancers. At high concentrations, resveratrol caused suppression of cell growth in three breast cancer cell lines: estrogen-receptor (ER)-positive KPL-1 and MCF-7 and ER-negative MKL-F. Growth inhibition was credited in part to up-regulation of Bax protein and activation of caspase-3 (a key mediator of apoptosis in mammalian cells). Resveratrol was also able to lessen the growth stimulatory effects of linoleic acid, a fatty acid frequently over-consumed in Western diets (Nakagawa et al. 2001).
  • Resveratrol significantly reduced tumor volume (42%), tumor weight (44%), and metastasis (56%) in mice with highly metastatic Lewis lung carcinoma. Resveratrol was able to inhibit angiogenesis and reduce oxidative stress (Kimura et al. 2001; Kozuki et al. 2001).
  • Different wine polyphenols (catechin, epicatechin, quercetin) including resveratrol may be effective against prostate cancer. Prostate cancer cell lines (LNCaP and DU145) produce high concentrations of nitric oxide; PC3 produces low concentrations. Researchers propose that the anti-proliferative effects of polyphenols are due to their ability to adjust nitric oxide production (Kampa et al. 2000). Grape extract, a rich source of resveratrol, inhibited prostate cancer growth up to 98% in a dose- and time-dependent manner (Agarwal et al. 2000b).
  • Resveratrol appears to be promising in the control of acute monocytic leukemia (Tsan et al. 2000). Resveratrol induced apoptotic cell death in human leukemia cells (HL60) (Clement et al. 1998) and stopped the growth of lymphocytic leukemia cells during the S-phase of the growth cycle (the time of DNA replication) (Bernhard et al. 2000).
  • Resveratrol inhibits NF-kB, thus inhibiting cell proliferation and cytokine production (Gao et al. 2001). The inhibition of cytokine production by resveratrol was found to be irreversible.

If using pure resveratrol, the suggested dosage is 7-50 mg a day. Beware of diluted supplements that provide very little active resveratrol. At the time of this writing, there were only a few sources of pure high-potency resveratrol available as dietary supplements.


Selenium–is protective against many types of cancers, promotes apoptosis, is a powerful antioxidant, and improves quality of life during aggressive cancer therapies
Many animal studies have been conducted to evaluate the effects of super nutritional levels of selenium on experimental carcinogenesis using chemical, viral, and transplantable tumor models. Two thirds of these studies found that high levels of selenium reduced the development of tumors at least moderately (14-35% compared to controls) and, in most cases, significantly (by more than 35%) (Whanger 1998).

The impact of selenium supplementation on basal cell carcinoma was studied on 1312 subjects (18-80 years of age, 75% of whom were men) (Clark et al. 1996). Within 6-9 months, the group receiving 200 mcg a day of selenium realized about a 67% increase in plasma selenium levels. The non-supplemented group, although judged “normal” in regard to plasma selenium levels, experienced twice the rate of cancer as those receiving selenium. Researchers concluded that higher amounts of dietary selenium than the amount recommended by the FDA are needed to prevent cancer.

Although the study failed to show the effectiveness of selenium in altering the course of either basal or squamous cell carcinoma, selenium impacted the incidence of other types of malignancies with amazing success. The overall reduction in cancer incidence was 37% in the selenium-supplemented group; a 50% reduction in cancer mortality was observed over a 10-year period (Clark et al. 1996).

The following are the site-specific reductions in cancer incidence observed in the study: colorectal cancers (58%), lung cancer (46%), and prostate cancer (63%). A selenium deficiency appears to increase the risk of prostate cancer four- to five-fold. It was determined that as the male population ages selenium levels decrease, paralleling an increase in prostate cancer (Brooks et al. 2001).

Data is compelling regarding the usefulness of selenium’s protective effects against cancer:

  • Selenium-enriched broccoli is protective against chemically induced mammary and colon cancer in rats (Davis et al. 2002).
    Note: While selenium is contributing to the lower incidence of malignancy, the anticancer affects of broccoli should also be factored into the defense. Please read the section What Should the Cancer Patient Eat (appearing in this protocol) for valuable information regarding dietary factors affecting patient outcome.
  • The relationship between serum levels of selenium and the development of upper digestive tract cancer was examined (Mark et al. 2000). The relative risk of esophageal cancer was 0.56 in individuals in the highest quartile of selenium level compared with those in the lowest quartile. The corresponding relative risk of gastric cardia cancer was 0.47. Based on the data, it was concluded that 26.4% of esophageal and gastric cardia cancers are attributable to low selenium levels.
  • Adding selenium to salt resulted in a significant reduction in the incidence of cancer (Whanger 1998).
  • A significant increase in apoptosis and a decrease in DNA synthesis in breast cancers cells (MCF-7 and SKBR-3) occurred with selenium supplementation. The selenium benefit was just as impressive in cancers of the lung (RH2), small intestine (HCF8), colon (Caco-2), and liver (HepG2). Prostate cancers (PC-3 and LNCaP) as well as colon cancer (T-84), although initially less affected by supplementation, became responsive when selenium was coadministered with Adriamycin or Taxol (Vadgama et al. 2000). This study suggests that selenium potentiates the anti-cancer effects of chemotherapy. Selenium supplementation in patients undergoing radiation therapy for rectal cancer improved quality of life and reduced the appearance of secondary cancers (Hehr et al. 1997).
  • It appears that selenium acts as an immunologic response modifier, normalizing every component of the immune system (Ferencik et al. 2003; Arthur et al. 2003)

An important form of selenium is Se-methylselenocysteine. This is the form of selenium found naturally in plants such as broccoli and garlic. A suggested selenium dosage is 200 mcg a day. The optimal dose for cancer patients is unknown at this time, but suggestions have ranged from 200-400 mcg a day depending upon the selenium content of the soil. Foods considered good sources of selenium include Brazil nuts, grains, onions, tomatoes, broccoli, chicken, eggs, garlic, liver, seafood, and wheat germ. Americans typically consume 60-100 mcg of selenium a day from dietary sources.


Silibinin (from milk thistle)–has antioxidant activity, increases sensitivity to chemotherapy while reducing its side effects, assists in arresting the growth of cancer, promotes differentiation, inhibits COX-2 enzyme, and suppresses NF-kB
Fourteen years ago, the Life Extension Foundation introduced silymarin, a hepato-protective herb, to members. The major active constituent of silymarin is silibinin; a long-recognized antioxidant with more recently ascribed anticarcinogenic traits. Silibinin inhibits the growth of various cancer cell lines. The silibinin acts synergistically with cisplatin and doxorubicin, common chemotherapeutic drugs, improving their efficacy. By arresting tumor cell division at a strategic stage, silibinin appears to make tumor cells more sensitive to chemotherapy. Also, the harsh side effects associated with cytotoxic chemicals are less damaging when silibinin is utilized (Bokemeyer et al. 1996).

Milk thistle is described as an adaptogenic herb. For example, it encourages new cell growth where repair is needed but arrests cell division in tumor tissue; it increases the activity of certain enzymes but inhibits others. Milk thistle inhibits COX-2 (Zhao et al. 1999). Note: Go to Cyclooxygenase (COX-2) Inhibitors (Naturally Occurring) appearing in this protocol for other nutraceuticals capable of inhibiting the COX-2 enzyme. Also, consult Cyclooxygenase Inhibitors in the protocol entitled Cancer Treatment: The Critical Factors to learn more about the COX-2-cancer connection.

Silibinin arrests cell growth in the early phase of the cycle known as G1, a period of growth before DNA replication. Silibinin discourages cell growth by inhibiting various kinase enzymes (those playing a pivotal role in regulatory mechanisms), enabling a critical stage in cellular development referred to as differentiation. Differentiated cells abandon their primitive façade and assume the physical likeness and behavioral patterns of healthy cells. In fact, silibinin caused differentiation of a significant number of malignant prostate cells to more normal cells, while simultaneously decreasing PSA levels (Zi et al. 1999).

Silibinin inhibits growth of drug-resistant breast and ovarian cancer lines. It binds to type II estrogen binding sites, an action that turns off the proliferative effects of the cell (Scambia et al. 1996). In addition, silymarin inhibited the secretion of VEGF (an angiogenic factor) by malignant cells, thwarting the formation of cancer’s vascular network (Jiang et al. 2000).
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Cancer Adjuvant Therapy

Silymarin potently suppressed NF-kB, but did not affect TNF-alpha-induced NF-kB, demonstrating a pathway-dependent inhibition by silymarin. It appears the inhibitory effect of silymarin on NF-kB activation is associated with its liver-protecting properties. Suppression of NF-kB, a key regulator in inflammatory and immune reactions, significantly improves the anticarcinogenic status of silymarin (Saliou et al. 1998).

Silymarin/silibinin is remarkable medicine for the liver. Numerous studies show that milk thistle is effective in treating virtually every type of liver disease, including cirrhosis and alcohol or chemical-induced liver damage (Jacobs et al. 2002; Flora et al. 1998). So worthy is the herb in protecting against life-threatening toxins that individuals poisoned by the Amanita mushroom survived when silibinin was utilized (Carducci et al. 1996). A healthy liver is essential to detoxification, a process key to restoring health to cancer patients.

Standardized milk thistle extract usually consists of 35% silibinin, whereas the silymarin concentrate used in Europe contains a minimum of 80% silibinin. The Life Extension Foundation recommends the highly beneficial 80% silibinin extract. A suggested therapeutic dosage of Silibinin Plus is up to 6 capsules daily (1950 mg a day). For protection, use about 1-2 capsules (325-650 mg a day).


Soy–is protective against certain malignancies, appears to be an alternative to signal transduction-inhibiting drugs, and inhibits angiogenesis, cell proliferation, and metastasis

Legumes, including the soybean, contain bioactive compounds classified broadly as phytoestrogens as opposed to estrogens. Phytoestrogens are nonsteroidal and can actually inhibit steroids such as aromatase. Most have little or no estrogenic activity. When others have such activity, it is usually beneficial and specific to a certain tissue. For example, some soy isoflavones (a type of phytoestrogen) benefit bone but do not affect the kidney. In pharmacology terms, this is called a selective estrogen receptor modulator (SERM). A compound in soy, genistein, is a natural SERM. Tamoxifen and Raloxifen are chemical SERMs (Setchell et al. 1999).

The most recent studies suggest that the reason that different estrogens have different effects on different tissues is because there is more than one type of estrogen receptor. So far, three variations of the estrogen receptor have been found: one alpha and two betas. They share similar estrogen structure. The estrogen receptor-receptor (ERb) may suppress the action of the estrogen receptor-alpha (ERa) – at least in cancer cells (Maruyama et al. 2001; Saji et al. 2002; Speirs et al. 2002). And, growth-promoting estrogens such as estradiol activate ERa. Phytoestrogens preferentially activate theERb, which is repressive (Barkhem et al. 1998). For this reason, phytoestrogens have been characterized as good estrogens, and whatever estrogenic effect they have (which is estimated to be 1000-10,000 times weaker than estradiol, where it exists) may be nullified by their inhibition of estrogen synthesis and repression of the receptor that allows estradiol into the cell (Shao et al. 2000).

In normal tissue, the two estrogen receptors apparently work together to control both the amount and the use of estrogen in the body. It has been demonstrated that some types of cancer cells lose one type of estrogen receptor, leaving the control mechanism inoperable (Iwao et al. 2000; Sampath et al. 2001). This has been demonstrated in prostate cancer. Some types of prostate cancers do not express their ERaand some lose beta. This is why some will respond to estrogen and stop growing and others will stop growing when an anti-estrogen, such as genistein or Tamoxifen, is added.

The loss or gain of estrogen receptors occurs because of methylation abnormalities that occur in DNA (Lau et al. 2000). DNA methylation abnormalities are caused by three known factors: poor diet (i.e., a diet lacking in methylation factors including folate, vitamins B6 and B12), chemicals, and age.

Phytoestrogens include many diverse plant compounds, including resveratrol from grapes (Kopp 1998), curcumin from roots (Jaga 2001), and polyphenols from tea leaves (Mazur 1998). It is a very broad category that is further broken down into dozens of classifications such as flavonoids and flavones. The anticancer effects of phytoestrogens are the subject of dozens of scientific studies (Adlercreutz 1995).


Soy Isoflavones
Soy contains phytoestrogens known as isoflavones, including daidzein, coumestrol, and genistein. Isoflavone supplements contain a mixture of many different types of these compounds. Interest in their anticancer potential stems from the lower occurrence of hormone-related cancers in Asians who eat a lot of soy. It is doubtful that the low rates of breast, prostate, and other hormonally related cancers are due solely to soy, but studies show that compounds isolated from soy have significant anticancer effects (Suthar et al. 2001).


Soy for Prostate Cancer
The most dangerous aspect of prostate cancer is metastasis (spreading to other areas). Prostate cancer can be controlled if it can be limited to the prostate gland. Unfortunately, many men with prostate cancer have undetected metastases.

Genistein has powerful and specific effects against the spread of prostate cancer. Genistein significantly activated 832 genes in prostate cancer cells, 13 of which are related to metastasis (Li et al 2002a,b; Sarkar et al. 2002).

Genistein down-regulated multiple genes that dissolve surrounding tissue to enable metastasis and invasion of surrounding tissue, and down-regulated genes that create new tumor blood vessels. Genistein also affected genes important in stopping the cell cycle, differentiation, apoptosis, and cell signaling communication (Li et al. 2002a).

Genistein has “potent anti-proliferative effects” against human prostate cells (Shen et al. 2000), and inhibits metastasis (Schleicher et al. 1999). Genistein is one component of soy. Soy has powerful effects in the prevention and eradication of prostate cancer. Different components of soy have different effects against prostate cancer cells. Genistein blocks an enzyme that destroys an anticancer vitamin D metabolite in cancer cells (Farhan et al. 2002).

Prostate cancer is a hormone-related cancer. In a study mice were fed three different soy products: soy protein without isoflavones, soy phytochemical concentrate (a combination of genistein, daidzein, glycitein, and other compounds), and genistein. All three feeds had a positive effect on hormones as they relate to prostate cancer growth. The androgen receptor, which correlates with tumor weight, was reduced 42% by soy protein. Genistein reduced serum dihydrotestosterone, a form of testosterone associated with hyperplasia and cancer, and caused a 57% reduction in tumor growth. Soy phytochemical concentrate inhibited the overall growth of prostate cancer by 70%. Soy phytochemical concentrate also stopped metastases to lymph nodes and lung. Cell death was induced, and angiogenesis was significantly inhibited (Zhou et al. 2002).

Healthy, normal rodents fed genistein for 2 weeks at a dietary level had significant reductions in androgen and the two estrogen receptors (Fritz et al. 2002). Minimizing the number of hormone receptors reduces levels of cell growth-promoting hormones in the prostate gland. The levels of phytoestrogens in 25 men with and without benign prostatic hyperplasia (BPH), a noncancerous overgrowth of prostate cells, were examined. Genistein levels in men with BPH were significantly lower than in those without BPH (Hong et al. 2002). Adding genistein to prostate tissue taken from men with BPH stops the prostate cancer growth (Geller et al. 1998).

Various soy diets have significant effects against prostate cancer compared to a casein (milk protein) diet. Soy significantly reduced insulin-like growth factor (IGF-1), a protein that helps tumors create blood vessels. Blood vessel density and tumor cell proliferation were decreased. Cell death was increased. Dietary soy works through “a combination of direct effects on tumor cells and indirect effects on tumor neovasculature” (blood vessels) (Zhou et al. 1999). The cell-killing effects of soy components are important not only for men who have been diagnosed with prostate cancer, but for healthy men as well.

Prostate-specific antigen (PSA) is elevated in men with prostate enlargement. PSA is regulated by androgens. Genistein and its precursor, biochanin A, markedly decrease PSA in prostate cancer cells by inactivating testosterone (Sun et al. 1998). A study on rats showed a 38% decline in PSA, along with a significant reduction in metastases when genistein was given subcutaneously (Schleicher et al. 1999; Zand et al. 2002).

The ability of genistein to reduce cellular proliferation in men with elevated PSA is currently under investigation. In addition, the ability of supplemental soy to lower PSA and kill cancer cells in men with localized prostate cancer is being studied. The ability of soy isoflavones to modulate hormones and cancer-related proteins in men with prostate cancer is also being studied.

Population-based studies have shown that men with high levels of soy and other isoflavones in their blood have the lowest risk of prostate cancer. In a study on men from Japan, China, and the United States, it was shown that legumes, including soy, reduce the incidence of prostate cancer by 38%. Eating yellow-orange vegetables reduces it 33%, and cruciferous vegetables reduce it 39%. These findings are consistent across ethnicities, indicating that isoflavones, not genes, are responsible for the reductions in risk (Kolonel et al. 2000). An analysis of data collected from 12,395 Seventh-Day Adventist men indicates that more than one serving per day of soymilk can reduce the risk of prostate cancer 70% (Jacobsen et al. 1998). Note: Seventh-Day Adventists are vegetarians; meat is a known risk factor for prostate cancer. Maintaining a vegetarian diet may have contributed to the low rates of prostate cancer.

Genistein down-regulates proteins that enhance prostate cancer growth, including HER2 neu. Genistein has no adverse toxicity, and the amount needed to reduce the proteins by half is achieved with supplemental genistein or a diet high in soy products. Genistein inhibits EGF signaling pathway suggesting that this phytoestrogen may be useful in both protecting against and treating prostate cancer (Dalu et al. 1998).

Soy isoflavones clearly work against prostate cancer through several mechanisms, including modulating hormones, blocking metastasis, interfering with cell signaling, stopping cell growth, inducing cell death, and possibly activating and deactivating cancer-related genes.


Soy for Breast Cancer
Soy phytoestrogens help to prevent and control hormone-related breast cancer (Zhou et al. 2004; Adlercreutz 2002). It is especially beneficial for Western women, who are exposed to a comparatively high level of environmental estrogens. Soy is anti-estrogenic. It prevents the conversion of estrone to 17-beta-estradiol. Estradiol fuels the growth of breast cancer, whereas estrone is a weaker estrogen. Genistein causes cancer cells to metabolize estradiol to estrogenically weaker or inactive metabolites (Brueggemeier et al. 2001).

Soy phytoestrogens naturally activate the receptor, known as ERb, which in turn suppresses the activation of Era and allows growth-promoting estradiol into cancer cells (Pettersson et al. 2000). ERa is the receptor referred to as “estrogen receptor positive;” “estrogen receptor negative” breast cancer cells have estrogen ERb. Estrogen receptor positive cells have lost their beta-receptors duringthe events leading to breast cancer. Normal cells have both types of estrogen receptors.

Genistein naturally activates ERb, inhibiting cell proliferation. Activating the beta-receptor down-regulates the alpha-receptor, or estradiol-activated, receptor. This negates estradiol’s cancer-promoting effects.

The consumption of soy reduced the risk of having ERa positive breast cancer by 56%, whereas the effect on both types of breast cancer was 30% (Dai et al. 2001).

Genistein interferes with cancer’s ability to grow blood vessels. A direct link between alpha-receptors and angiogenesis has been discovered in estrogen receptor positive cancer cells (MCF-7). These cells have too many alpha-receptors and not enough beta-receptors. When estradiol attaches to the alpha-receptors, it activates a protein that promotes the formation of new blood vessels (Sampath et al. 2001). Genistein blocks the formation of new blood vessels (Zhou et al. 1998; Wietrzyk et al. 2001). Furthermore, genistein prevents vitamin D from being degraded by cancer cells (Farhan et al. 2002).

In a study on estrogen receptor positive breast cancer cells (MCF-7), genistein competed successfully with estradiol for access to the cells, and once inside, blocked estradiol from inducing cell growth. In a study on Japanese women who drank soymilk containing 100 mg of isoflavones a day, estrone and estradiol levels fell by almost 30% (Nagata et al. 1998).

Breast cancer cells have elevated levels of enzymes that produce estradiol. One of the enzymes, known as 17-beta-hydroxysteroid dehydrogenase type 1 (17HSD1), causes the conversion of “weak estrogen” (estrone) to “strong estrogen” (estradiol) and helps cancer cells grow. A variant known as 17HSD2 does the opposite. Breast cancer cells have elevated amounts of 17HSD1, and insufficient 17HSD2 (Miyoshi et al. 2001). Studies show that if cancer cells are treated with genistein, 17HSD2 will be made, and “strong estrogen” (estradiol) will be converted to “weak” (estrone) (Hughes et al. 1997). A woman with breast cancer may have the same level of estrogen in her blood as a woman without breast cancer. The elevated estradiol levels occur inside cancer cells where abnormalities create imbalances in enzymes. Such 17HSDvariances favor the accumulation of estrogen for cell growth.

Genistein also inhibits an enzyme that is elevated in breast cancer cells known as “aromatase” (Kao et al. 1998; Breuggemeier et al. 2001). Aromatase helps convert testosterone to estrogen. Elevated male hormones, enlarged prostate, and abnormal cell growth do not promote prostate cancer in mice that lack aromatase (McPherson et al. 2001).

Asian women get early protection by eating soy their entire lives (Lamartiniere et al. 1998). The genistein in soy promotes more differentiated tissue in the breast, which leaves less tissue that can become cancerous. Soy isoflavones decrease density in the breast enabling easier detection of cancer by mammogram (Maskarenic et al. 2001). A serving of tofu every week decreases the risk of breast cancer by 15% (Wu et al. 1996). It is well-established that when Asian women abandon their traditional diet, their risk of breast cancer escalates. It is important to realize, however, that while it has been proven that soy components have direct and powerful effects against cancer cells, it cannot be assumed that soy alone is responsible for the reduced risk of hormone-related cancers in Asians. There are many aspects of the Asian diet that undoubtedly play a role, including the low consumption of animal fat. Green tea is another component of the Asian diet that has proven anticancer effects. A polyphenol from black tea has no effect on prostate cancer cells. However, when combined with genistein, it stops proliferation (Sakamoto 2000).

HER2/neu and EGFR are both related to breast cancers resistant to treatment with tamoxifen and other therapies (Ross et al. 1998). Genistein blocks an enzyme that promotes the proliferation of cancer cells. Because protein tyrosine kinases activate other cancer-promoting factors, genistein is a very attractive candidate for the prevention and treatment of various types of cancer. A dietary amount of the soy compound genistein significantly delayed the appearance of the HER2/neu-type cancer. It did not, however, reduce tumor size or number in this study (Jin et al. 2002).

It is important to note that DDT and other chlorine-related chemicals activate tyrosine kinases (TK), including HER2/neu-related ones in human cancer cells. Although DDT was banned decades ago, Americans are still being exposed to it. Genistein and other isoflavones block the activation of TK by DDT and related estrogen-mimicking chemicals, but tamoxifen does not (Enan et al. 1998; Verma et al. 1998).

A mouse study shows that increasing amounts of genistein retard cancer growth, in accordance with the cell studies (Shao et al. 1998). The animals must be implanted with estradiol to make the cancer cells grow (Santell et al. 2000; Allred et al. 2001; Ju et al. 2001). When mice are fed the equivalent of what Asians usually consume in their diets, the appearance of a genetic type breast cancer (as opposed to a chemically induced one) is significantly delayed by genistein, soy isoflavones, and daidzein, another soy compound (Jin et al. 2002).

Studies in monkeys, the closest animal model to humans, show that soy phytoestrogens impede the proliferation of cells responsive to estrogen. “Soybean phytoestrogens are not estrogenic at dietary doses” (Cline et al. 2001). Statistics on the rate of hormone-related cancers in Asians prove that soy is extremely beneficial against hormone-related cancers in humans. They show that people who eat large amounts of soy products have the lowest levels of strong estrogen in their bodies and the lowest rates of breast and prostate cancers.
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Cancer Adjuvant Therapy


Soy and Other Types of Cancer

Soy has powerful anticancer effects that do not involve hormones. Genistein inhibits a chemical reaction used by many different types of cancer cells to multiply and spread. Compounds that can do this are called tyrosine kinase (TK) inhibitors. Dozens of studies in different types of cancer cells show that genistein is a powerful and effective TK inhibitor.


Glioma. Glioma cancer cells have very high TK activity, which correlates with cancer growth. Several in vitro studies show that genistein inhibits the growth of glioma (Baltuch et al. 1996; Tu et al. 2000; Khoshyomn et al. 2002). Genistein also enhances the effectiveness of the chemotherapeutic drugs carmustine and camptothecin with a 40% decrease in growth and a 50% increased killing effect in some cells (Ciesielski et al. 1999; Khoshyomn et al. 2002). The amount of genistein needed to enhance the effectiveness of carmustine is not high. The appropriate amount of genistein can be obtained by following the supplement program recommended in the Soy Dosing and Precautions section.


Bladder Cancer. Genistein’s ability to inhibit TK may be of great benefit in keeping bladder cancer localized. In Asia, the incidence of invasive bladder cancer is much lower than in the United States, leading some researchers to investigate the effects of soy. Invasive bladder cancers have high levels of a protein known as epidermal growth factor receptor (EGFR), which enables the cancer to invade muscle. EGFR is activated by TK and can be reversed by genistein (Theodorescu et al. 1998).

The effects of genistein, soy protein isolate, and soy phytochemical concentrate on human bladder cancer cells and bladder cancer were studied in mice. The three soy products reduced tumor volume 40%, 37%, and 48%, respectively. They blocked tumor blood vessel formation and induced tumor cell death, stopping the cells from growing at the G2-M part of the cell cycle (Zhou et al. 1998).

A mixture of isoflavones work better than a single soy compound for bladder cancer. In a study on seven different cell lines, genistein plus isoflavones inhibited tumor growth and induced cell death at levels obtainable through the diet or soy supplements. Both genistein and combined isoflavones exhibited a significant tumor suppressor effect in vivo. These results justify the potential use of soybean isolateas a practical chemoprevention approach for patients with urinary tract cancer (Su et al. 2000).


Stomach Cancer. The effects of soy products on 10 different types of human gastrointestinal cancer cells found that genistein and biochanin A (a genistein precursor) strongly inhibited proliferation of stomach, colon, and esophageal cancers (Yanagihara et al. 1993). Data from a study involving over 30,000 people was analyzed and it was found that people who eat the most soy products reduced their risk of stomach cancer by half compared to those who eat the least (Nagata et al. 1998).


Melanoma. Studies on the effects of genistein on human melanoma cancer cells showed that genistein is a powerful inhibitor of the growth of this cancer and that it stops the cell cycle as effectively as the chemotherapeutic drugs adriamycin and etoposide (Darbon et al. 2000).

Studying melanoma in mice revealed that genistein reduces the blood supply to lung tumors and has an additive effect with the drug cyclophosphamide. In laboratory rodents, genistein can reduce the growth of tumors by half through supplements and/or diet (Record et al. 1997).


Lung Cancer. Genistein has several actions against small cell and non-small cell lung tumors. In a study in which Lewis lung cancer was transplanted into mice, genistein reduced the tumor colonies by half, and genistein plus cyclophosphamide reduced them by 90% (Wietrzyk et al. 2001). Several studies show that genistein stops lung cancer cells from growing and induces cell death (Tallett et al. 1996; Fujimoto et al. 2002; Wietrzyk et al. 2000). Genistein inhibits enzymes that help lung cancer cells to proliferate and spread (Leyton et al. 2001). Genistein up-regulates tumor suppressor genes p53 and p21 (Lian et al. 1999). Genistein reverses the multidrug resistance-associated protein, a protein that makes lung cancer cells resistant to daunorubicin, doxorubicin, etoposide, and vinblastine (Versantvoort et al. 1994; Berger et al. 1997).

Researchers in Japan analyzed information from 333 people with lung cancer. They found that eating tofu every day reduced the risk of lung cancer 45% in men and 86% in women (Wakai et al. 1999).


Colon Cancer. Soy has anticancer effects against cells that line the digestive tract. For this reason, it may have beneficial effects against different types of digestive tract cancers. Researchers looking at how three different types of human colon cancer cells react to soy confirmed that colon cancer is susceptible to soy’s anticancer effects (Zhu et al. 2002). Some colon cancers may be estrogen dependent. Estradiol activates four kinase enzymes in colon cancer cells, two of which are tyrosine dependent and therefore potentially susceptible to genistein. Genistein blocks at least one of these enzymes and retards cell growth (Di Domenico et al. 1996). Genistein also suppresses the growth of nonestrogen-dependent colon cancer cells, which also respond to treatment with tamoxifen (Arai et al. 2000).

In a study that investigated how tamoxifen, genistein, and estradiol affect intestinal cells, genistein and tamoxifen emerged as the strongest inhibitors of cell proliferation, inhibiting TK and inducing the death of cancer cells (Booth et al. 1999). Genistein reverses resistance to doxorubicin and other chemotherapeutic drugs in at least one type of colon cancer by a “novel drug resistance pathway” (Rabindran et al. 1995). However, a study in mice showed that soy isoflavones may not counteract a bad diet. Mice fed a Western high fat, low fiber, and low calcium diet developed colon cancer despite isoflavones in their food (Sorensen et al. 1998). Soy could not reverse colon cancer (whereas rye lignans could) in mice on high fat diets (Davies et al. 1999).


Thyroid Cancer. Soy may have beneficial effects against thyroid cancer. Six hundred and eight cases of thyroid cancer, found that people who consume soy compounds, genistein and daidzein, in their diet reduced their risk of this cancer by one-third. However, adding soy flour or protein to a Western diet was not effective (Horn-Ross et al. 2002).


Leukemia. A few studies have been done on human leukemia cells treated with genistein. Of nine compounds tested, genistein showed the strongest inhibitory effects against human promyelocytic leukemia (HL-60) cells. All nine compounds are found in miso (Hirota et al. 2000). In human leukemia cells resistant to chemotherapy, genistein was able to reverse the drug resistance almost completely (Nagasawa et al. 1996). The anti-proliferative effect of genistein against human leukemia was significantly augmented by vitamin D analogs (Siwinska et al. 2001).


Free-Radical Scavenging Effects
The antioxidant effects of soy were the focus of much of the early research on how soy prevents cancer. The powerful free-radical scavenging effects of soy compounds and how they impact cancer continue to emerge.

Soy has an additive effect with vitamin E; it lowers rather than elevates estrogen levels in women and androgen levels in men (Jenkins et al. 2000). Damage to DNA caused by certain types of free radicals is strongly inhibited by genistein and other soy compounds (Breinholt et al. 1999; Davis et al. 2001). This helps prevent cancer. Dietary amounts significantly lower free-radical damage (Davis et al. 2001; Exner et al. 2001).

In addition to blocking free-radical damage, soy phytoestrogens also block inflammation, a contributor to cancer growth, notably in the colon (Davis et al. 2001; Zheng et al. 2002).

The effects of genistein against the activation of EGFR by free radicals were demonstrated. In this study, genistein reversed the free-radical activation of EGFR in normal cells (Chen et al. 2001). The benefits of genistein against oxidative stress are evident from a study on brain cells exposed to hydrogen peroxide. Free radicals generated by this oxidant degrade phospholipids and activate enzymes, which are crucial for memory and other brain functions. Genistein, through its ability to inhibit a tyrosinekinase enzyme that sets off the reaction, rescues cells from damage (Servitja et al. 2000).


Soy Precautions and Dosage
While the data are persuasive regarding the chemoprotective effects of soy, many questions remain. Some nutritionally based oncologists do not permit soy in their patients’ regime. Others believe that soy should be avoided by everyone and have launched massive public relations campaigns to discredit soy and discourage even moderate consumption by healthy people.

Breast cancer patients should avoid soy until their estrogen receptor status has been determined. Estrogen receptor alpha-positive breast cancer patients may benefit from genistein, while beta-receptor positive breast cancer patients’ tumors cells may proliferate faster in response to genistein. It has been suggested that patients avoid soy supplements 1 week prior to, during, and 1 week after radiation therapy, although new studies appearing in the Cancer Radiation Therapy protocol indicate a potential benefit to using soy isoflavones during radiation therapy.

Some people believe that soy is toxic to the thyroid gland, yet this may be a concern only in cases of iodine deficiency (Doerge et al. 2002). Some of the more credible arguments deal with soy-based infant formulas (Tuohy 2003).

There are a number of human clinical studies being conducted on the use of soy to both prevent and treat cancer (http://clinicaltrials.gov/ct/search?term=soy). When the findings of these studies are published, perhaps more definitive recommendations can be made about soy supplements. Based on the information available to us as of this writing, those concerned about cancer may consider these guidelines: a suggested dosage is five 700-mg capsules 4 times a day of a soy extract providing a minimum of 40% isoflavones. For prevention purposes, as little as 135 mg of a 40% soy isoflavone extract once a day may be adequate.


Theanine–increases efficacy of chemotherapeutic drugs
Researchers speculate that drinking 1 cup of green tea favors a positive mental attitude and increases the efficacy of chemotherapy. However, components of green tea have been identified (caffeine, epigallocatechin gallate (EGCG), flavonoids, and theanine) that better explain the chemotherapeutic advantage beyond its soul-soothing effects (Sadzuka et al. 2000a).

Japanese researchers focused specifically on theanine and its influence on the anti-tumor activity of Adriamycin (doxorubicin). In vitro, theanine inhibited the outflow of Adriamycin (ADR) from cancerous cells, increasing concentrations within the cell by almost three-fold. An increase in ADR concentrations was not observed in normal tissues, suggesting theanine protects healthy organs, such as the heart and liver. (Sadzuka et al. 1996). Illustrative of the enhancing qualities of theanine, injecting ADR into ovarian sarcoma-bearing (M5076) mice did not inhibit tumor growth, whereas a combination of theanine and ADR reduced tumor weight 62% (Sugiyama et al. 1998).

When theanine was added to pirarubicin, intracellular concentrations of pirarubicin increased 1.3-fold and the overall therapeutic efficacy of the drug increased 1.7-fold (Sugiyama et al. 1999). Satisfying results were also found when theanine was used with Idarubicin (IDA), which is highly toxic to bone marrow and an anti-leukemia agent similar to doxorubicin. Risk factors permitted only about one-fourth of the standard IDA dose to be used in combination with theanine. However, theanine reduced toxicities and increased IDA anti-tumor activity, rendering the chemotherapeutic agent a possibility for the treatment of leukemia (Sadzuka et al. 2000b).

Part of theanine’s anticancer effects can be attributed to mimicking glutamate, an amino acid that potentiates glutathione. Glutathione detoxifies chemotherapeutic agents, barricading chemicals from cells, and inhibiting tumor cell kill. Theanine is structurally similar to glutathione and crowds out glutamate transport into tumor cells. Cancer cells (in confusion) erringly take in theanine and theanine induces glutathione production. Glutathione (derived from theanine) does not detoxify like natural glutathione, and instead blocks the ability of cancer cells to neutralize cancer-killing agents. Deprived of glutathione, cancer cells cannot remove chemotherapeutic agents, and the tumor cell dies as a result of chemical poisoning (Sadzuka et al. 2001).

Administered with doxorubicin, the suggested dose of theanine is 500-1000 mg a day, although no human studies have been conducted with chemotherapy and theanine.


Thymus Extract–improves T-cell response and regulates the activity of cytokines
The thymus gland was at one time removed as an unnecessary appendage. It is an essential organ of the immune system, increasing stamina, energy, well-being, and the ability to ward off infections and cancer. Since 1965, when Burnet was awarded the Nobel Prize for demonstrating the endocrine function of the thymus gland, medical interest has focused on the thymus. It is now largely accepted that the thymus gland plays a central role in the mammalian immune system.

The immune system is made up of B-cells that protect against bacterial and viral infections and T-cells that guard against viral and fungal infections, as well as cancer. This powerful body of cells normally treats a developing cancer as foreign tissue, destroying aberrant cells before rapid multiplication occurs.

The effectiveness of T-cell mediated immunity depends upon the activity of T-lymphocytes (T-cells), which are programmed by proteins from the thymus gland. Immature (naïve) T-4 cells do not function properly until programmed by thymic proteins. As new T-lymphocytes migrate from the bone marrow to the thymus, they are programmed to distinguish between self-tissue (the host) and nonself tissue (an invading pathogen).

The thymus gland, a lymphoid organ situated in the anterior superior mediastinum, reaches its maximum weight near puberty and then undergoes involution, or degenerative change, shrinking to about one-sixth of its original size. By the age of 40, the thymus gland is scarcely functional in many individuals; therefore, the essential thymus-provided protein is no longer available to program T-4 cells. More than 20 years ago, thymic protein A was isolated and purified from bovine thymus cells (by Dr. Terry Beardsley, an immunologist). Dr. Beardsley patented a technology to grow thymus cells in the laboratory and then purify a specific thymus protein (Thymic Protein A) that helps T-cells to mature with immune competency. The active ingredient in Thymic Protein A is the precise thymus protein that programs the T-4 lymphocytes to locate abnormal cells and then directs T-8 killer cells to destroy them.

Three types of cells emerge from the thymus: T-4 helper cells (master regulators), T-8 cytotoxic killer cells (guided by T-4 helper cells to attack and destroy invading cells), and T-8 suppressor cells. T-4 helper cells regulate many key functions, including the activity of IL-2 and interferon.

High dose thymosin, a humoral factor secreted by the thymus, in conjunction with intensive chemotherapy was administered to 21 patients with advanced lung cancer. Ordinarily, patients with late stage lung cancer live about 240 days; the median survival rate more than doubled (500 days) among patients receiving thymosin. Some of the thymosin-treated group were alive and disease-free 2 years after treatment (Chretien et al. 1979).

Blood tests to measure the immune response are extremely valuable when detailing either a preventive or a therapeutic program to fight cancer. While determining T-lymphocyte numbers is important, assessing their activity is even more crucial. It is possible for a person with a total count of 1000 T-4 cells to have only 50% of these cells activated by the thymus. It is important that the patient know the degree of immune impairment in order to structure a corrective program. Tests to evaluate the activity of the immune system are performed at the Immuno-Science Laboratory (Los Angeles), (310) 657-1077.

A suggested dosage for healthy individuals is 1 packet of BioPro Thymic Protein A daily or every other day. Cancer patients may wish to increase this amount. For example, HIV patients use 3 doses a day until blood tests remain normal for 3-6 months. For maintenance, reduce to 1 dose a day. Use the thymic protein under the tongue, retaining for 3 minutes to allow for maximum absorption. Typically, patients undergoing chemotherapy maintain acceptable white blood cell counts if Thymic Protein A accompanies treatment.
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Cancer Adjuvant Therapy


Vitamin A–offers protection against radiation induced tissue damage, down-regulates telomerase activity, and is involved at almost every juncture of cancer control
Retinoids induce cell differentiation, control cancer growth and angiogenesis, repair precancerous lesions, prevent secondary carcinogenesis and metastasis, and act as an immunostimulant. After FAR therapy (5-fluorouracil-retinol palmitate with radiation and surgery), the disease-specific, 5-year survival was nearly 50% in various head and neck cancers (Yamamoto 2001). Retinoids, at pharmacological levels, assist in preventing the appearance of secondary tumors following curative therapy for epithelial malignancies.

It is well-established that a vitamin A deficiency (in laboratory animals) correlates with a higher incidence of cancer and an increased susceptibility to chemical carcinogens. This is in agreement with epidemiological studies, which indicate that individuals with a lower dietary vitamin A intake are at a higher risk of developing cancer (Sun et al. 2002). The chemotherapeutic possibilities surrounding vitamin A areplentiful.

Two vitamin A analogs currently in large chemoprevention, intervention trials, or epidemiological studies are all-trans-retinoic acid (ATRA) and 13-cis-retinoic acid (13-cis-RA).

Note: Retinoic acid is biologically active in two forms: all- trans- retinoic acid and 9-cis-retinoic acid. Vitamin A and 13-cis-RA are converted to these biologically active forms.

Thirty-two women with previously untreated cervical carcinoma (ages 14-60) were treated for at least 2 months using oral 13-cis-RA (1 mg per kg body weight a day) and alpha-interferon subcutaneously (6 million units daily): 16 of the women (50%) had major reactions, including four complete clinical responses. Remission occurred in 15 of the patients within 2 months and in one patient within 1 month; toxicity to treatment was described as manageable (Espinoza et al. 1994). The positive results were replicated in other studies using a similar model (Hansgen et al. 1998, 1999).

The role of 13-cis-RA on a human prostate cancer cell line (LNCaP) was studied. It was found that 13-cis-RA significantly inhibited PSA secretion and the ability to form new tumors. It was also noted that tumors that appeared (having escaped 13-cis-RA inhibition) were smaller compared to tumors in nontreated animals (Dahiya et al. 1994). During the course of 13-cis-RA therapy, prostate cancer cells became more differentiated, that is, they resembled (microscopically) normal prostate cells.

A combination of phenylbutyrate and 13-cis-RA as a differentiation and anti-angiogenesis strategy against prostate cancer was evaluated. Phenylbutyrate, considered nontoxic, is used to arrest tumor growth and induce differentiation of premalignant and malignant cells. Tissue examination of tumors showed decreased cell proliferation and increased apoptosis, as well as reduced microvessel density in animals treated with 13-cis-RA and phenylbutyrate; tumor growth was inhibited by 82-92%. In contrast, researchers reported 13-cis-RA and phenylbutyrate, when used singularly, were suboptimal in terms of clinical benefit (Pili et al. 2001).

A pilot study conducted at M.D. Anderson Cancer Center found ATRA alone ineffective as a long-term treatment for chronic myelogenous leukemia (CML). Only four of 13 subjects showed a transient, nonsustaining indication of an anti-leukemic effect (Cortes et al. 1997). However, combinations of therapeutic agents that included ATRA were promising in the treatment of CML. The combination included alpha-interferon plus ATRA, which reduced proliferation 50-60% (Marley et al. 2002).

Cisplatin (a popular chemotherapeutic agent) shares a similar chemotherapeutic profile with ATRA (the ability to induce cytotoxicity through apoptosis). A combination of ATRA and cisplatin induced apoptosis in significantly more cancer cells, particularly in ovarian and head and neck carcinomas, than either drug alone (Aebi et al. 1997). A combination of ATRA and IL-2 showed therapeutic value in treating resistant metastatic osteosarcoma, a malignant tumor of the bone (Todesco et al. 2000).

For decades, researchers have searched for ways to minimize the damage to the heart during Adriamycin therapy. Adriamycin, though relatively effective, damages the heart muscle. Several animal studies indicated that supplemental vitamin A reduced Adriamycin-induced inflammation and preserved heart tissue. Vitamin A appears not only to counter Adriamycin damage, but also to increase survival in animals (Tesoriere et al. 1994). Vitamin A extends similar protection to patients using cisplatin, a drug often used for bladder and ovarian cancer, as well as small cell carcinoma.

Radiation-induced lung injury frequently limits the total dose of thoracic radiotherapy that can be delivered to a patient undergoing treatment, restricting its effectiveness. Animal studies suggest that supplemental vitamin A may reduce lung inflammation after thoracic radiation and modify radiotherapy damage to the lungs (Redlich et al. 1998).

Vitamin A (in dosages of 25,000 IU a day) offers significant protection against radiation-induced tissue damage. Various cancer patients use more than 100,000 IU of a water-soluble vitamin A liquid a day, a dosage that must be supervised by a physician. Do not supplement with vitamin A if the cancer involves the thyroid gland or if the liver is damaged. Both professionals and patients should consult Appendix A to read about avoiding vitamin A toxicity. Good food sources of vitamin A include liver and fish liver oils, green and yellow fruits and vegetables such as apricots, asparagus, broccoli, cantaloupe, carrots, collards, papayas, peaches, pumpkins, spinach, and sweet potatoes. High-potency water-soluble vitamin A is available as a dietary supplement.


Vitamin C (ascorbic acid)–has a chemotherapeutic effect on many cancers, promotes collagen production, sequestering the tumor, and reduces the toxicity of conventional therapies
Linus Pauling, winner of the Nobel Prize for chemistry in 1954 and the Nobel Prize for Peace in 1963, believed strongly that vitamin C could play an important role in cancer treatment. Dr. Pauling suggested 10 grams of vitamin C a day for patients with advanced cancer for whom conventional treatments had ceased to be of benefit (Cameron et al. 1993). Over an 8-year period, 500 patients with varying stages and types of cancer were treated with vitamin C therapy. Those receiving 10 grams of vitamin C a day improved their state of well-being, as measured by increased appetite and mental alertness, as well as a decreased need for pain-killing drugs. A retrospective analysis showed that those using vitamin C lived considerably longer than those not supplemented.

Various clinics are using intravenous vitamin C and with positive results. Dr. Hugh Riordan, recognized as a world authority on this procedure, practices from Wichita, KS, at the Center for the Improvement of Human Functioning International. Dr. Riordan’s vitamin C story began in 1984 when he treated his first cancer patient; a 70-year-old renal cell carcinoma patient with metastasis to the lung and liver, using injectable vitamin C. Renal cell carcinoma has only a 5% response rate.

The initial treatment began with 15 grams of vitamin C administered intravenously 2 times a week; showing excellent tolerance, the vitamin C dosage was increased to 30 grams twice weekly. Within 6 weeks, the patient showed a favorable response to treatment and at the 12-week interval was pronounced tumor-free. The patient lived 14 additional years and died of congestive heart failure with no evidence of tumors.

In light of the favorable initial response to intravenous (IV) vitamin C, ascorbic acid was investigated. Vitamin C is preferentially toxic to tumor cells, that is, it kills tumor cells but not normal cells.

In low doses, vitamin C assumes the nature of an antioxidant; in high dosages, vitamin C changes roles and becomes a prooxidant, inducing peroxide production. Tumor cells have a relative catalase deficiency, an enzyme necessary to detoxify hydrogen peroxide to water and oxygen. A 10- to 100-fold difference in catalase concentrations exists between tumor cells and normal cells. Without the protection of catalase, peroxide accumulates in cancerous cells, along with aldehydes (toxic byproducts of the reaction), causing death to malignant cells. On the other hand, normal, healthy tissues have the protection of the detoxification enzyme and are spared destruction by peroxide and aldehyde. Vitamin C, a virtually nontoxic nutrient (Bowie et al. 2000), could cause a transient diarrhea if not absorbed properly.

Vitamin C is safe compared to standard chemotherapeutics and has an ability to preserve immune function. Many patients succumb, not because of cancer, but rather from a post-chemotherapeutic toxicity, resulting from a damaged immune system. Vitamin C protects the immune system. Vitamin C is preferentially toxic to many types of cancer cells, including 20 different melanoma cell lines. Ovarian cell lines are more susceptible to vitamin C-induced toxicity than pancreatic cells. Breast cancer appears to be one of the most responsive cancers to IV vitamin C.

Much higher concentrations of vitamin C are required to kill cancer cells than originally thought, about 600 mg/dL. Also, as the density of the cells increases, the efficacy of vitamin C decreases. It is extremely difficult to reach vitamin C concentrations greater than 200 mg/dL even when administered intravenously (Riordan et al. 2000). To increase the sensitivity of tumor cells to vitamin C, other approaches need to be employed.

Alpha-lipoic acid, a water- and lipid-soluble antioxidant that recycles vitamin, enhances the toxic effect of ascorbic acid. Lipoic acid decreases the dose of vitamin C required to kill tumor cells from 700 to 120 mg/dL (Riordan et al. 2000). Vitamin C toxicity is further enhanced by 1000 mcg of vitamin B12, which forms cobalt ascorbate, a benign but cancer-cell-toxic agent. Vitamin K, selenium, quercetin, niacinamide, biotin, and grape seed extract are also regarded as potentiation factors.

The goal is to achieve and maintain 400 mg/dL of vitamin C in the plasma. At this concentration, every cancer cell line so far tested has been found to be sensitive to vitamin C. After reaching an ascorbic acid peak, as occurs during infusion, the level returns to near baseline levels 24 hours after the IV infusion.

Vitamin C has an ability to increase collagen production. Vitamin C is required for the hydroxylation of proline, which in turn is required for collagen production. Vitamin C has the ability to inhibit enzymes that degrade or break down the extracellular matrix. Vitamin C dramatically increased the collagen within tumor cells, an act that tended to immobilize the cells

Vitamin C (supported by lipoic acid) has been used as a cancer therapy. It is strongly advised that patients contact a physician trained in administering infusions and monitoring progress. By giving vitamin C intravenously, doctors can achieve a blood saturation that far exceeds that attained by administering vitamin C orally (200% versus 2%). A high dose of vitamin C is critical to achieve tumor cell kill.

A Hickman line allows large doses of vitamin C to be self-administered at home on a daily to weekly basis over a period of months, modulating down or up in frequency according to response. Otherwise the treatment can be administered as an outpatient. Contraindications to vitamin C therapy are few but include individuals with kidney failure and on dialysis, as well as those with hemochromatosis. Also, physicians should screen patients for a red blood cell glucose-6 phosphate dehydrogenase deficiency, a rare condition whose presence can lead to a hemolytic crisis involving red blood cell breakdown.

Large doses of vitamin C should be reached gradually to establish tolerance. For example, 15 grams for one or two sessions and then 50 grams to 100 grams if necessary. The exact dose is determined by the individual’s plasma saturation immediately after an infusion. The therapy should not be stopped abruptly because a rebound effect could result in scurvy. Patients should allow weeks or even months to wean off the treatment, with oral vitamin C therapy used on the days between infusions.

A 10-year research project using high dose IV vitamin C has been completed. While a number of orthomolecular physicians are using IV vitamin C therapy, it is recommended that Dr. Riordan’s protocol become the backbone of the therapy. Instructions are available to physicians upon request from the center (Riordan et al. 2003).

Center for the Improvement of Human Functioning
3100 North Hillside Avenue
Wichita, KS 67219
(316) 682-3100

Other chemotherapeutic credits awarded to vitamin C:

  • Vitamin C prolongs the lives of animals undergoing conventional cancer treatment by protecting normal cells against chemotherapy-induced toxicity; in tandem, vitamin C increases the cytotoxicity targeted at the cancer (Antunes et al. 1998; Giri et al. 1998). When 5-FU was administered together with vitamin C, the tumor cell kill rate was boosted from 38 to 95.5%. X-ray therapy decreased cancer growth 72%, but adding vitamin C to the regime decreased cancer growth by 98.2%. Full spectrum antioxidants rather than isolated nutrients are suggested (Prasad et al. 1999; Moss 2000).
  • Infection: Heliobacter pylori increases the risk of developing stomach cancer (Uemura et al. 2001), as well as pancreatic cancer (Stolzenberg-Solomon et al. 2001). High doses of vitamin C inhibit the growth of H. pylori, both in vitro and in vivo (Zhang et al. 1997). A study showed vitamin C levels to be consistently low in individuals with the H. pylori infection (The Analyst 2002).
  • Frequent intake of vitamin C from food and supplement sources was associated with a protective effect against multiple myeloma, particularly among Caucasians. African Americans benefited less from ascorbic acid intake (Brown et al. 2001).
  • NF-kB is a central mediator of altered gene expression during inflammation and is implicated in cancer. Vitamin C inhibited the activation of NF-kB by multiple stimuli, including IL-1 and TNF-alpha (Bowie et al. 2000).

It should be re-emphasized that oral vitamin C does not bestow equal benefits compared to intravenous vitamin C. If a patient with a solid tumor elects to use oral vitamin C, ascorbic acid buffered with sodium may produce better results. If the cancer is blood-borne (leukemia, lymphoma, or myeloma), ascorbic acid crystals buffered with calcium appears to offer greater efficacy. The majority of the patients use 6-12 grams a day. Food sources of vitamin C are berries, citrus fruits, papayas, and pineapple, as well as tomatoes, broccoli, Brussels sprouts, dandelion and mustard greens, peas, red peppers, and spinach.


Vitamin D–promotes differentiation, inhibits angiogenesis, regulates cell division
Current recommendations to avoid natural sunrays to thwart the possibility of deadly melanoma may be allowing other endangerments. For more than 50 years, medical literature has affirmed that regular sun exposure is associated with a substantial decrease in death rates from certain types of cancers. It is estimated that moderate sun exposure without sunscreen – enough to stimulate vitamin D production but not enough to damage the skin – could prevent 30,000 cancer deaths in the United States each year (Ainsleigh 1993). The most damaging of the sun’s rays occur between the hours of 10 a.m. and 3 p.m. and are thus the hours demanding the greatest watchfulness.

Evidence points to a prostate, breast, and colon cancer belt in the United States, which lies in northern latitudes under more cloud cover than other regions (Studzinski et al. 1995). Certain regions in the United States, such as the San Joaquin Valley cities and Tucson, AZ; Phoenix, AZ; Albuquerque, NM; El Paso, TX; Miami, FL; Jacksonville, FL; Tampa, FL; and Orlando, FL; have a lower incidence of breast and bowel cancers. Conversely, New York; Chicago; Boston; Philadelphia; New Haven, CT; Pittsburgh; and Cleveland, OH; have the highest rates of breast and intestinal cancer of the 29 major cites in the United States. The greater hours of year-round sunlight correlate to a lower rate of breast and intestinal cancer in the U.S.A.

Vitamin D is formed in the skin of animals and humans by the action of shortwave UV light, the so-called fast-tanning sunrays. Precursors of vitamin D in the skin are converted into cholecalciferol, a weak form of vitamin D3, which is then transported to the liver and kidneys where enzymes convert it to 1,25-dihydroxycholecalciferol, the more potent form of vitamin D3 (Sardi 2000). Although vitamin D exists in two molecular forms, vitamin D3 (cholecalciferol) found in animal skin and vitamin D2 (ergocalciferol) found in yeast, vitamin D3 is believed to exhibit more potent cancer-inhibiting properties and is therefore the preferred form.

Dark-skinned people require more sun exposure to produce vitamin D because the thickness of the skin layer (the stratum corneum) affects the absorption of UV radiation. Black human skin is thicker than white skin and thus transmits only about 40% of the UV rays needed for vitamin D production. Darkly pigmented individuals who live in sunny equatorial climates experience a higher mortality rate from breast and prostate cancer when they move to geographic areas that are deprived of sunlight exposure in winter months (Angwafo 1998; Sardi 2000).
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Cancer Adjuvant Therapy

Women with polymorphisms (genetic variations) of the vitamin D receptor gene may be less able to benefit from the nutrient. There is some evidence that vitamin D receptor gene polymorphisms play a role in the breast cancer (Bretherton-Watt et al. 2001); however, recent studies do not support this evidence (Buyru et al. 2003).
Identifying the at-risk groups, through the assessment of genetic variations in the vitamin D receptor, appears to be a forthcoming tool for planning intervention strategies.

Human leukemia cells cultured in the presence of vitamin D exhibited a reduced rate of tumor growth when injected into mice. Cells grown in vitamin D3 failed to form detectable tumors in 11 of 12 inoculated mice (Wang et al. 1997). The anticarcinogenic properties of vitamin D, confronts multiple stages of cancer development, including apoptosis, differentiation, angiogenesis, and metastasis, as well as regulating the cell growth cycle (van den Bemd et al. 2002).

Since vitamin D can cause calcium to be released from bones (a condition referred to as hypercalcemia), large doses of vitamin D cannot be used in patients whose medical history or genetics puts them at increased risk. Using a combination of Vitamin D3 and vanadium (a metallic element) enables vitamin D to retain its anticancer activity and vanadium addresses the problem of hypercalcemia (Basak et al. 2000).

Rats were supplemented with vanadium or vitamin D3 or both vanadium and D3 four weeks prior to induced liver cancer and continued thereafter until the 20th week. After 20 weeks of supplementation, the vitamin D3-vanadium combination had significantly reduced the number and size of abnormal hepatic nodules. The combination also showed an additive effect, reducing the number and size of hyperplastic nodes from 83.3% to 37.5%. In addition, vanadium effectively blocked the entry of calcium into cells.

A modified form of vitamin D (referred to as a deltanoid) delays the onset and reduces the number of skin cancers in laboratory mice. The microscopically altered structure of vitamin D produced a potentially effective cancer therapeutic. The vitamin D analog retains its anticancer profile but diminishes the threat of hypercalcemia. The most effective of four analogs tested was a doubly modified hybrid compound containing fluorine (Posner 2000).

During one study, mice painted with a chemical substance, inducing cancerous tumors were concurrently the animals were given the deltanoid. After 20 weeks, the fluorine-containing analog had reduced the incidence of tumors more than 28%, while the actual number fell 63% (Kensler et al. 2000). Deltanoids are in the early stages of development and, unfortunately, it may take 10 years before they become available (Guyton et al 2003). It is possible that deltanoids could lessen the need for hormone treatments or aggressive chemotherapy. Patients could theoretically stay on the treatment for the remainder of their life to keep the cancer from advancing.

Studies indicate that moderate or severe hypovitaminosis D was present in 66% of patients taking daily vitamin D in amounts less than the recommended dosage for their age. Adults may need a minimum of 5 times the 200-IU RDA, (or 1000 IU daily), to protect against cancer (Vieth 1999). Therapeutic dosages of vitamin D typically range from 800-4000 IU a day. Monthly kidney function blood tests (creatine, BUN, etc.) should be performed if daily vitamin D intake exceeds 1400 IU. These tests are included in most standard blood chemistry tests that cancer patients regularly perform to guard against anemia and overt immunosuppression.

Food sources of vitamin D include egg yolks, organ meats, fortified dairy products, butter, cod liver oil, and cold-water fish, such as salmon, herring, and mackerel. Vitamin D enhancers are vitamins A and C, calcium, magnesium, phosphorus, and choline. Antagonists are mineral oil, phenobarbital, and laxatives.


Vitamin E–is an antioxidant that can protect smokers, reduces radiation damage, potentiates chemotherapy, and inhibits many types of cancers
The inhibitory role of vitamin E in the growth of a number of human tumor cells, as well as its defensive functions in overcoming treatment-induced toxicity have been examined. The impact of vitamin E (perhaps acting through its antioxidant strengths) is significant, as evidenced by the following studies:

  • After examining 29,000 male smokers in Finland, researchers found that high blood levels of alpha-tocopherol reduced the incidence of lung cancer by approximately 19%. The relationship appears stronger among younger persons and among those with less cumulative smoke exposure. These findings suggest that high levels of alpha-tocopherol, if present during the early critical stages of tumorigenesis, may inhibit lung cancer development (Woodson et al. 1999).
  • A combination of vitamin E and pentoxifylline (PTX), a drug that inhibits abnormal platelet aggregation, allowing more blood to reach irradiated areas, resulted in a 50% regression of superficial radiation-induced fibrosis (the proliferation of fibrous connective tissue) in half of the patients studied (Gottlober et al. 1996; Delanian 1998). A suggested dosage is 800 mg a day of PTX and 1000 IU per day of vitamin E.
  • An anti-melanoma effect obtained from vitamin E succinate in vivo has been reported (Malafa et al. 2002).
  • Gamma-tocopherol inhibits COX-2 activity, demonstrating anti-inflammatory properties (Jiang et al. 2001; Life Extension Magazine 2002).
  • The use of vitamin E, in combination with vitamins A and C, led to a four-fold reduction in p53 mutations (Brotzman et al. 1999). This is an extremely important finding because p53 mutations indicate a more malignant, aggressive form of cancer.
  • Men with a high intake of vitamin E are 65% less likely to develop colorectal adenomas (precursors to colon cancer) compared to men with low vitamin E intake (Tseng et al. 1996).
  • Lower morbidity and mortality from prostate cancer in men taking 50 mg of synthetic alpha-tocopherol daily. Subsequent testing determined gamma-tocopherol to be superior, however, to alpha-tocopherol in terms of tumor cell inhibition (Moyad et al. 1999). Men in the highest fifth of the distribution for gamma-tocopherol had a five-fold reduction in the risk of developing prostate cancer compared to those in the lowest fifth. In addition, statistically significant protection from high levels of selenium and alpha-tocopherol occurred only when gamma-tocopherol concentrations were also high (Helzlsourer et al. 2000).
  • Vitamin E’s mode of efficacy in regard to prostate protection: Vitamin E interferes with two proteins (the receptor for testosterone and prostate-specific antigen [PSA]). The fewer androgen receptors there are on a prostate cancer cell, the less capable the remaining receptors are of turning on genes that stimulate prostate cancer growth and progression. PSA serves as a good marker molecule for androgen receptor activity (Mercola 2002b).
  • Tocotrienols, quite similar to a tocopherol (but for the addition of an unsaturated tail in its chemical structure), accumulate in adipose tissues, including mammary glands. If a cell becomes diseased, the tocotrienol is prepared for action, ready to inhibit growth and regulate aberrant cellular activity at onset. Curiously, the more cancerous the cell, the more susceptible it is to tocotrienols. Scientists apparently have been focusing upon the wrong form of vitamin E (the tocopherols), which show little protection against breast cancer. Tocotrienols appear to inhibit proliferation of human breast cancer cells by as much as 50% (Nesaretnam et al. 1998). Results suggest that tocotrienols are effective inhibitors of both estrogen receptor-negative and estrogen receptor-positive cells and that combination with tamoxifen should be considered as a possible improvement in breast cancer therapy. This strategy could significantly reduce the amount of tamoxifen required to affect the cancer (Guthrie et al. 1997).
  • Cortisol (associated with poorer survival) and IL-6 (a negative marker for various cancers) were significantly lower in laboratory animals that received alpha-tocopherol before a cortisol-IL-6 challenge (Webel et al. 1998).
Vitamin E Chemotherapeutic Agent Combination with Vitamin E
47% growth inhibition Bleomycin, 46% tumor reduction 71% reduction
5-FU, 37% tumor reduction 85% reduction
Adriamycin, 58% tumor reduction 88% reduction
Cisplatin, 57% tumor reduction 82% reduction

A suggested vitamin E dosage is from 400-1200 IU a day of alpha-tocopherol together with gamma E tocopherol. For optimal results, use 80% alpha-tocopherol and 20% gamma-tocopherol. A tocotrienol dosage is 240 mg each day. Good food sources of vitamin E are cold-pressed vegetable oils, wheat germ, eggs, dark green vegetables, nuts, brown rice, and butter.


Vitamin K–is a growth regulator, promotes apoptosis, and decreases pro-inflammatory cytokines
A novel form of vitamin K that appears extremely promising in the treatment of primary liver cancer, a type notoriously resistant to chemotherapy has been discovered by scientists at the University of Pittsburgh Cancer Institute (UPCI). The research published in the Journal of Biological Chemistry described an innovative approach to treat, and possibly prevent, cancer by triggering apoptosis (Ni et al.1998).

The UPCI team found that a vitamin K analog, Compound 5 (CPD5), causes an imbalance in the normal activity of enzymes that controls the addition or removal of small molecules (phosphate groups) from proteins inside cells. Specifically, CPD5 blocks the activity of enzymes (protein-tyrosine phosphatases) that normally remove phosphate groups from selected proteins inside liver cancer cells. CPD5, however, does not interfere with another group of enzymes called protein tyrosine-kinases, which add phosphate groups to the same proteins. The result is an excess of tyrosine-phosphorylated proteins, which triggers a variety of activities within cells, including the shutting down and subsequent death of the cell.

It may be possible to remove some individuals from liver transplant waiting lists if CPD5 is as effective in humans as it is experimentally. However, the vitamin K compound is not limited to killing liver cancer; in tissue culture the compound was also effective against melanoma and breast cancers. Although the new vitamin K is not in clinical testing at this time, clients and physicians may contact the UPCI’s Cancer Information and Referral Service at 412-647-2811 for periodic updates regarding the treatment.  Inquirers can also visit the University’s website at http://www.upci.upmc.edu .

Vitamin K compounds inhibited IL-6 production by lipopolysaccharide-stimulated fibroblasts, which are recognized as rich sources of cytokines (Reddi et al. 1995). This finding has significant anticancer implications because over-expression of IL-6 is intricately involved in the inflammatory process, bone resorption, the activation of telomerase, and cancer proliferation. A suggested vitamin K dosage is 10 mg a day. Interesting research relating to the use of vitamin K concurrent with anticoagulant therapy (not usually a recommended practice) appears in the protocol Cardiovascular Disease: Comprehensive Analysis in the section dedicated to vitamin K.


OTHER FACTORS AFFECTING PATIENT OUTCOME


What Should Cancer Patients Eat?
For a cancer patient who appreciates the importance of a properly planned diet, the task is daunting. The diversity of the population minimizes the likelihood of a universal diet; nonetheless, most diets are hyped as being nutritionally correct for everyone. This section explores dietary variables, conceding that many generalities exist, that is, eat organic when available and eat on schedule to avoid blood glucose swings. Select foods characterized by color and texture. Avoid synthetic and refined foods: white flour products and sugar as well as trans fats (those fats altered by overheating, hydrogenation, and refining). Avoiding well-done meats and exposure to heterocyclic amines (formed during high temperature cooking) eliminates another significant cancer source (Zheng et al. 1998).

Tumors are primarily obligate glucose metabolizers, meaning they require sugar for survival. Even though the brain normally uses high amounts of glucose, hepatomas (a tumor of the liver) and fibrosarcomas (a sarcoma that contains fibrous connective tissue) consume roughly as much glucose as the brain. Some Americans continuously satisfy cancer’s appetite, ingesting as much as 295 pounds of sugar a year.

Nobel laureate Otto Warburg, Ph.D., discovered in 1955 that cancer cells use glucose for fuel. But glucose accomplishes another strategic maneuver that strongly favors the cancer: it immobilizes internal defenses, the actions of the immune system. A study involving 10 healthy human volunteers assessed fasting blood glucose levels and the phagocytic index of neutrophils, a type of white blood cell. Glucose, fructose, sucrose, honey, and orange juice all significantly decreased the capacity of neutrophils to engulf bacteria. A diet structured away from sugars deprives cancer of its energy and increases the reliability of the immune response.

Dr. Jeff Bland advises selecting foodstuffs low on the glycemic index to avoid gratifying the tumor’s appetite. The glycemic index lists the relative speed at which different foods are digested and raise blood sugar levels. Each food is compared to the effect of the same amount of pure glucose on the body’s blood sugar curve. Glucose itself has a glycemic index rating of 100. Foods that are broken down and raise blood glucose levels quickly have higher ratings. The closer to 100, the more the food resembles glucose. The lower the rating, the more gradually that food affects blood sugar levels.

Common foods have the following glycemic ratings: baked potatoes, 95; white bread, 95; mashed potatoes, 90; chocolate candy bar, 70; corn, 70; boiled potatoes, 70; bananas, 60; white pasta, 55; peas, 50; unsweetened fruit juice, 40; rye bread, 40; lentils, 30; soy, 15; green vegetables; and tomatoes, < 15.

Note: The glycemic index should not be relied upon without factoring in the glycemic load, which is the glycemic index of a food times its carbohydrate content in grams, a concept developed at Harvard School of Public Health in 1997. Carrots, for instance, have a high glycemic index, but a very low glycemic load. This means that carrots consumed in moderation usually do not present a problem. Refer to the Obesity protocol for complete information about the glycemic index load.

An admonition, based more on folk medicine than scientific certainty, to avoid the white foods (all sugar-containing foods, as well as rice, and white flour and flour-based products) appears to have validity when applied to the glycemic index. A diet structured principally around carbohydrates that promotes hyperglycemia (high blood sugar level) and hyperinsulinemia (high blood insulin level) provides an environment that feeds the fire of cancer. High blood insulin levels drive protein tyrosine kinase (leading to cell division) and high blood glucose metabolically feeds cancer cells. On the other hand, a diet centered on fiber-, vitamin-, and mineral-rich foods that cause no blood glucose rise or insulin rush is an excellent target for healthy eating.

The diseases such as obesity and diabetes mellitus (often characterized by hyperinsulinemia) are associated with an increased risk of endometrial, colorectal, and breast cancers. The mechanisms underlying insulin-mediated neoplasias appear to include enhanced DNA synthesis (with the resultant tumor cell growth), inhibited apoptosis, and an altered sex hormone milieu. The reduced insulin levels seen with physical activity, weight loss, and a high fiber diet may in fact account for the decreased cancer incidence observed in individuals who maintain normal glucose and insulin levels (Gupta et al. 2002). Comment: Reducing blood insulin levels may result in remarkable improvements in men with prostate disease, with a concurrent drop in PSA levels (Hsing et al 2001).

Unfortunately, glucose modulation is an under-utilized component of cancer treatment. Some aspects of traditional treatments actually contribute to higher blood levels of glucose. For example, consider hospital meals, often favoring sugar-based foodstuffs. In addition, if the patient is on an IV solution, the infusion is largely dextrose based, feeding the cancer and perpetuating its growth.

The American Cancer Society believes that 30% of all cancer is due to inadequate consumption of vegetables and fruits. About 91% of Americans fail to achieve target recommendations, that is, 5 vegetable servings a day or 2-3 pounds a week. Asians who consume from 15-20 servings of fruits and vegetables a day have a much lower incidence of some cancers.

Vegetables of the cruciferous family isolate the anticarcinogenic constituents of Brassica plants. Glucosinolates (appearing in cruciferous vegetables) can inhibit, retard, or even reverse experimental multistage carcinogenesis (Fimognari et al. 2002). As enzymatic processes hydrolyze glucosinolates, isothiocyanates are released, including sulphoraphane. Sulphoraphane wields a strong arm against cancer, promoting apoptosis, inducing Phase II detoxification enzymes, increasing p53 and participating in the regulatory mechanisms of the cell’s growth cycle. Necrosis (localized death of diseased tissues) is typically observed after prolonged exposure to elevated doses of sulphoraphane.
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Cancer Adjuvant Therapy

For the past several years, researchers at Johns Hopkins University have urged the inclusion of broccoli sprouts in the diet. According to Dr. Paul Talalay, broccoli sprouts have 20-50 times more anticancer sulphoraphanes than grown vegetables (Fahey et al. 1997). Eating a few tablespoons of sprouts daily can supply the same amount of chemoprotection as 1-2 pounds of broccoli eaten weekly (Talalay 1997).

Broccoli sprouts contain a chemical that kills H. pylori, even in antibiotic-resistant conditions. The release of anticarcinogenic chemicals from Brassica vegetables is a sequential process that occurs as the plant tissue is broken down. Indole-3-carbinol (I3C), a product of cruciferous metabolism, is referred to as a secondary metabolite, meaning it is not found in a preformed state in the vegetables. Rather, I3C is formed after myrosinase (an enzyme inherent to the plant) is exposed to a phytochemical in the vegetable (glucobrassicin), a glucosinolate that subsequently delivers indole-3-carbinol. This occurs only when vegetable cells are crushed or eaten, a process known as enzymatic hydrolysis. I3C, thus formed, is then broken down in the presence of stomach acid to various byproducts including diindolylmethane (DIM), another powerful defense against cancer (Lukaczer 2001). It appears highly possible that the breakdown products of I3C may be delivering as much protection as I3C itself (Katchamart et al. 2001; Lukaczer 2001; Lord et al. 2002).

An undesirable effect is the conversion of estrone to a carcinogenic material called 16-alpha hydroxyestrone that damages DNA and inhibits apoptosis. The ratio of 2-hydroxyestrone to 16-hydroxyestrone indicates a woman’s risk for developing breast and ovarian cancer. Levels of 2-hydroxyestrone are typically higher in women who do not get cancer; 16-hydroxyestrone is higher in women with cancer. When breast cancer cells are treated with I3C (in vitro) 90% of cells undergo growth inhibition, whether the cells are estrogen positive or negative (Galland 2000).

Broccoli (500 grams for 12 days) increased the average 2-alpha-hydroxyestrone:16- alpha-hydroxyestrone ratio (Kall et al. 1997). Hence, consuming vegetables rich in indole-3-carbinol gives hope that as 2-hydroxyestrone increases, cancers will be decreased in both men and women. The ability of I3C to neutralize estrogen metabolites as well as to block aflatoxin (a mycotoxin that promotes prostate cancer) makes cruciferous vegetables equally important to men.

By inhibiting protein kinases and other growth factors, restoring p21 activity, and encouraging apoptosis, I3C appears an effective chemopreventive/therapeutic agent against many types of malignancies (Chinni et al. 2001; Roman-Gomez et al. 2002). Evidencing its benefits, I3C reduced the incidence of cervical cancer from 76 to 8% in laboratory mice (Jin et al. 1999), and administered together with tamoxifen, I3C inhibited the growth of estrogen-dependent human MCF-7 breast cancer more effectively than either agent used alone (Cover et al. 1999).

If vegetables providing I3C are in short supply in the diet, indole-3-carbinol capsules are available. For those under 120 pounds, one 200-mg capsule taken 2 times a day is suggested; those between 120-180 pounds could take 200 mg 3 times a day, while those over 180 pounds could take four 200 mg a day. If the diet generally lacks adequate amounts of vegetables, powdered vegetable extracts are available, an example is PhytoFood; a suggested dosage for cancer patients is 1-2 tbsp daily (with food).


Cholesterol (Can It Be Too Low?)
Hypocholesterolemia (abnormally low levels of cholesterol) has been shown in several epidemiological studies to be related to increased mortality from human cancer. Cholesterol and triglyceride levels in 135 patients with squamous cell and small cell lung carcinoma were evaluated. All lung cancer patients had higher rates of hypocholesterolemia as well as lower triglyceride levels compared to a healthy control group. Total cholesterol concentrations were lower in both histological types, but triglyceride levels were lower only in patients with squamous cell lung cancer (Siemianowicz et al. 2000).

An article in Hematology and Oncology reported that 90% of 83 patients with acute myeloid leukemia were hypocholesterolemic (Zyada et al. 1990). Additionally, another article in the European Journal of Haemtology reported that remission in acute myelogenous leukemia was associated with a significant increase in cholesterol levels in those patients with low cholesterol concentrations or high leukocyte counts at diagnosis (Reverter et al. 1988).

Various reports have emerged showing that low cholesterol levels are associated with higher death rates (particularly among elderly people), from cancer and infection (Weverling-Rijnsburger et al. 1997; Schatz et al. 2001). These findings raise concerns regarding hypocholesterolemic drug therapy and diet manipulation to drastically lower cholesterol levels in a subset of the population.


STRESS AND CANCER

Few events are as stressful as a diagnosis of cancer. As the stress level increases, the outpouring of the adrenal cortex hormone (cortisol) also increases. Women with breast cancer who had abnormal cortisol rhythms survived an average of 3.2 years, while those with normal rhythms survived an average of 4.5 years (more than a year longer). The difference in survival times began to emerge about 1 year after the cortisol testing and continued for at least 6 additional years (Richter 2000).

Animal studies, mostly involving rats, demonstrated stress as a causal factor in cancer. The onset of cancer appears similarly allied in humans, with the immune system highly responsive to emotional pitfalls. It is well established that when the individual is emotionally challenged, cancer has a significant advantage (Levy et al. 1987).

Psychobiologist Shamgar Ben-Eliyahu, Ph.D., has been working for the past decade on stress, tumor development, and the activity of NK cells (Ben-Eliyahu et al. 2000). Considering all immune system cells, NK cells show the strongest activity in preventing metastasis and the strongest response to stress. Even short-term stress decreases NK cell activity in laboratory animals, significantly increasing the risk of certain types of cancer and metastasis. Gender plays a significant role in the NK cell response to stress, with men more adversely affected than women (Irwin 2000). The stress of abdominal surgery promotes the growth of cancerous tumors in rats, a sequence thought orchestrated by NK cell suppression (Ben-Eliyahu et al. 1999).

High levels of neuropeptide-gamma are observed in the bloodstream of depressed individuals, an elevation synonymous with immune suppression (Ader et al. 1981; Scanlan et al. 2001). Macrophages (pathogen scavengers) have receptor sites that attract endorphins (mood enhancers with analgesic traits). With the right emotional programming, white blood cells swim through the bloodstream with determination; conversely, under stress, immune competence falters, and the immune attack becomes lethargic.

Breast cancer patients with the most anxiety had a weaker immune response and were less equipped to fight the disease. The following stress-associated situations and personality types are associated with breast cancer: (1) the use of denial or repression as a coping strategy, (2) an experience of separation or loss, (3) a history of stressful life experiences, (4) a tendency toward melancholy and hopelessness (this trait has, since antiquity, been associated with uterine and breast cancers), and (5) a personality type characterized by conflict avoidance. It is theorized that the genes that cause one to avoid conflict are the same genes that increase susceptibility to cancer (Goodkin et al. 1986; Darmon 1993).

Also, psychological stress induces the production of pro-inflammatory cytokines, such as TNF-alpha, IL-6, and IL-10 (Maes et al. 2000). Please refer to the protocol Cancer: Gene Therapies, Stem Cells, Telomeres, and Cytokines for a full discussion regarding pro-inflammatory cytokine’s role in malignancies.

The effect of chronic stress on the immune system of 116 recently treated breast cancer patients found (reproducibly) that stress levels significantly predicted (1) lower NK cell activity, (2) diminished response of NK cells to interferon-gamma, and (3) decreased proliferation of lymphocytes, white blood cells considered the army of the immune system (Andersen et al. 1998). Oncologists often suggest stress management, such as meditation, yoga and breathing exercises, guided imagery, or spirituality, to help bring about calm.

Because the cells responsible for cancer surveillance work best in an environment favoring confidence and calm, it is important that the message springing from our thoughts and transmitted to cells is commensurate with healing. Fright, pessimism, and melancholy send uncertain instructions and the cells respond with a feeble effort. The enduring message (fear or assurance, despair or hopefulness, laughter or tears) reflects our hour-to-hour psyche and sets the tone for health victories or failures. Expect little more from your body than the quality of your thoughts at this very moment: “As a man thinks in his heart, so is he” (Proverbs 23:7).


SUMMARY

The drugs, hormones, and nutrients discussed in this protocol have documented mechanisms of action that may benefit the cancer patient. The objective of implementing an adjuvant regimen consisting of multiple agents is to increase the odds of achieving a long remission. Once a remission is achieved, preventing recurrence and secondary cancers becomes a lifetime commitment.

Few oncologists aggressively seek to prevent recurrence once the primary disease appears to have been eradicated. However, the regrettable facts are that colonies of cancer cells can remain dormant in the body for years or decades before reappearing as full-blown disease that is highly resistant to treatment. This has been documented in autopsy studies of people who died of diseases other than cancer but nonetheless showed significant residual metastatic tumors in their bodies.

Nutrient Preventive Dose Cancer Adjuvant Dose
R-dyhydro-lipoic acid 150-600 mg/day 600-1200 mg/day
Coenzyme Q10 30-300 mg/day Up to 400 mg/day
EPA-DHA fatty acids 1400 mg/day 2800-4200 mg/day
Kyolic Reserve Garlic 600 mg/day Up to 5400 mg/day
Indole 3 Carbinol w/Resveratrol 1-2 caps/day 1-2 caps/day
Green Tea (725 mg) 1-2 caps/day 5 capsules 3 times/day
Life Extension Mix* 1 tbsp of powder, 9 tabs, or 14 capsules daily 1 tbsp of powder, 9 tabs, or 14 capsules daily
Liquid Emulsified Vitamin A Up to 35,000 IU/day** Up to 100,000 IU/day**
Vitamin C (included in LE Mix) 6-12 grams/day
Vitamin D3 Up to 1400 IU/day 800-4000 IU/day**
Gamma Tocopherol w/Seseame Lignans 1 capsule/day 2-4 capsules/day
Grape Seed Extract 100 mg/day 300 mg/day
Phyto-Food (cruciferous vegetable concentrate) 1 tbsp/day 1-4 tbsp/day
Melatonin 300 mcg-6 mg/day 3-50 mg/day
Selenium (included in LE Mix) 200-400 mcg/day 200-400 mcg/day
Silibinin 260 mg/day Up to 2000 mg/day
Curcumin 900 mg/day 2700 mg 3 times/day
GLA (gamma-linolenic acid) 1 softge per day 900 mg/day
*Those individuals using the Life Extension Mix (powder, tablets, or capsules) are receiving a storehouse of nutrients targeted at maintaining good health. Very few of the cornerstone nutrients are not contained in the Life Extension Mix Formula, but exceptions are alpha-lipoic acid, coenzyme Q10, essential fatty acids, garlic, and melatonin. If indicated, the reader may wish to emphasize these nutrients for maximum support. Some people bolster their nutritional program by incorporating the Life Extension Booster (complete with gamma E tocopherol) together with the Life Extension Mix. These formulas are popular from both financial and convenience perspectives. While individuals with cancer will benefit from these suggestions, a more comprehensive program is recommended, such as supplements with precise anticancer mechanisms, targeted at specific cancer cell lines or established weaknesses.
**Refer to safety precautions that appear in this protocol when taking high doses of vitamins A and D.

In too many cases, a breast, melanoma, or other cancer reemerges that was supposed to have been cured. Scientists speculate that the body has natural anticancer control mechanisms that may diminish with age and exposure to physical and emotional stress factors. It is thus important for cancer patients to be vigilant in maintaining an inhospitable environment for cancer cells to propagate and protecting against age-associated immune dysfunction.

We have prepared the chart above to summarize recommendations on the basic dietary supplements and suggested doses for cancer prevention and adjuvant treatment. In addition to the agents listed here, a number of other potential adjuvant approaches are discussed in this protocol. For long-term control of cancer, some cancer patients attempt to incorporate as many of these adjuvant approaches as are tolerable and affordable. Others pick and choose which drugs, hormones, and supplements they want to consume over the long term.

Patients should read the other cancer protocols in this book, with special attention given to Cancer: Should Patients Take Dietary Supplements? and Cancer Treatment: The Critical Factors. If surgery, radiation, or chemotherapy is being considered, please refer to these specific protocols: Cancer Surgery, Cancer Radiation, and Cancer Chemotherapy.

Note: While it would be wholly inappropriate for the Life Extension Foundation to steer individuals in decisions of omission or commission regarding therapies, it would be equally improper to shun responsibility. Because we are challenged by a professional and moral commitment to assist in overcoming appalling statistics, we have discussed some controversial issues in this protocol. We look forward to new findings to better substantiate optimal therapeutic approaches.

PRODUCT AVAILABILITY

R-dyhydro-lipoic acid, alpha-tocopherol succinate, L-arginine, buffered ascorbic acid, Bio Pro Thymic Protein A, biotin, calcium, Cell Forte with IP-6, Chloroplex, coenzyme Q10, conjugated linoleic acid (CLA), flaxseed oil, Gamma-E-Tocopherol/w Sesame Lignans, glutathione, goldenseal, grape seed-skin extract, green tea bags (organic), Kyolic Reserve Garlic, indole-3-carbinol w/Broccoli Extract, lactoferrin, L-glutamine, Life Extension Mix (caps, powder, or tablets), Super EPA/DHA w/Sesame Lignans, Mega GLA w/Sesame Lignans, melatonin, N-acetyl-cysteine, Pecta-Sol, perilla oil, Phyto-Food, Super Curcumin, selenium, Silibinin Plus, Ultra Soy Extract, Mega Green Tea Extract, Indole 3 Carbinol w/Resveratrol, theanine, tocotrienol w/Sesame Lignans, vitamin A, vitamin B12, vitamin D, and vitamin E are available by calling (800) 544-4440 or by ordering online.

STAYING INFORMED

The information published in this protocol is only as current as the day the book was sent to the printer. This cancer protocol raises many issues that are subject to change as new data emerge. Furthermore, cancer is still a disease with unacceptably high mortality rates, and none of our suggested treatment regimens can guarantee a cure.

The Life Extension Foundation is constantly uncovering information to provide the cancer patient with more ammunition to battle their disease. A special website has been established for the purpose of updating patients on new findings that directly pertain to the cancer protocols published in this book. Whenever Life Extension discovers information that points to a better way of treating cancer, it will be posted on the website www.lefcancer.org.

Before utilizing the cancer protocols in this book, we suggest that you log on to www.lefcancer.org to see if any substantive changes have been made to the recommendations described in this protocol. Based on the sheer number of newly published findings, there could be significant alterations to the information you have just read.
Alternatively, call 1-800-226-2370 and ask a Health Advisor if your topic of interest has been updated on the website – www.lefcancer.org
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These statements have not been evaluated by the FDA. These products are not intended to diagnose, treat, cure or prevent any disease. The information provided on this site is for informational purposes only and is not intended as a substitute for advice from your physician or other health care professional or any information contained on or in any product label or packaging. You should not use the information on this site for diagnosis or treatment of any health problem or for prescription of any medication or other treatment. You should consult with a healthcare professional before starting any diet, exercise or supplementation program, before taking any medication, or if you have or suspect you might have a health problem. You should not stop taking any medication without first consulting your physician.

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Life Extension Cancer Research Abstracts 2004

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Posted 28 Feb 2010 — by James Street
Category General Cancer Research, Life Extension Foundation

Please visit the Life Extension Foundation Web page for further information

and other reports on possible new cancer therapies:

Go to LEF Website Life Extension Cancer Research Abstracts

Life Extension Cancer Research Abstracts

Cancer Adjuvant Therapy
Updated: 08/26/2004

ABSTRACTS Prognostic value and expression of p21(waf1/cip1) protein in prostate cancer.

Aaltomaa S, Lipponen P, Eskelinen M, et al.

Prostate. 1999 Apr 1; 39(1):8-15.

BACKGROUND: p21(waf1/cip1) protein is a cyclin-dependent kinase inhibitor able to arrest the cell cycle at the G1 phase by inhibiting DNA replication. The expression of p21(waf1/cip1) and its prognostic value in prostate cancer are largely unexplored. METHODS: We used immunohistochemistry to analyze the expression of p21(waf1/cip1) in 213 prostate cancer cases, and the results were related to other known prognostic factors and patient survival during a long-term follow-up. RESULTS: The expression of p21 (waf1/cip1) protein was significantly associated with high Gleason score (P = 0.001), DNA aneuploidy (P = 0.013), high S-phase fraction (P = 0.019), and expression of Ki-67 (P = 0.021) and bcl-2 (P = 0.001) as well as cyclin A (P = 0.035) and D proteins (P<0.001). In univariate survival analysis the signal of p21(waf1/cip1) was significantly related to unfavorable prognosis (P = “0.010)” both in the entire cohort and in local tumors (P = “0.034).” In multivariate analysis, M-category, clinical T-category, Gleason score, and patient age were independent prognostic factors. In local tumors the expression of p21(waf1/cip1) together with clinical T-category and S-phase fraction were significant independent predictors of cancer related survival. CONCLUSIONS: The results suggest that the expression of p21(waf1/cip1) protein is associated both with cell proliferation and patient survival in prostate cancer

Breast Cancer Blues.

ABC News.

2000

Garlic revisited: therapeutic for the major diseases of our times?

Abdullah TH, Kandil O, Elkadi A, et al.

J Natl Med Assoc. 1988 Apr; 80(4):439-45.

Enhancement of natural killer cell activity in AIDS with garlic.

Abdullah TH.

Dtsch Z Onkol. 1989; 21

Immunosuppressive effect of tetrahydrocannabinol plus cyclophosphamide.

Ader R, Grota LJ.

N Engl J Med. 1981 Aug 20; 305(8):463.

Phytoestrogens: epidemiology and a possible role in cancer protection.

Adlercreutz H.

Environ Health Perspect. 1995 Oct; 103 Suppl 7:103-12.

Because many diseases of the Western Hemisphere are hormone-dependent cancers, we have postulated that the Western diet, compared to a vegetarian or semivegetarian diet, may alter hormone production, metabolism, or action at the cellular level by some biochemical mechanisms. Recently, our interest has been mainly focused on the cancer-protective role of some hormonelike diphenolic phytoestrogens of dietary origin, the lignans and the isoflavonoids. The precursors of the biologically active compounds originate in soybean products (mainly isoflavonoids), whole grain cereal food, seeds, and probably berries and nuts (mainly lignans). The plant lignan and isoflavonoid glycosides are converted by intestinal bacteria to hormonelike compounds with weak estrogenic but also antioxidative activity; they have now been shown to influence not only sex hormone metabolism and biological activity but also intracellular enzymes, protein synthesis, growth factor action, malignant cell proliferation, differentiation, and angiogenesis in a way that makes them strong candidates for a role as natural cancer-protective compounds. Epidemiologic investigations strongly support this hypothesis because the highest levels of these compounds in the diet are found in countries or regions with low cancer incidence. This report is a review on recent results suggesting that the diphenolic isoflavonoids and lignans are natural cancer-protective compounds

Phytoestrogens and breast cancer.

Adlercreutz H.

J Steroid Biochem Mol Biol. 2002 Dec; 83(1-5):113-8.

The role of phytoestrogens and consumption of phytoestrogen-rich foods such as soy containing isoflavones and whole grain products with lignans for the prevention of breast cancer is reviewed. It is concluded that soy-containing diet in adult women is not or only slightly protective with regard to breast cancer, but that it may be beneficial if consumed in early life before puberty or during adolescence supporting results of immigrant and epidemiological studies. No negative effects of soy on breast cancer have been observed. On the other hand, a diet low in lignans, resulting in a low plasma enterolactone concentration, increases risk both in a case-control and a prospective study, but some controversial results have also been obtained. Some of these results may be explained by the fact that the determinants of plasma or urinary enterolactone concentration are very different in different countries. In Scandinavia, the main determinants are whole grain cereal food, vegetables and berries. Whether the protective effect is caused by the phytoestrogens in the diet or whether they are only biomarkers of a healthy diet has not been established

all-trans retinoic acid enhances cisplatin-induced apoptosis in human ovarian adenocarcinoma and in squamous head and neck cancer cells.

Aebi S, Kroning R, Cenni B, et al.

Clin Cancer Res. 1997 Nov; 3(11):2033-8.

Cisplatin exerts its cytotoxicity by inducing apoptosis. Similarly, all-trans retinoic acid (ATRA) causes apoptosis in certain cells. We studied the interaction of cisplatin and ATRA in human ovarian adenocarcinoma cells 2008, in human head and neck squamous carcinoma cells UMSCC10b, and in their respective cisplatin-resistant sub-lines. ATRA enhanced the cytotoxicity of cisplatin. The interaction of the drugs was synergistic in combination index-isobologram analyses (combination index >0.5 at 50% cell survival) in all of the cell lines tested. ATRA inhibited the cellular accumulation of the cisplatin analogue [3H] cis-dichloroethylenediamineplatinum(II) by 22-33% in three of four cell lines tested but did not alter the cellular content of reduced glutathione. The expression of Bcl-2 relative to Bax decreased more after combined treatment with cisplatin and ATRA than after either drug alone. The apoptotic mechanism of cell death was confirmed by demonstrating cleavage of poly(ADP-ribose)polymerase and by morphological analysis. The combined treatment with ATRA and cisplatin induced apoptosis in significantly more cells than either drug alone. We conclude that ATRA enhances the cytotoxicity of cisplatin by facilitating apoptosis in ovarian and head and neck carcinoma cells

Lovastatin augments sulindac-induced apoptosis in colon cancer cells and potentiates chemopreventive effects of sulindac.

Agarwal B, Rao CV, Bhendwal S, et al.

Gastroenterology. 1999 Oct; 117(4):838-47.

BACKGROUND & AIMS: 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (HRIs) were found incidentally to reduce new cases of colon cancer in 2 large clinical trials evaluating coronary events, although most patients in both treatment and control group were taking nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs are associated with reduced colon cancer incidence, predominantly by increasing apoptosis. We showed previously that lovastatin induces apoptosis in colon cancer cells. In the present study we evaluated the potential of combining lovastatin with sulindac for colon cancer chemoprevention. RESULTS: Lovastatin, 10-30 micromol/L, augmented sulindac-induced apoptosis up to 5-fold in 3 colon cancer cell lines. This was prevented by mevalonate (100 micromol/L) or geranylgeranylpyrophosphate (10 micromol/L) but not farnesylpyrophosphate (100 micromol/L), suggesting inhibition of geranylgeranylation of target protein(s) as the predominant mechanism. In an azoxymethane rat model of chemical-induced carcinogenesis, the total number of colonic aberrant crypt foci per animal (control, 161 +/- 11) and the number of foci with 4+ crypts (control, 40 +/- 4.5) decreased to 142 +/- 14 (NS) and 43 +/- 2.9 (NS), respectively, with 50 ppm lovastatin alone; to 137 +/- 5.4 (P = 0.053) and 36 +/- 2.1 (NS) with 80 ppm sulindac alone; and to 116 +/- 8.1 (P = 0.004) and 28 +/- 3.4 (P = 0.02) when 50 ppm lovastatin and 80 ppm sulindac were combined. CONCLUSIONS: Addition of an HRI such as lovastatin may augment chemopreventive effects of NSAIDs or/and may allow lower, less toxic doses of these drugs to be used

Anticarcinogenic effect of a polyphenolic fraction isolated from grape seeds in human prostate carcinoma DU145 cells: modulation of mitogenic signaling and cell-cycle regulators and induction of G1 arrest and apoptosis.

Agarwal C, Sharma Y, Agarwal R.

Mol Carcinog. 2000 Jul; 28(3):129-38.

There is an increasing interest in identifying potent cancer preventive and therapeutic agents against prostate cancer (PCA). In a recent study, we showed that a polyphenolic fraction isolated from grape seeds (hereafter referred to as GSP) that is substantially rich in antioxidant procyanidins exerts exceptionally high preventive effects against tumorigenesis in a murine skin model. In the present study, we investigated the anticarcinogenic effect of GSP against PCA by employing DU145 human prostate carcinoma cells. GSP treatment (10-100 microg/mL doses for 2-6 d) of cells resulted in a highly significant (P < 0.01-0.001) inhibition of cell growth in both dose- and time-dependent manner. Compared with the vehicle, 2 d of GSP treatment resulted in 27, 39, and 76% growth inhibition at 50, 75, and 100 microg/mL doses, respectively, whereas 28-97% and 12-98% inhibition was evident at 10-100 microg/mL doses of GSP after 4 and 6 d of treatment, respectively. These doses of GSP also resulted in dose- and time-dependent cell death (6-50%, P <0.1-0. 001) that was later characterized as apoptotic death. In molecular mechanistic studies, treatment of DU145 cells with GSP at 25-75 microg/mL doses for 24, 48, and 72 h resulted in 77-88%, 65-93%, and 38-98% reduction, respectively (P < 0.001), in phospho-extracellular signal-regulated protein kinase (ERK) 1 and 78%, 19-76%, and 63-71% reduction (P < 0.1-0.001) in phospho-ERK2 levels, respectively. In other studies, similar doses of GSP showed up to 1.9-fold increases in Cip1/p21 and a significant (P < 0.001) decrease in cyclin-dependent kinase (CDK) 4 (up to 90% decrease), CDK2 (up to 50% decrease), and cyclin E (up to 60% decrease). GSP treatment of DU145 cells also resulted in a significant (P < 0.001) G1 arrest in cell-cycle progression in a dose-dependent manner. The growth-inhibitory and cell-death effects of GSP were also observed in another human PCA line, LNCaP. Together, these results suggest that GSP may exert strong anticarcinogenic effect against PCA and that this effect possibly involves modulation of mitogenic signaling and cell-cycle regulators and induction of G1 arrest, cell-growth inhibition, and apoptotic death. Mol. Carcinog. 28:129-138, 2000

Tomato lycopene and its role in human health and chronic diseases.

Agarwal S, Rao AV.

CMAJ. 2000 Sep 19; 163(6):739-44.

Lycopene is a carotenoid that is present in tomatoes, processed tomato products and other fruits. It is one of the most potent antioxidants among dietary carotenoids. Dietary intake of tomatoes and tomato products containing lycopene has been shown to be associated with a decreased risk of chronic diseases, such as cancer and cardiovascular disease. Serum and tissue lycopene levels have been found to be inversely related to the incidence of several types of cancer, including breast cancer and prostate cancer. Although the antioxidant properties of lycopene are thought to be primarily responsible for its beneficial effects, evidence is accumulating to suggest that other mechanisms may also be involved. In this article we outline the possible mechanisms of action of lycopene and review the current understanding of its role in human health and disease prevention

Histamine dihydrochloride: inhibiting oxidants and synergising IL-2-mediated immune activation in the tumour microenvironment.

Agarwala SS, Sabbagh MH.

Expert Opin Biol Ther. 2001 Sep; 1(5):869-79.

The potential role of histamine in cancer immunotherapy has been a subject of interest for more than a decade. A significant body of research has elucidated the action of histamine in a model system that mimics the tumour microenvironment. In vitro evidence indicates that histamine inhibits the generation and release of reactive oxygen species (ROS) by monocytes/macrophages (MO) during respiratory burst. Since ROS have been shown to abrogate peritumoural and intratumoural cytokine activation of natural killer (NK) and T-cells and induce apoptosis of these cells in vitro, inhibition of ROS may enable cytokines to activate NK and T-cells and restore their antineoplastic, cytotoxic capabilities. Experimental data indicate that histamine and interleukin-2 (IL-2) act synergistically to activate NK cell cytotoxicity (NKCC). Although IL-2, a regulator of immune responses, has been shown to promote NKCC in monotherapy for metastatic melanoma (MM), renal cell carcinoma (RCC) and acute myeloid leukaemia (AML), objective responses occur in a minority of patients and survival is not significantly extended, except for a minority of patients with MM using high-dose regimens which have not been widely adopted. In vitro findings suggest that the addition of histamine to IL-2 therapy might improve response rates and disease-free survival by protecting the cells of the immune system from oxidative stress and inducing natural endogenous immune cytotoxicity. An IL-2/histamine Phase III trial is in progress in a population of AML patients. A recently completed Phase III trial of IL-2 vs. IL-2/histamine in patients with MM demonstrated a trend towards a superior survival benefit from IL-2/histamine for all patients entered, and a statistically significant survival benefit for patients with hepatic metastases

Green tea polyphenol epigallocatechin-3-gallate differentially modulates nuclear factor kappaB in cancer cells versus normal cells.

Ahmad N, Gupta S, Mukhtar H.

Arch Biochem Biophys. 2000 Apr 15; 376(2):338-46.

Green tea has shown remarkable anti-inflammatory and cancer chemopreventive effects in many animal tumor bioassays, cell culture systems, and epidemiological studies. Many of these biological effects of green tea are mediated by epigallocatechin 3-gallate (EGCG), the major polyphenol present therein. We have earlier shown that EGCG treatment results in apoptosis of several cancer cells, but not of normal cells (J. Natl. Cancer Inst. 89, 1881-1886 (1997)). The mechanism of this differential response of EGCG is not known. In this study, we investigated the involvement of NF-kappaB during these differential responses of EGCG. EGCG treatment resulted in a dose-dependent (i) inhibition of cell growth, (ii) G0/G1-phase arrest of the cell cycle, and (iii) induction of apoptosis in human epidermoid carcinoma (A431) cells, but not in normal human epidermal keratinocytes (NHEK). Electromobility shift assay revealed that EGCG (10-80 microM) treatment results in lowering of NF-kappaB levels in both the cytoplasm and nucleus in a dose-dependent manner in both A431 cells and NHEK, albeit at different concentrations. EGCG treatment was found to result in a dose-based differential inhibition of TNF-alpha- and LPS-mediated activation of NF-kappaB in these cells. The inhibition of NF-kappaB constitutive expression and activation in NHEK was observed only at high concentrations. The immunoblot analysis also demonstrated a similar pattern of inhibition of the constitutive expression as well as activation of NF-kappaB/p65 nuclear protein. This inhibition of TNF-alpha-caused NF-kappaB activation was mediated via the phosphorylative degradation of its inhibitory protein IkappaBalpha. Taken together, EGCG was found to impart differential dose-based NF-kappaB inhibitory response in cancer cells vs normal cells; i.e., EGCG-mediated inhibition of NF-kappaB constitutive expression and activation was found to occur at much higher dose of EGCG in NHEK as compared to A431 cells. This study suggests that EGCG-caused cell cycle deregulation and apoptosis of cancer cells may be mediated through NF-kappaB inhibition

Pro-oxidant, anti-oxidant and cleavage activities on DNA of curcumin and its derivatives demethoxycurcumin and bisdemethoxycurcumin.

Ahsan H, Parveen N, Khan NU, et al.

Chem Biol Interact. 1999 Jul 1; 121(2):161-75.

Curcumin, a naturally occurring phytochemical responsible for the colour of turmeric shows a wide range of pharmacological properties including antioxidant, anti-inflammatory and anti-cancer effects. We have earlier shown that curcumin in the presence of Cu(II) causes strand cleavage in DNA through generation of reactive oxygen species, particularly the hydroxyl radical. Thus, curcumin shows both antioxidant as well as pro-oxidant effects. In order to understand the chemical basis of various biological properties of curcumin, we have studied the structure-activity relationship between curcumin and its two naturally occurring derivatives namely demethoxycurcumin (dmC) and bisdemethoxycurcumin (bdmC). Curcumin was found to be the most effective in the DNA cleavage reaction and a reducer of Cu(II) followed by dmC and bdmC. The rate of formation of hydroxyl radicals by the three curcuminoids also showed a similar pattern. The relative antioxidant activity was examined by studying the effect of these curcuminoids on cleavage of plasmid DNA by Fe(II)-EDTA system (hydroxyl radicals) and the generation of singlet oxygen by riboflavin. The results indicate that curcumin is considerably more active both as an antioxidant as well as an oxidative DNA cleaving agent. The DNA cleavage activity is the consequence of binding of Cu(II) to various sites on the curcumin molecule. Based on the present results, we propose three binding sites for Cu(II). Two of the sites are provided by the phenolic and methoxy groups on the two benzene rings and the third site is due to the presence of 1,3-diketone system between the rings. Furthermore, both the antioxidant as well as pro-oxidant effects of curcuminoids are determined by the same structural moieties

Beneficial effects of sun exposure on cancer mortality.

Ainsleigh HG.

Prev Med. 1993 Jan; 22(1):132-40.

For more than 50 years, there has been documentation in the medical literature suggesting that regular sun exposure is associated with substantial decreases in death rates from certain cancers and a decrease in overall cancer death rates. Recent research suggests that this is a causal relationship that acts through the body’s vitamin D metabolic pathways. The studies reviewed here show that (a) sunlight activation is our most effective source of vitamin D; (b) regular sunlight/vitamin D “intake” inhibits growth of breast and colon cancer cells and is associated with substantial decreases in death rates from these cancers; (c) metabolites of vitamin D have induced leukemia and lymphoma cells to differentiate, prolonged survival of leukemic mice, and produced complete and partial clinical responses in lymphoma patients having high vitamin D metabolite receptor levels in tumor tissue; (d) sunlight has a paradoxical relationship with melanoma, in that severe sunburning initiates melanoma whereas long-term regular sun exposure inhibits melanoma; (e) frequent regular sun exposure acts to cause cancers that have a 0.3% death rate with 2,000 U.S. fatalities per year and acts to prevent cancers that have death rates from 20-65% with 138,000 U.S. fatalities per year; (f) there is support in the medical literature to suggest that the 17% increase in breast cancer incidence during the 1991-1992 year may be the result of the past decade of pervasive anti-sun advisories from respected authorities, coinciding with effective sunscreen availability; and (g) trends in the epidemiological literature suggest that approximately 30,000 U.S. cancer deaths yearly would be averted by the widespread public adoption of regular, moderate sunning.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of invasion, gelatinase activity, tumor take and metastasis of malignant cells by N-acetylcysteine.

Albini A, D’Agostini F, Giunciuglio D, et al.

Int J Cancer. 1995 Mar 29; 61(1):121-9.

The thiol N-acetylcysteine (NAC) is currently considered one of the most promising cancer chemopreventive agents by virtue of its multiple and coordinated mechanisms affecting the process of chemical carcinogenesis. Recent studies have shown that an unpaired cysteine residue in the propeptide plays a key role in inactivation of latent metastasis-associated metalloproteinases: the present study was designed to assess whether NAC could also affect tumor take, invasion and metastasis of malignant cells. As assessed by zymographic analysis, NAC completely inhibited the gelatinolytic activity of type-IV collagenases in the cells tested (gelatinases A and B). Moreover, NAC was efficient in inhibiting the chemotactic and invasive activities of tumor cells of human (A2058 melanoma) and murine origin (K1735 and B16-F10 melanoma cells as well as C87 Lewis lung carcinoma cells) in Boyden-chamber assays, which are predictive of the invasive and metastatic properties. Reduced glutathione (GSH) had a similar, although less effective activity. The number of lung metastases decreased sharply when B16-F10 murine melanoma cells, injected i.v. into nude mice, were pre-treated with NAC and resuspended in medium supplemented with 10 mM NAC. In other experiments NAC was given in drinking water, starting 48-72 hr before subcutaneous inoculation of either B16-F10 cells or of their highly metastatic variant B16-BL6, or intramuscular injection of LLC cells. In all experiments NAC treatment decreased the weight of the locally formed primary tumor and produced a dose-related delay in tumor formation. Spontaneous metastasis formation by B16-F10 and B16-BL6 tumors was slightly yet significantly reduced by oral administration of NAC. However, this was not observed for Lewis lung tumors. These data indicate that NAC affects the process of tumor-cell invasion and metastasis, probably due to inhibition of gelatinases by its sulfhydryl group, with the possible contribution of other mechanisms, including the potent antioxidant activity of this thiol

Soy diets containing varying amounts of genistein stimulate growth of estrogen-dependent (MCF-7) tumors in a dose-dependent manner.

Allred CD, Allred KF, Ju YH, et al.

Cancer Res. 2001 Jul 1; 61(13):5045-50.

We have demonstrated that the isoflavone, genistein, stimulates growth of estrogen-dependent human breast cancer (MCF-7) cells in vivo (C. Y. Hsieh et al., Cancer Res., 58: 3833-3838, 1998). The isoflavones are a group of phytoestrogens that are present in high concentrations in soy. Whether consumption of genistein from soy protein will have similar effects on estrogen-dependent tumor growth as pure genistein has not been investigated in the athymic mouse tumor implant model. Depending on processing, soy protein isolates vary widely in concentrations of genistein. We hypothesize that soy isolates containing different concentrations of genistein will stimulate the growth of estrogen-dependent cells in vivo in a dose-dependent manner. To test this hypothesis we conducted experiments in which these soy protein isolates were fed to athymic mice implanted s.c. with estrogen-dependent tumors. Genistein content (aglycone equivalent) of the soy isolate diets were 15, 150, or 300 ppm. Positive (with 17beta-estradiol pellet implant) and negative (no 17beta-estradiol) control groups received casein-based (isoflavone-free) diets. Tumor size was measured weekly. At completion of the study animals were killed and tumors collected for evaluation of cellular proliferation and estrogen-dependent gene expression. Incorporation of bromodeoxyuridine into cellular DNA was used as an indicator of cell proliferation, and pS2 mRNA was used as an estrogen-responsive gene. Soy protein diets containing varying amounts of genistein increased estrogen-dependent tumor growth in a dose-dependent manner. Cell proliferation was greatest in tumors of animals given estrogen or dietary genistein (150 and 300 ppm). Expression of pS2 was increased in tumors from animals consuming dietary genistein (150 and 300 ppm). Here we present new information that soy protein isolates containing increasing concentrations of genistein stimulate the growth of estrogen-dependent breast cancer cells in vivo in a dose-dependent manner

ACS Monograph 173: Chemical Carcinogens 1976.

American Chemical Society.

1976

Helicobactor pylori Infection 2002.

Analyst.

2002;Mar 2002

Stress and immune responses after surgical treatment for regional breast cancer.

Andersen BL, Farrar WB, Golden-Kreutz D, et al.

J Natl Cancer Inst. 1998 Jan 7; 90(1):30-6.

BACKGROUND: Adults who undergo chronic stress, such as the diagnosis and surgical treatment of breast cancer, often experience adjustment difficulties and important biologic effects. This stress can affect the immune system, possibly reducing the ability of individuals with cancer to resist disease progression and metastatic spread. We examined whether stress influences cellular immune responses in patients following breast cancer diagnosis and surgery. METHODS: We studied 116 patients recently treated surgically for invasive breast cancer. Before beginning their adjuvant therapy, all subjects completed a validated questionnaire assessing the stress of being cancer patients. A 60-mL blood sample taken from each patient was subjected to a panel of natural killer (NK) cell and T-lymphocyte assays. We then developed multiple regression models to test the contribution of psychologic stress in predicting immune function. All regression equations controlled for variables that might exert short- or long-term effects on these responses, and we also ruled out other potentially confounding variables. RESULTS: We found, reproducibly between and within assays, the following: 1) Stress level significantly predicted lower NK cell lysis, 2) stress level significantly predicted diminished response of NK cells to recombinant interferon gamma, and 3) stress level significantly predicted decreased proliferative response of peripheral blood lymphocytes to plant lectins and to a monoclonal antibody directed against the T-cell receptor. CONCLUSIONS: The data show that the physiologic effects of stress inhibit cellular immune responses that are relevant to cancer prognosis, including NK cell toxicity and T-cell responses. Additional, longitudinal studies are needed to determine the duration of these effects, their health consequences, and their biologic and/or behavioral mechanisms

Oral glutamine reduces the duration and severity of stomatitis after cytotoxic cancer chemotherapy.

Anderson PM, Schroeder G, Skubitz KM.

Cancer. 1998 Oct 1; 83(7):1433-9.

BACKGROUND: Mouth sores and/or difficulty swallowing are common and painful consequences of cytotoxic chemotherapy for cancer. In previous studies oral glutamine was found to protect animals from the effects of whole abdominal radiation and methotrexate-induced enteritis. Glutamine also was found to reduce oral mucositis in a nonrandomized pilot study in humans. Therefore, the authors attempted to determine the efficacy of oral glutamine in a randomized, double blind, crossover trial in cancer patients receiving chemotherapy. METHODS: Twenty-four patients (16 children and 8 adults) received glutamine or placebo (glycine) suspension (2 g amino acid/M2/dose twice daily) to swish and swallow on days of chemotherapy administration and for at least 14 additional days. Patients completed a calendar indicating days of mouth pain associated with each chemotherapy course and the effect of mouth pain on oral intake. RESULTS: Paired data indicated significant amelioration of stomatitis associated with glutamine administration after chemotherapy. The duration of mouth pain was 4.5 days less in chemotherapy courses in which glutamine supplementation was compared with placebo (Wilcoxon’s signed rank test, P=0.0005). The severity of oral pain also was reduced significantly when glutamine was provided with chemotherapy (the amount of days mucositis restricted oral intake to soft foods [> or =Grade 2; Modified Eastern Cooperative Oncology Group grading system] was 4 days less with glutamine compared with placebo; Wilcoxon’s signed rank test, P=0.002). CONCLUSIONS: Low dose oral glutamine supplementation during and after chemotherapy significantly reduced both the duration and severity of chemotherapy-associated stomatitis. Oral glutamine appears to be a simple and useful measure to increase the comfort of many patients at high risk of developing mouth sores as a consequence of intensive cancer chemotherapy

Migration and prostate cancer: an international perspective.

Angwafo FF.

J Natl Med Assoc. 1998 Nov; 90(11 Suppl):S720-S723.

There are intra- and interracial differences in prostate cancer incidence and mortality rates worldwide. The environment and migration patterns seem to influence the disparities in cancer statistics. The lowest incidence rate is recorded in Chinese, followed by other Asians, South Americans, southern Europeans, and northern Europeans, in ascending order. However, people of African descent have the highest incidence so far. Until recently, African Americans in Alameda County (California) in the United States had the highest reported incidence (160/1000,000). An incidence of 314/100,000 recently was reported in African Caribbeans from Jamaica. These high rates contrast with the low incidence rates reported in continental (Sub-Saharan) Africa. Angwafo et al have reported higher age-adjusted incidence rates in Yaounde, Cameroon (93.8/100,000). They highlighted the importance of diagnostic methodology, availability of and access to diagnostic techniques and trained manpower, and adjustments for the age distribution of populations when comparing incidence rates between regions. The great disparity in cancer statistics over large geographic areas and races has oriented studies toward genes and gene products susceptible to environmental risk factors such as diet, ultraviolet rays, and cadmium, which may be associated with or causative of prostate cancer. Randomized studies on suspected risk factors and promoters of prostate cancer need to be conducted worldwide. However, caution is in order when inferences are made comparing populations with access to health care to those without

Effects of high doses of vitamins C and E against doxorubicin-induced chromosomal damage in Wistar rat bone marrow cells.

Antunes LM, Takahashi CS.

Mutat Res. 1998 Nov 9; 419(1-3):137-43.

Doxorubicin (DXR) is one of the major antitumoral agents available for clinical use. In addition to intercalating into the DNA molecule, this drug generates free radicals. Vitamins C (VC) and E (VE) can protect normal cells from the damage caused by radicals without interfering with the cytotoxicity of DXR against tumors. The objective of the present study was to investigate the possible protective effect of VC and/or VE on mammalian cells treated with DXR in vivo. Animals treated with the lowest doses of VC and/or VE, alone or in combination, plus a single dose of DXR presented a statistically significant reduction in total number of chromosome aberrations and in number of abnormal metaphases. The highest vitamin doses tested caused no changes in the parameters analyzed when compared with control. Under the present experimental conditions, the efficiency of VC and/or VE in protecting against chromosome damage was dependent on the dose used

Estrogen receptor beta mRNA in colon cancer cells: growth effects of estrogen and genistein.

Arai N, Strom A, Rafter JJ, et al.

Biochem Biophys Res Commun. 2000 Apr 13; 270(2):425-31.

Knowledge regarding the expression of the recently cloned estrogen receptor beta (ERbeta) in colonic mucosa is limited. In this study, we demonstrated that five human colon cancer cell lines, HT29, Colo320, Lovo, SW480, and HCT116, expressed ERbeta mRNA, but lacked ERalpha mRNA. Results from a cell growth assay demonstrated that these colon cancer cells were not influenced by estrogen, while genistein possessed slight growth inhibitory effects on HT29, Colo320 and Lovo cells at 10 microM, at which concentration is stimulated the growth of ERalpha-positive human breast cancer MCF-7 cells. Tamoxifen inhibited the growth of HT29 and Colo320 cells, dose-dependently, as well as MCF-7 cells. A transfected reporter plasmid containing a vitellogenin estrogen response element could be activated by estradiol in Colo320 cells. Taken together with previous reports, these data suggest that ERalpha and ERbeta may have different biological functions in colon cells

Curcumin is an in vivo inhibitor of angiogenesis.

Arbiser JL, Klauber N, Rohan R, et al.

Mol Med. 1998 Jun; 4(6):376-83.

BACKGROUND: Curcumin is a small-molecular-weight compound that is isolated from the commonly used spice turmeric. In animal models, curcumin and its derivatives have been shown to inhibit the progression of chemically induced colon and skin cancers. The genetic changes in carcinogenesis in these organs involve different genes, but curcumin is effective in preventing carcinogenesis in both organs. A possible explanation for this finding is that curcumin may inhibit angiogenesis. MATERIALS AND METHODS: Curcumin was tested for its ability to inhibit the proliferation of primary endothelial cells in the presence and absence of basic fibroblast growth factor (bFGF), as well as its ability to inhibit proliferation of an immortalized endothelial cell line. Curcumin and its derivatives were subsequently tested for their ability to inhibit bFGF-induced corneal neovascularization in the mouse cornea. Finally, curcumin was tested for its ability to inhibit phorbol ester-stimulated vascular endothelial growth factor (VEGF) mRNA production. RESULTS: Curcumin effectively inhibited endothelial cell proliferation in a dose-dependent manner. Curcumin and its derivatives demonstrated significant inhibition of bFGF-mediated corneal neovascularization in the mouse. Curcumin had no effect on phorbol ester-stimulated VEGF production. CONCLUSIONS: These results indicate that curcumin has direct antiangiogenic activity in vitro and in vivo. The activity of curcumin in inhibiting carcinogenesis in diverse organs such as the skin and colon may be mediated in part through angiogenesis inhibition

Proliferation of cultured human astrocytoma cells in response to an oxidant and antioxidant.

Arora-Kuruganti P, Lucchesi PA, Wurster RD.

J Neurooncol. 1999; 44(3):213-21.

The role of reactive oxygen species (ROS) in initiation, promotion and progression of several (lung, skin, colon, bladder, breast) tumors is well-documented. Indirect evidence for ROS involvement in tumor proliferation is provided by numerous in vivo and in vitro studies that show antioxidants inhibit tumor proliferation. However, despite strong epidemiological and experimental support for ROS involvement in brain tumor proliferation, to date little is known about the role of ROS in brain tumor promotion at a cellular level. In the present study ROS involvement in proliferation of a cultured, human astrocytoma cell line (U373-MG) was tested by studying effects of an oxidant (hydrogen peroxide, H2O2), and an antioxidant (N-acetylcysteine, NAC) on astrocytoma on proliferation of these cultured cells. Proliferation was assessed by evaluating changes in cell counts and DNA synthesis. Results from these experiments clearly indicate that NAC inhibits tumor cell proliferation and DNA synthesis induced by both serum and H2O2 (10(-5) M). NAC alone did not have any significant effects on the proliferation of serum-starved cells. Thus, ROS are capable of inducing proliferation in cultured astrocytoma cells and antioxidants block ROS- and serum-induced proliferation. Further investigation using primary cultures and animal models will be needed to substantiate the therapeutic potential of antioxidants in future brain tumor therapy

Selenium in the immune system.

Arthur JR, McKenzie RC, Beckett GJ.

J Nutr. 2003 May; 133(5 Suppl 1):1457S-9S.

Selenium as an essential component of selenocysteine-containing protein is involved in most aspects of cell biochemistry and function. As such, there is much potential for selenium to influence the immune system. For example, the antioxidant glutathione peroxidases are likely to protect neutrophils from oxygen-derived radicals that are produced to kill ingested foreign organisms. When the functions of all selenoproteins are described, only then will it be possible to fully understand their role in maintaining optimal immune function

Induction of interferon and activation of NK cells and macrophages in mice by oral administration of Ge-132, an organic germanium compound.

Aso H, Suzuki F, Yamaguchi T, et al.

Microbiol Immunol. 1985; 29(1):65-74.

After oral administration of an organic germanium compound, Ge-132 (300 mg/kg), a significant level of interferon (IFN) activity was detected in the sera of mice at 20 hr and it reached a maximum of 320 U/ml at 24 hr. This IFN activity was lost after heat- or acid-treatment, suggesting that the induced IFN is of gamma-nature. The molecular weight of this IFN was estimated to be 50,000 daltons by gel filtration. The NK activity of spleen cells was increased 24 hr after the oral administration of Ge-132, and cytotoxic macrophages were induced in the peritoneal cavity by 48 hr. In the mice receiving an intraperitoneal (ip) injection of trypan blue or carrageenan 2 days before oral administration of Ge-132, neither induction of IFN nor augmentation of NK activity occurred, and X-ray irradiation of mice also rendered the mice incapable of producing IFN, all indicating that both macrophages and lymphocytes are required for this IFN induction. Both NK and cytotoxic macrophages appeared 18 hr after ip administration of the induced IFN with a titer as low as 20 U/ml. These facts suggest that both the augmentation of NK activity and activation of macrophages in mice after oral administration of Ge-132 are mediated by the induced IFN

Resveratrol, a natural product derived from grapes, is a new inducer of differentiation in human myeloid leukemias.

Asou H, Koshizuka K, Kyo T, et al.

Int J Hematol. 2002 Jun; 75(5):528-33.

A natural product, resveratrol (3,4,40-trihydroxy-trans-stilbene), a phytoalexin found in grapes and other food products, is known as a cancer chemopreventive agent. We studied the in vitro biological activity of this compound by examining its effect on proliferation and differentiation in myeloid leukemia cell lines (HL-60, NB4, U937,THP-1, ML-1, Kasumi-1) and fresh samples from 17 patients with acute myeloid leukemia. Resveratrol (20 microM, 4 days) alone inhibited the growth in liquid culture of each of the 6 cell lines. Resveratrol (10 microM) enhanced the expression of adhesion molecules (CD11a, CD11b, CD18, CD54) in each of the cell lines except for Kasumi-1. Moreover, resveratrol (25 microM, 4 days) induced 37% of U937 cells to produce superoxide as measured by the ability to reduce nitroblue tetrazolium (NBT). The combination of resveratrol (10 microM) and all-trans-retinoic acid (ATRA) (50 nM, 4 days) induced 95% of the NB4 cells to become NBT-positive, whereas <1% and 12% of the cells became positive for NBT after a similar exposure to either resveratrol or ATRA alone, respectively. In U937 cells exposed to resveratrol (25 microM, 3 days), the binding activity of nuclear factor-kappaB (NFkappaB) protein was suppressed. Eight of 19 samples of fresh acute leukemia cells reduced NBT after exposure to resveratrol (20 microM, 4 days). Taken together, these findings show that resveratrol inhibits proliferation and induces differentiation of myeloid leukemia cells

Ingestion of green tea rapidly decreases prostaglandin E2 levels in rectal mucosa in humans.

August DA, Landau J, Caputo D, et al.

Cancer Epidemiol Biomarkers Prev. 1999 Aug; 8(8):709-13.

The objective of this Phase I/II study was to assess the potential for green tea to be used as a colorectal cancer chemopreventive agent. This study measured the dose-related biological effects of administration of a single dose of green tea on the rectal mucosa of normal volunteers. Volunteers were admitted to the Robert Wood Johnson Medical School Clinical Research Center for 24 h. Baseline blood and rectal biopsy samples were obtained before the volunteers drank 0.6, 1.2, or 1.8 g of green tea solids dissolved in warm water. Blood samples were taken 2, 4, 8, and 24 h after the tea administration. Rectal biopsies were obtained at 4, 8, and 24 h. Prostaglandin E2 (PGE2) levels were analyzed by ELISA. Tea polyphenol levels in the blood, urine, and rectal tissue were measured by high-performance liquid chromatography using a Coulochem electrode array detection system. Statistical comparisons were made using ANOVA. Decreased levels of PGE2 in rectal mucosa were observed at 4 and 8 h after consumption of green tea. There was no correlation between inhibition of PGE2 and tissue or plasma levels of tea polyphenols. Ten of 14 subjects demonstrated a response to green tea, as evidenced by at least a 50% inhibition of PGE2 levels at 4 h. We conclude that green tea constituents have biological activity in inhibiting PGE2 synthesis. Given the 71% “response rate,” we believe these data support the study of green tea as a colorectal chemopreventive agent in more long-term Phase II trials

Signal transduction for proliferation of glioma cells in vitro occurs predominantly through a protein kinase C-mediated pathway.

Baltuch GH, Yong VW.

Brain Res. 1996 Feb 26; 710(1-2):143-9.

Previous work has demonstrated that glioma cells have very high protein kinase C (PKC) enzyme activity when compared to non-malignant glia, and that their PKC activity correlates with their proliferation rate. The purpose of this study was to determine whether the elevated PKC activity in glioma is secondary to an autonomously active PKC isoform implying oncogenic transformation, or whether this activity is driven by upstream ligand-receptor tyrosine kinase interactions. We treated established human glioma cell lines A172, U563 or U251 with either the highly selective PKC inhibitor CGP 41 251, or with genistein, a tyrosine kinase inhibitor. The proliferation rate and PKC activity of all the glioma lines was reduced by CGP 41 251; the IC50 values for inhibiting cell proliferation corresponded to the IC50v values for inhibition of PKC activity. Genistein also inhibited cell proliferation, with IC50 proliferation values approximating those for inhibition of tyrosine kinase activity in cell free protein extracts. Importantly, in genistein-treated cells, downstream PKC enzyme activity was dose dependently reduced such that the correlation coefficient for effects of genistein on proliferation rate and PKC activity was 0.92. These findings suggest that upstream tyrosine kinase linked events, rather than an autonomously functioning PKC, result in the high PKC activity observed in glioma. Finally, fetal calf serum (FCS) evoked a strong mitogenic effect on glioma cell lines. This mitogenic activity was completely blocked by CGP 41 251, suggesting that although the many mitogens in FCS for glioma cells signal initially through genistein-inhibitable tyrosine kinases, they ultimately channel through a PKC-dependent pathway. We conclude that proliferative signal transduction in glioma cells occurs through a predominantly PKC-dependent pathway and that selectively targeting this enzyme provides an approach to glioma therapy

Decrease in linoleic acid metabolites as a potential mechanism in cancer risk reduction by conjugated linoleic acid.

Banni S, Angioni E, Casu V, et al.

Carcinogenesis. 1999 Jun; 20(6):1019-24.

Previous research suggested that conjugated linoleic acid (CLA) feeding during the period of pubescent mammary gland development in the rat resulted in diminished mammary epithelial branching which might account for the reduction in mammary cancer risk. Terminal end buds (TEB) are the primary sites for the chemical induction of mammary carcinomas in rodents. One of the objectives of the present study was to investigate the modulation of TEB density by increasing levels of dietary CLA and to determine how this might affect the risk of methylnitrosourea-induced mammary carcinogenesis. The data show a graded and parallel reduction in TEB density and mammary tumor yield produced by 0.5 and 1% CLA. No further decrease in either parameter was observed when CLA in the diet was raised to 1.5 or 2%. Thus, optimal CLA nutrition during pubescence could conceivably control the population of cancer-sensitive target sites in the mammary gland. Since both CLA and linoleic acid are likely to share the same enzyme system for chain desaturation and elongation, it is possible that increased CLA intake may interfere with the further metabolism of linoleic acid. Fatty acid analysis of total lipid showed that CLA and CLA metabolites continued to accumulate in mammary tissue in a dose-dependent manner over the range 0.5-2% CLA. There was no perturbation in tissue linoleic acid, however, linoleic acid metabolites (including 18:3, 20:3 and 20:4) were consistently depressed by up to 1% CLA. Of particular interest was the significant drop in 20:4 (arachidonic acid), which is the substrate for the cyclooxygenase and lipoxygenase pathways of eicosanoid biosynthesis. Thus the CLA dose-response effect on arachidonic acid suppression corresponded closely with the CLA dose-response effect on cancer protection in the mammary gland. This information is critical in providing new insights regarding the biochemical action of CLA

Differential response of estrogen receptor alpha and estrogen receptor beta to partial estrogen agonists/antagonists.

Barkhem T, Carlsson B, Nilsson Y, et al.

Mol Pharmacol. 1998 Jul; 54(1):105-12.

The existence of two rather than one estrogen receptor, today characterized as estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta), indicates that the mechanism of action of 17beta-estradiol and related synthetic drugs is more complex than previously thought. Because the homology of amino acid residues in the ligand-binding domain (LBD) of ERbeta is high compared with those amino acid residues in ERalpha LBD, previously shown to line the ligand binding cavity or to make direct contacts with ligands, it is not surprising that many ligands have a similar affinity for both receptor subtypes. We report that 17alpha-ethynyl, 17beta-estradiol, for example, has an ERalpha-selective agonist potency and that 16beta,17alpha-epiestriol has an ERbeta-selective agonist potency. We also report that genistein has an ERbeta-selective affinity and potency but an ERalpha-selective efficacy. Furthermore, we show that tamoxifen, 4-OH-tamoxifen, raloxifene, and ICI 164,384 have an ERalpha-selective partial agonist/antagonist function but a pure antagonist effect through ERbeta. In addition, raloxifene displayed an ERalpha-selective antagonist potency, in agreement with its ERalpha-selective affinity. However, although ICI 164,384 showed an ERbeta-selective affinity, it had a similar potency to antagonize the effect of 17beta-estradiol in the ERalpha- and ERbeta-specific reporter cell lines, respectively. In conclusion, our data indicate that the ligand binding cavity of ERbeta is probably more different from that of ERalpha than can be anticipated from the primary sequences of the two ER subtypes and that it will be possible to develop receptor-specific ligands that may form the basis of novel pharmaceuticals with better in vivo efficacy and side effect profile than current available drugs

Combined supplementation of vanadium and 1alpha,25-dihydroxyvitamin D(3) inhibit diethylnitrosamine-induced rat liver carcinogenesis.

Basak R, Basu M, Chatterjee M.

Chem Biol Interact. 2000 Aug 15; 128(1):1-18.

A combination of a differentiation-inducing agent like 1alpha, 25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] with a compound that blocks entry of calcium into cells like vanadium (V) may offer a new approach to differentiation therapy and address the problem of hypercalcemia. Initiation of hepatocarcinogenesis was performed by a single intraperitoneal injection of diethylnitrosamine (DEN) (200 mg/kg b.wt.) in male Sprague-Dawley rats. Supplementation of V, 1, 25(OH)(2)D(3), or both V and 1,25(OH)(2)D(3) were started 4 weeks prior to DEN injection and continued thereafter till 20th week. It was observed that supplementation of V (0.5 ppm) in drinking water ad libitum or 1,25(OH)(2)D(3) (3 microg/ml propylene glycol) per os twice weekly for the entire period of the experiment significantly reduces the number and size of hyperplastic nodules while the combination treatment offered an additive effect in reducing it to 37.5% from 83.3%. V-1,25(OH)(2)D(3) combination was also effective in elevating the level of hepatic microsomal cytochrome P-450 (Cyt. P-450) (P<0.001). Moreover, A significant reduced level of cytosolic glutathione (GSH) (P<0.001) and glutathione S-transferase (GST) (P<0.001) activity as well as reduction in the appearance of gamma-glutamyltranspeptidase (GGT)-positive foci (P<0.001) as compared to carcinogen control were observed in V plus 1, 25(OH)(2)D(3) treated group. These results suggest that V may be useful in combination with 1,25(OH)(2)D(3) in the inhibition of experimental rat hepatocarcinogenesis

Inositol-phosphate-induced enhancement of natural killer cell activity correlates with tumor suppression.

Baten A, Ullah A, Tomazic VJ, et al.

Carcinogenesis. 1989 Sep; 10(9):1595-8.

In recent studies, we have demonstrated that inositol hexaphosphate (InsP6) inhibits experimental colon carcinogenesis. Since natural killer (NK) cells are involved in tumor cell destruction, we investigated the effect of InsP6 on murine NK cell activity. We show that; (i) 1,2-dimethylhydrazine (DMH), a colon carcinogen, depresses NK activity; (ii) in vivo treatment of mice with InsP6 enhances baseline NK activity and reverses DMH-induced depressed NK activity with an inverse correlation (r = -0.9811) with tumor incidence, (iii) short-term in vitro treatment of spleen cells and NK-enriched fraction with InsP6 also enhances NK cytotoxicity in a dose-dependent manner, (iv) inositol potentiates the action of InsP6. Our data suggest yet another important role of inositol phosphates in the regulation of cellular activity

Vitamin Protects Against Cancer 2000 Aug 22.

BBC News.

BBC News. 2000;2000 Aug 22

Effect of natural beta-carotene supplementation in children exposed to radiation from the Chernobyl accident.

Ben Amotz A, Yatziv S, Sela M, et al.

Radiat Environ Biophys. 1998 Oct; 37(3):187-93.

Attempts were made to evaluate 709 children (324 boys and 385 girls) who had been exposed long-term to different doses of radiation during and after the Chernobyl accident and had moved to Israel between 1990 and 1994. Upon arrival, all of them underwent a check-up for most common clinical disorders and were then divided into three groups according to their residences (distance from the reactor) and the level of irradiation exposure: no radiation, 5 Ci/m2, respectively. Blood serum analyses for total carotenoids, retinol, alpha-tocopherol and oxidized conjugated dienes in 262 of the children showed increased HPLC levels of conjugated dienes, indicating increased levels of oxidation of in vivo blood lipids in children from the contaminated areas. The levels were higher in girls than in boys. Some 57 boys and 42 girls were given a basal diet with a diurnal supplementation of 40 mg natural 9-cis and all-trans equal isomer mixture beta-carotene in a capsulated powder form of the alga Dunaliella bardawil, for a period of 3 months. Blood serum analyses were regularly conducted before supplementation to determine the baseline effect of radiation exposure to the children, after 1 and 3 months of natural beta-carotene supplementation. After supplementation, the levels of the oxidized conjugated dienes decreased in the children’s sera without any significant changes in the level of total carotenoids, retinol or alpha-tocopherol. Other common blood biochemicals were within the normal range for all tests and no statistical differences before or after supplementation of beta-carotene were noted. High pressure liquid chromatography (HPLC) analyses for carotenoids in the blood detected mainly oxycarotenoids, and to a lesser extent, all-trans beta-carotene, alpha-carotene, but not 9-cis beta-carotene. The results suggest that irradiation increases the susceptibility of lipids to oxidation in the Chernobyl children and that natural beta-carotene may act as an in vivo lipophilic antioxidant or radioprotector

Evidence that stress and surgical interventions promote tumor development by suppressing natural killer cell activity.

Ben Eliyahu S, Page GG, Yirmiya R, et al.

Int J Cancer. 1999 Mar 15; 80(6):880-8.

Stress and surgery have been suggested to compromise host resistance to infectious and malignant diseases in experimental and clinical settings. Because stress affects numerous physiological systems, the role of the immune system in mediating such effects is unclear. In the current study, we assessed the degree to which stress-induced alterations in natural killer (NK) cell activity underlie increased susceptibility to tumor development in F344 rats. Two stress paradigms were used: forced swim and abdominal surgery. Host resistance to tumor development was studied using 3 tumor models syngeneic to inbred F344 rats: CRNK-16 leukemia and the MADB106 mammary adenocarcinoma, both sensitive to NK activity, and the NK-insensitive C4047 colon cancer. Swim stress increased CRNK-16-associated mortality and metastatic development of MADB106 but not metastasis of C4047 cells. In both stress paradigms, stress suppressed NK activity (NKA) for a duration that paralleled its metastasis-enhancing effects on the MADB106 tumor. In vivo depletion of large granular lymphocyte/NK cells abolished the metastasis-enhancing effects of swim stress but not of surgical stress. Our findings indicate that stress-induced suppression of NKA is sufficient to cause enhanced tumor development. Under certain stressful conditions, suppression of NKA is the primary mediator of the tumor-enhancing effects of stress, while under other conditions, additional factors play a significant role. Clinical circumstances in which surgical stress may induce enhanced metastatic growth are discussed

Suppression of NK cell activity and of resistance to metastasis by stress: a role for adrenal catecholamines and beta-adrenoceptors.

Ben Eliyahu S, Shakhar G, Page GG, et al.

Neuroimmunomodulation. 2000; 8(3):154-64.

Although acute stress has been reported to suppress natural killer cell activity (NKA) and host resistance to metastasis, it is unclear whether the sympathetic nervous system (SNS) has a role in these effects. The current study in Fischer 344 rats assessed the involvement of adrenal catecholamines and beta(1)- and beta(2)-adrenoceptors in mediating these deleterious effects of swim stress. In addition to assessing the number and activity of NK cells following swim stress, we used a tumor model based on the MADB106 mammary adenocarcinoma line: this syngeneic tumor metastasizes only to the lungs, and its lung tumor retention (LTR) and metastatic colonization are highly sensitive to NKA. The findings indicate that stress increased both LTR, assessed 24 h after inoculation, and the number of lung metastases, counted 3 weeks later. These effects were attenuated or completely abolished by the ganglionic blocker chlorisondamine (3 mg/kg i.p.), by adrenal demedullation, by a selective beta-adrenergic antagonist (nadolol, 0.4 mg/kg), and additively by a selective beta(1)- (atenolol, 1-6 mg/kg) and a selective beta(2)-antagonist (either butoxamine 4-32 mg/kg or ICI-118,551 0.3-8 mg/kg). Stress also suppressed NKA, and adrenal demedullation prevented this suppression. Administration of adrenaline (0.1-1 mg/kg) or of a beta-adrenergic agonist (metaproterenol, 0.8 mg/kg), in physiologically relevant doses, suppressed NKA in a dose-dependent manner, and increased LTR to levels characteristic of swim stress. Taken together, these findings suggest that acute stress, by releasing catecholamines from the adrenal glands and activating beta(1)- and beta(2)-adrenoceptors, suppresses NKA and consequently compromises resistance to NK-sensitive metastasis

The promotion of tumor metastasis by surgery and stress: immunological basis and implications for psychoneuroimmunology.

Ben Eliyahu S.

Brain Behav Immun. 2003 Feb; 17 Suppl 1:S27-S36.

This mini-review emphasizes a psychoneuroimmunology (PNI) perspective of the hypothesis that stress and surgical excision of the primary tumor can promote tumor metastasis. It first establishes the empirical and theoretical basis for control of metastasis by cell-mediated immunity (CMI), as well as the interactive role of non-immunological risk factors. It then describes the various aspects of surgery that suppress CMI, and the neuroendocrine mechanisms mediating suppression by stress and surgery. Last, it briefly reviews the empirical evidence, from animal and human studies, for the promotion of metastasis by stress and surgery, with specific reference to the mediating role of CMI. It is concluded that: (a) Immunological mechanisms most likely play a role in limiting metastasis in patients with solid tumors. (b) Immunosuppression can be deleterious, especially when surgery is conducted early, before the tumor develops insurmountable mechanisms to escape immune destruction. (c) The most sensitive period for the establishment of metastases is the immediate aftermath of surgery. Interventions aiming at reducing stress and immunosuppression should thus strive to start beforehand. (d) ‘Psychological and physiological insults activate similar neuroendocrine mechanisms of immunosuppression. Therefore, a multimodal therapeutic approach should be used to prevent tumor metastasis during the perioperative period. (e) Studies employing interventions aimed at reducing the surgical stress response should preferably assess immunological indices with an established clinical relevance, and follow up long-term recurrence provided sample size assure statistical power. (f) The progress toward earlier detection of cancer, and our growing understanding of immunosuppression, continuously improves the chances for successful PNI interventions

New advances in the biology and treatment of myeloma bone disease.

Berenson JR.

Semin Hematol. 2001 Apr; 38(2 Suppl 3):15-20.

The bisphosphonates provide effective therapy for the skeletal complications of multiple myeloma (MM). Although the earliest bisphosphonates had poor bioavailability and relatively low potency, newer compounds such as pamidronate and zoledronic acid have greater potency. Bisphosphonates block the development of monocytes into osteoclasts and are thought to promote apoptosis of osteoclasts. These agents prevent osteoclasts from moving to the bone surface and seem to inhibit the production of bone-resorbing cytokines such as interleukin-6 (IL-6) by bone marrow stromal cells. In addition, bisphosphonates seem to have a direct antimyeloma effect by inducing apoptosis of malignant plasma cells. The beneficial effects of pamidronate have been demonstrated in a clinical trial setting. Patients who failed to respond to chemotherapy had a slight prolongation of survival and better performance status and quality of life. Ongoing clinical trials with ibandronate and zoledronic acid indicate the latter is 100 to 1,000 times more potent than pamidronate. Biochemical effects of zoledronic acid continue for as long as 8 weeks after a single administration. In a new trial comparing pamidronate and zoledronic acid, 90% of the patients who received zoledronic acid were normocalcemic, compared with 69% of those who received pamidronate at 10 days. In addition, the time to relapse or development of hypercalcemia was shorter for patients receiving pamidronate compared with zoledronic acid

[Effect of thioctic acid (alpha-limpoic acid) on the chemotherapeutic efficacy of cyclophosphamide and vincristine sulfate].

Berger M, Habs M, Schmahl D.

Arzneimittelforschung. 1983; 33(9):1286-8.

Pretreatment with thioctic acid has no negative influence on the chemotherapeutic efficacy of cyclophosphamide against i.p. transplanted Yoshida sarcoma and vincristine sulfate against i.p. transplanted Walker carcinosarcoma 256. The toxic side effects of vincristine sulfate are lowered to such a degree that an increase results in median survival time compared to animals treated only with vincristine sulfate. A diminution of the toxic side effects of cyclophosphamide due to adjuvant treatment with thioctic acid could not be proven

Expression of the multidrug resistance-associated protein (MRP) and chemoresistance of human non-small-cell lung cancer cells.

Berger W, Elbling L, Hauptmann E, et al.

Int J Cancer. 1997 Sep 26; 73(1):84-93.

Human non-small-cell lung cancer (NSCLC) is considered to be a chemotherapy-refractory malignancy. The underlying mechanisms remain rather obscure. The multidrug resistance-associated protein (MRP), mediating a multidrug resistance (MDR) phenotype, has been reported to be overexpressed in several drug-selected lung cancer cell lines. A few previous studies have described intrinsic MRP expression in both NSCLC and normal lung tissues. However, the drug-transporting activity as well as the correlation with chemoresistance is unclear. Using 15 unselected cell lines, we show that MRP (mRNA and protein as detected by reverse transcriptase polymerase chain reaction and immunoblot) is frequently expressed intrinsically, with markedly varying intensity, in NSCLC. Two cell lines expressed high MRP levels, one comparable to the drug-selected controls (GLC4/ADR, HL-60/AR) without, however, amplification of the MRP gene (Southern hybridization). Using 3H-daunomycin (3H-DM) and calcein as MRP substrates and probenecid (PRO), genistein (GEN), benzbromarone (BB), N-ethylmaleimide (NEM) and verapamil (VP) as MRP modulators, drug accumulation studies revealed a transporting activity of MRP that correlated significantly with the gene expression data. Moreover, a significant correlation between MRP expression and chemoresistance against daunomycin (DM), doxorubicin (DOX), etoposide (VP-16) and vinblastine (VBL), but not cisplatin (CDDP) and bleomycin (Bleo) (MTT-based survival assay), was detected. Correlations mainly rested on the pronounced chemoresistance of 2 highly MRP-expressing cell lines and did not reach significance when these cell lines were excluded

Resveratrol causes arrest in the S-phase prior to Fas-independent apoptosis in CEM-C7H2 acute leukemia cells.

Bernhard D, Tinhofer I, Tonko M, et al.

Cell Death Differ. 2000 Sep; 7(9):834-42.

Resveratrol (3,5,4′-trihydroxy-trans-stilbene), in the concentration range of 20 microM and above, induced arrest in the S-phase and apoptosis in the T cell-derived T-ALL lymphocytic leukemia cell line CEM-C7H2 which is deficient in functional p53 and p16. Expression of transgenic p16/INK4A, which causes arrest in G0/G1, markedly reduced the percentage of apoptotic cells. Antagonist antibodies to Fas or FasL, or constitutive expression of crmA did not diminish the extent of resveratrol-induced apoptosis. Furthermore, a caspase-8-negative, Fas-resistant Jurkat cell line was sensitive to resveratrol-induced apoptosis which could be strongly inhibited in the Jurkat as well as in the CEM cell line by z-VAD-fmk and z-IETD-fmk. The almost complete inhibition by z-IETD-fmk and the lack of inhibition by crmA suggested caspase-6 to be the essential initiator caspase. Western blots revealed the massive conversion of procaspase-6 to its active form, while caspase-3 and caspase-2 were proteolytically activated to a much lesser extent

Adriamycin associated cardiotoxicity: research on prevention with coenzyme Q.

Bertazzoli C, Ghione M.

Pharmacol Res Commun. 1977 Mar; 9(3):235-50.

Inhibition of angiogenesis and induction of endothelial and tumor cell apoptosis by green tea in animal models of human high-grade non-Hodgkin’s lymphoma.

Bertolini F, Fusetti L, Rabascio C, et al.

Leukemia. 2000 Aug; 14(8):1477-82.

Recent reports suggest that green tea consumption may prevent or delay the growth of human cancer, possibly by impairing tumor invasion and/or by an anti-angiogenic effect. In NOD/SCID mice transplanted intraperitoneally with human non-Hodgkin’s lymphoma (NHL) cell lines, Namalwa, RAP1-EIO and HS-Sultan, green tea prevented 50% of Namalwa tumors (P = 0.0017 by log-rank) and significantly inhibited RAP1-EIO and HS-Sultan tumor growth. Notably, treatment with the chemotherapy drug cyclophosphamide at the maximum tolerable dose was unable to prevent Namalwa tumor occurrence. In the three models evaluated, the frequency of apoptotic endothelial and tumor cells was significantly increased in mice given green tea compared to controls. These results support further trials in NHL to evaluate whether green tea, alone or in combination with chemotherapy, may delay or prevent disease progression

Antioxidants inhibit cytokine production and suppress NF-kappaB activation in CAPAN-1 and CAPAN-2 cell lines.

Blanchard JA, Barve S, Joshi-Barve S, et al.

Dig Dis Sci. 2001 Dec; 46(12):2768-72.

Interleukin (IL) -6 and IL-8 are cytokines that have been shown to play a role in several pancreatic diseases, including acute pancreatitis, chronic pancreatitis, and pancreatic adenocarcinoma. Previously, we have demonstrated that tumor necrosis factor-alpha (TNF-alpha) and gram-negative bacterial lipopolysaccharide stimulate production of IL-6 and IL-8 and activation of the transcription factor NF-kappaB in the well-differentiated pancreatic ductal adenocarcinoma cell lines CAPAN-1 and CAPAN-2. In these studies we have examined the effect of chain-breaking and glutathione-enhancing antioxidants on NF-kappaB activation and production of IL-6 and IL-8 in these cell lines. Generally, suppression of NF-kappaB activation correlated well with inhibition of IL-6 and IL-8 secretion. In the CAPAN-2 cell line, antioxidants inhibited both NF-kappaB activation and IL-6 and IL-8 secretion. In the CAPAN-1 cell line, antioxidants generally failed to suppress both NF-kappaB activation and IL-6 and IL-8 secretion. The single exception was the chain-breaking antioxidant butylated hydroxyanisole (BHA), which markedly inhibited IL-6 and IL-8 secretion, but had no effect on NF-kappaB activation. These findings may have implications for the treatment of acute and chronic pancreatitis and pancreatic cancer

Coenzymes Q: stimulants of the phagocytic activity in rats and immune response in mice.

Bliznakov E, Casey A, Premuzic E.

Experientia. 1970 Sep 26; 26(9):953-4.

Role of transforming growth factor beta in human disease.

Blobe GC, Schiemann WP, Lodish HF.

N Engl J Med. 2000 May 4; 342(18):1350-8.

Silibinin protects against cisplatin-induced nephrotoxicity without compromising cisplatin or ifosfamide anti-tumour activity.

Bokemeyer C, Fels LM, Dunn T, et al.

Br J Cancer. 1996 Dec; 74(12):2036-41.

Cisplatin is one of the most active cytotoxic agents in the treatment of testicular cancer, but its clinical use is associated with side-effects such as ototoxicity, neurotoxicity and nephrotoxicity. Long-term kidney damage from cisplatin particularly affects the proximal tubular apparatus and can be detected by increased urinary excretion of brush-border enzymes, such as L-alanine-aminopeptidase (AAP), and magnesium. In the current study, the flavonoid silibinin was used as a nephroprotectant for cisplatin-induced nephropathy in a rat animal model. Infusion of silibinin before cisplatin results in a significant decrease in glomerular (indicated by creatinine clearance and serum urea level) and tubular kidney toxicity (excretion of brush-border enzymes and magnesium). Silibinin given alone had no effect on renal function. In order to exclude an inhibition of the anti-tumour activity of cisplatin and 4-hydroperoxy-ifosfamide by co-administration of silibinin, in vitro studies were performed in three established human testicular cancer cell lines. Dose-response curves for cisplatin (3-30 000 nmol) combined with non-toxic silibinin doses (7.25 x 10(-6) or 7.25 x 10(-5) mol l-1) did not deviate significantly from those of cisplatin alone as measured by relative cell survival during a 5 day assay using the sulphorhodamine-B staining technique. Also silibinin did not influence the cytotoxic activity of 4-hydroperoxy-ifosfamide (30-10 000 nmol) in vitro. In summary, these in vitro data rule out a significant inhibition of the anti-tumour activity of the major nephrotoxic components, cisplatin and 4-hydroperoxy-ifosfamide, by co-administration of silibinin in a human germ cell tumour cell line model. Together with these demonstrated cytoprotection effects in the rat animal model, these data form the basis for a randomised clinical trial of silibinin for the protection of cisplatin-associated nephrotoxicity in patients with testicular cancer

Toxicological, pharmacokinetic and metabolic studies on acetylcysteine.

Bonanomi L, Gazzaniga A.

Eur J Respir Dis Suppl. 1980; 111:45-51.

Antioxidant-related parameters in patients treated for cancer chemoprevention with N-acetylcysteine.

Bongers V, de Jong J, Steen I, et al.

Eur J Cancer. 1995 Jun; 31A(6):921-3.

N-acetylcysteine (NAC) is an antioxidant, possibly effective in the early steps of carcinogenesis, and is applied to prevent second primary tumours in the upper aerodigestive tract and the lungs. In this study, we evaluated the pharmacodynamic profile of 600 mg NAC treatment, given daily for 3 months. Treatment caused a significant increase of the non-protein-SH concentration in blood plasma (38%) and erythrocytes (31%). Glutathione levels in exfoliated buccal mucosa cells appeared not to be influenced by treatment. The total radical-trapping ability parameter (TRAP) of blood plasma showed no change. In vitro, the addition of glutathione, but not of NAC did increase the TRAP value. In addition, when peroxyl radicals were generated in vitro, NAC was shown to be consumed more rapidly than glutathione. This suggests that NAC prevents early damage, while glutathione functions over a longer time period

Isoflavones inhibit intestinal epithelial cell proliferation and induce apoptosis in vitro.

Booth C, Hargreaves DF, Hadfield JA, et al.

Br J Cancer. 1999 Jul; 80(10):1550-7.

There have been many reports that high soya-based diets reduce the risk of certain types of cancer. This effect may be due to the presence of high levels of isoflavones derived from the soya bean, particularly genistein which has been shown to be a protein tyrosine kinase (PTK) inhibitor and have both oestrogenic and anti-oestrogenic properties. We have examined the effect of genistein and a number of novel synthetic analogues on both normal (IEC6, IEC18) and transformed (SW620, HT29) intestinal epithelial cell lines. Responses were compared to those elicited by oestradiol, the anti-oestrogen tamoxifen, and the tyrosine kinase inhibitor tyrphostin. Genistein and tamoxifen were potent inhibitors of cell proliferation. Of seven novel isoflavones tested, none were more potent inhibitors than genistein, and all displayed similar relative activities across the different cell lines. In addition to inhibiting cell proliferation, cell death via apoptosis was observed when the cells were exposed to the isoflavones and all but one exhibited PTK inhibitory activity. These data suggest that by reducing proliferation and inducing apoptosis, possibly due in part to PTK inhibition, isoflavones may have a role in protecting normal intestinal epithelium from tumour development (reducing the risk) and may reduce colonic tumour growth

Pharmacokinetics of N-acetylcysteine in man.

Borgstrom L, Kagedal B, Paulsen O.

Eur J Clin Pharmacol. 1986; 31(2):217-22.

N-Acetylcysteine was given intravenously and as three fast dissolving and one slow-release formulation, on separate occasions, as a single dose of 600 mg to 10 fasting (5 men and 5 women) healthy volunteers. Blood and urine were sampled for the following 12 h. Renal clearance constituted around 30% of total body clearance, which was 0.21 l/h/kg. Volume of distribution was 0.33 l/kg, consistent with distribution mainly to extracellular water. The late elimination half-life was 2.27 h and the mean residence time 1.62 h. The slow-release tablet resulted in a flattened plasma concentration-time curve typical of slow release formulations, while the other three oral formulations were rapidly absorbed. The oral availability of N-acetylcysteine varied between 6 and 10%, with the slow-release tablet having the lowest and the fast dissolving tablet the highest availability

Bax expression correlates with cellular drug sensitivity to doxorubicin, cyclophosphamide and chlorambucil but not fludarabine, cladribine or corticosteroids in B cell chronic lymphocytic leukemia.

Bosanquet AG, Sturm I, Wieder T, et al.

Leukemia. 2002 Jun; 16(6):1035-44.

In B-CLL, non-proliferating B cells accumulate due to defective apoptosis. Cytotoxic therapies trigger apoptosis and deregulation of apoptotic pathways contributes to chemoresistance. Loss of the apoptosis-promoting Bax has been implicated in resistance to cytotoxic therapy. We therefore evaluated ex vivo drug sensitivity of CLL, producing chemoresponse data which are prognostic indicators for B-CLL, in particular in the case of purine nucleoside analogs. To analyze the underlying mechanisms of drug resistance, we compared endogenous Bax and Bcl-2 expression to ex vivo response to eight drugs, and to survival in 39 B-CLL patients. We found that reduced Bax levels correlated well with ex vivo resistance to traditional B-CLL therapies – anthracyclines, alkylating agents and vincristine (all P 0.5). Mutational analysis of p53 could not explain the loss of Bax protein expression. Levels of Bcl-2 were not associated with sensitivity to any drug. In contrast to the ex vivo data, neither Bax or Bcl-2 expression nor doxorubicin sensitivity were associated with increased survival whereas sensitivity to fludarabine correlated with better overall survival (P = 0.031). These findings suggest that the resistance to purine nucleoside analogs and corticosteroids in B-CLL is due to inactivation of pathways different from those activated by anthracyclines, vinca alkaloids and alkylating agents and may be the molecular rationale for the efficacy of purine analogs in this disease

Vitamin C inhibits NF-kappa B activation by TNF via the activation of p38 mitogen-activated protein kinase.

Bowie AG, O’Neill LA.

J Immunol. 2000 Dec 15; 165(12):7180-8.

The transcription factor NF-kappaB is a central mediator of altered gene expression during inflammation, and is implicated in a number of pathologies, including cancer, atherosclerosis, and viral infection. We report in this study that vitamin C inhibits the activation of NF-kappaB by multiple stimuli, including IL-1 and TNF in the endothelial cell line ECV304 and in primary HUVECs. The induction of a NF-kappaB-dependent gene, IL-8, by TNF was also inhibited. The effect requires millimolar concentrations of vitamin C, which occur intracellularly in vivo, particularly during inflammation. Vitamin C was not toxic to cells, did not inhibit another inducible transcription factor, STAT1, and had no effect on the DNA binding of NF-kappaB. Inhibition by vitamin C was not simply an antioxidant effect, because redox-insensitive pathways to NF-kappaB were also blocked. Vitamin C was shown to block IL-1- and TNF-mediated degradation and phosphorylation of I-kappaBalpha (inhibitory protein that dissociates from NF-kappaB), due to inhibition of I-kappaB kinase (IKK) activation. Inhibition of TNF-driven IKK activation was mediated by p38 mitogen-activated protein kinase, because treatment of cells with vitamin C led to a rapid and sustained activation of p38, and the specific p38 inhibitor SB203580 reversed the inhibitory effect of vitamin C on IKK activity, I-kappaBalpha phosphorylation, and NF-kappaB activation. The results identify p38 as an intracellular target for high dose vitamin C

Differential effects of dietary flavonoids on drug metabolizing and antioxidant enzymes in female rat.

Breinholt V, Lauridsen ST, Dragsted LO.

Xenobiotica. 1999 Dec; 29(12):1227-40.

1. Gavage administration of the natural flavonoids tangeretin, chrysin, apigenin, naringenin, genistein and quercetin for 2 consecutive weeks to the female rat resulted in differential effects on selected phase 1 and 2 enzymes in liver, colon and heart as well as antioxidant enzymes in red blood cells (RBC). 2. Glutathione transferase (GST) activity assayed by use of the substrate 1-chloro-2,4-dinitrobenzene was significantly induced by apigenin, genistein and tangeretin in the heart but not in colon or liver. 3. In RBC chrysin, quercetin and genistein significantly decreased the activity of glutathione reductase (GR), catalase (CAT) and glutathione peroxidase (GPx), whereas superoxide dismutase (SOD) was only significantly decreased by genistein. 4. The oxidative status of the animal, measured as plasma malondialdehyde, revealed that chrysin, quercetin, genistein, and beta-naphthoflavone (BNF) significantly protected against, 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP)-induced oxidative stress. Hepatic PhIP-DNA adduct formation was not affected by any of the administered flavonoids, whereas PhIP-DNA adduct formation in colon was slightly, but significantly, inhibited by quercetin, genistein, tangeretin and BNF. 5. The observed effects of chrysin, quercetin and genistein on antioxidant enzymes, concurrently with a protection against oxidative stress, suggest a feedback mechanism on the antioxidant enzymes triggered by the flavonoid antioxidants. 6. Despite the use of high flavonoid doses, which by far exceed the human exposure levels, the effect on drug metabolizing and antioxidant enzymes was still very minor. The role of singly administered flavonoids in the protection against cancer and heart disease is thus expected to be limited

Vitamin D receptor gene polymorphisms are associated with breast cancer risk in a UK Caucasian population.

Bretherton-Watt D, Given-Wilson R, Mansi JL, et al.

Br J Cancer. 2001 Jul 20; 85(2):171-5.

There is increasing evidence that vitamin D can protect against breast cancer. The actions of vitamin D are mediated via the vitamin D receptor (VDR). We have investigated whether polymorphisms in the VDR gene are associated with altered breast cancer risk in a UK Caucasian population. We recruited 241 women following a negative screening mammogram and 181 women with known breast cancer. The VDR polymorphism Bsm I, an intronic 3′ gene variant, was significantly associated with increased breast cancer risk: odds ratio bb vs BB genotype = 2.32 (95% CI, 1.23-4.39). The Bsm I polymorphism was in linkage disequilibrium with a candidate translational control site, the variable length poly (A) sequence in the 3′ untranslated region. Thus, the ‘L’ poly (A) variant was also associated with a similar breast cancer risk. A 5′ VDR gene variant, Fok I, was not associated with breast cancer risk. Further investigations into the mechanisms of interactions of the VDR with other environmental and/or genetic influences to alter breast cancer risk may lead to a new understanding of the role of vitamin D in the control of cellular and developmental pathways

Natural cytotoxicity in breast cancer patients receiving neoadjuvant chemotherapy: effects of L-arginine supplementation.

Brittenden J, Heys SD, Ross J, et al.

Eur J Surg Oncol. 1994 Aug; 20(4):467-72.

Certain cytotoxic drugs have been shown to suppress host anti-cancer defence mechanisms. The amino acid L-arginine can significantly enhance natural killer (NK) and lymphokine-activated killer (LAK) cell cytotoxicity in patients with locally advanced breast cancer. In this study, the effect of L-arginine supplementation on natural cytotoxicity was determined in patients with breast cancer receiving CHOP chemotherapy. This cytotoxic regimen caused a transient immunosuppression, maximal on day 14 of each cycle (P < 0.001); this was not cumulative during the four cycles of treatment. Those patients receiving L-arginine supplementation (30 g/day for 3 days prior to each course of chemotherapy) had a smaller and delayed onset of immunosuppression (day 14), compared with those patients who had CHOP only (day 9). L-Arginine was able to repeatedly stimulate NK and LAK cell cytotoxicity in patients who were receiving CHOP chemotherapy (P < 0.003). In conclusion, further studies are required to determine the optimal use of chemotherapeutic agents, alone or in combination with immunostimulators, to avoid inhibition of host anti-cancer defence mechanisms

Plasma selenium level before diagnosis and the risk of prostate cancer development.

Brooks JD, Metter EJ, Chan DW, et al.

J Urol. 2001 Dec; 166(6):2034-8.

PURPOSE: Epidemiological studies and a randomized intervention trial suggest that the risk of prostate cancer may be reduced by selenium intake. We investigated whether plasma selenium level before diagnosis correlated with the risk of later developing prostate cancer. MATERIALS AND METHODS: A case control study was performed on men from the Baltimore Longitudinal Study of Aging registry, including 52 with known prostate cancer and 96 age matched controls with no detectable prostatic disease. Plasma selenium was measured at an average time plus or minus standard deviation of 3.83 +/- 1.85 years before the diagnosis of prostate cancer by graphite furnace atomic absorption spectrophotometry. Adjusted odds ratio and 95% confidence interval were computed with logistic regression. RESULTS: After correcting for years before diagnosis, body mass index, and smoking and alcohol use history, higher selenium was associated with a lower risk of prostate cancer. Compared with the lowest quartile of selenium (range 8.2 to 10.7 microg./dl.), the odds ratios of the second (10.8 to 11.8), third (11.9 to 13.2) and fourth (13.3 to 18.2) quartiles were 0.15 (95% confidence interval 0.05 to 0.50), 0.21 (0.07 to 0.68) and 0.24 (0.08 to 0.77, respectively, p =0.01). Furthermore, plasma selenium decreased significantly with patient age (p <0.001). CONCLUSIONS: Low plasma selenium is associated with a 4 to 5-fold increased risk of prostate cancer. These results support the hypothesis that supplemental selenium may reduce the risk of prostate cancer. Because plasma selenium decreases with patient age, supplementation may be particularly beneficial to older men

Antioxidants may limit key mutations.

Brotzman M.

ScienceNewsOnline. 1999; 155(17)

Diet and nutrition as risk factors for multiple myeloma among blacks and whites in the United States.

Brown LM, Gridley G, Pottern LM, et al.

Cancer Causes Control. 2001 Feb; 12(2):117-25.

OBJECTIVES: To explore whether dietary factors contribute to the risk of multiple myeloma and the two-fold higher incidence among blacks compared to whites in the United States. METHODS: Data from a food-frequency questionnaire were analyzed for 346 white and 193 black subjects with multiple myeloma, and 1086 white and 903 black controls who participated in a population-based case-control study of multiple myeloma in three areas of the United States. RESULTS: Elevated risks were associated with obese vs. normal weight (OR = 1.9, 95% confidence interval (CI) = 1.2-3.1 for whites and OR = 1.5, 95% CI = 0.9-2.4 for blacks), while the frequency of obesity was greater for black than white controls. Reduced risks were related to frequent intake of cruciferous vegetables (OR = 0.7, 95% CI = 0.6-0.99) and fish (OR = 0.7, 95% CI = 0.5-0.9) in both races combined, and to vitamin C supplements in whites (OR = 0.6, 95% CI = 0.5-0.9) and blacks (OR = 0.8, 95% CI = 0.5-1.4), with the frequency of vitamin supplement use being greater for white than black controls. However, frequent intake of vitamin C from food and supplements combined was associated with a protective effect in whites (OR = 0.6, 95% CI = 0.4-0.9), but not blacks (OR = 1.2, 95% CI = 0.8-2.1). CONCLUSIONS: The greater use of vitamin C supplements by whites and the higher frequency of obesity among blacks may explain part of the higher incidence of multiple myeloma among blacks compared to whites in the United States. In addition, the increasing prevalence of obesity may have contributed to the upward trend in the incidence of multiple myeloma during recent decades

Effects of phytoestrogens and synthetic combinatorial libraries on aromatase, estrogen biosynthesis, and metabolism.

Brueggemeier RW, Gu X, Mobley JA, et al.

Ann N Y Acad Sci. 2001 Dec; 948:51-66.

Approximately 60% of breast cancer patients have hormone-dependent breast cancer containing estrogen receptors and requiring estrogen for tumor growth. The extent of estrogen biosynthesis and metabolism in the breast cancer tissue microenvironment influences breast-tumor development and growth, and endogenous and exogenous agents may alter the levels of hormonally active estrogens and their metabolites. Isoflavonoid phytoestrogens such as genistein exhibit numerous biochemical activities; however, their effects on estrogen biosynthesis and metabolism in breast cancer cells have not been fully examined. MCF-7 cells (hormone-dependent) and MBA-MB-231 cells (hormone-independent) were treated with genistein (100 nM) for five days and then incubated with radiolabeled estradiol (100 nM, 2.5 microCi) for 0 to 48 h. Media were extracted with ethyl acetate, and the organic residues analyzed by reverse-phase HPLC with a radioactivity flow detector. The major metabolite formed in all cases is estrone, although differences were observed between the cell lines and the various drug treatments. The formation of estrone in untreated MCF-7 cells (approximately 9.3% of radioactivity at 24 h) is relatively limited, in contrast to untreated MDA-MB-231 cells (approximately 32.0% of radioactivity at 24 h). Treatment of MCF-7 cells with 100 nM genistein increased the conversion of estradiol to estrone up to 19.5% in 24 h. The effect of genistein on estrone formation in MDA-MB-231 cells resulted in 37.7% of the radioactivity being estrone. Thus, genistein treatment of breast cancer cells resulted in increased 17-betahydroxysteroid dehydrogenase activity and elevated formation of estrone. Increased levels of oxidative 17-betahydroxysteroid dehydrogenase activity (Type II) were confirmed by Western blots. Therefore, exposure of breast cancer cells to genistein results in elevated conversion of estradiol to estrogenically weaker or inactive metabolites. The regulation of breast-tissue aromatase by exogenous agents such as drugs and environmental agents is being investigated. The benzopyranone-ring system is a molecular scaffold of considerable interest, and this scaffold is found in flavonoid natural products that have weak aromatase inhibitory activity. Medicinal chemistry efforts focus on diversifying the benzopyranone scaffold and utilizing combinatorial chemistry approaches to construct small benzopyranone libraries as potential aro- matase inhibitors. Several compounds in the initial libraries have demonstrated moderate aromatase inhibitory activity in screening assays

Eicosapentaenoic Acid As a Targeted Therapy for Cancer Cachexia.

Bruera ED.

J Clin Oncol. 2003 21(24):4657-58.

Serologic precursors of cancer: serum micronutrients and the subsequent risk of pancreatic cancer.

Burney PG, Comstock GW, Morris JS.

Am J Clin Nutr. 1989 May; 49(5):895-900.

In a nested case-control study the stored, frozen sera from 22 cases of cancer of the pancreas and 44 matched control subjects were assayed for retinol, retinol-binding protein, total carotenoids, beta-carotene, lycopene, vitamin E (alpha-tocopherol), and selenium. Prediagnostic serum levels of lycopene and Se were lower among cases than among matched control subjects. These differences remained after adjustment was made for possible confounding by smoking, educational level, and the other measured serum levels. Low levels of serum vitamin E appeared to have a protective effect but a chance association between vitamin E and cancer of the pancreas could not reasonably be excluded. The association between cancer of the pancreas and serum Se was significant when the data were analyzed as a whole but its effect was seen principally in men

Influence of alpha-lipoic acid on intracellular glutathione in vitro and in vivo.

Busse E, Zimmer G, Schopohl B, et al.

Arzneimittelforschung. 1992 Jun; 42(6):829-31.

The influence of alpha-lipoic acid (CAS 62-46-4) on the amount of intracellular glutathione (GSH) was investigated in vitro and in vivo. Using murine neuroblastoma as well as melanoma cell lines in vitro, a dose-dependent increase of GSH content was observed. Dependent on the source of tumor cells the increase was 30-70% compared to untreated controls. Normal lung tissue of mice also revealed about 50% increase in glutathione upon treatment with lipoic acid. This corresponds with protection from irradiation damage in these in vitro studies. Survival rate of irradiated murine neuroblastoma was increased at doses of 100 micrograms lipoic acid/d from 2% to about 10%. In agreement with the in vitro studies, in vivo experiments with whole body irradiation (5 and 8 Gy) in mice revealed that the number of surviving animals was doubled at a dose of 16 mg lipoic acid/kg. Improvement of cell viability and irradiation protection by the physiological compound lipoic acid runs parallel with an increase of intracellular GSH/GSSG ratio

Vitamin D receptor gene polymorphisms in breast cancer.

Buyru N, Tezol A, Yosunkaya-Fenerci E, et al.

Exp Mol Med. 2003 Dec 31; 35(6):550-5.

Breast cancer is the leading cause of cancer death among women around the world and its incidence is annually increasing. The vitamin D receptor (VDR) gene is a member of the nuclear receptor superfamily, which is expressed in breast tissue and known to modulate the rate of cell proliferation. Association between the VDR gene polymorphisms and cancer development has been suggested by several studies. However, the relationship between VDR polymorphisms and breast cancer is controversial and has not been confirmed by all studies. The purpose of this study was to investigate the genotype frequencies and association of the VDR Bsm I and Taq I polymorphisms with breast cancer in Turkish patients. In this study, 78 patients with breast cancer and 27 healthy individuals were enrolled. The prevalence of the VDR Taq I and Bsm I alleles and the genotype frequencies in patients with breast cancer was similar to that in the normal population. Our data indicate that no significant differences exist between the patients and control subjects

Divergent effects of omega-6 and omega-3 fatty acids on mammary tumor development in C3H/Heston mice treated with DMBA.

Cameron E.

Nutr Res. 1989(9):383-93.

Cancer and Vitamin C 1993.

Cameron EPL.

1993;

[Silibinin and acute poisoning with Amanita phalloides].

Carducci R, Armellino MF, Volpe C, et al.

Minerva Anestesiol. 1996 May; 62(5):187-93.

The aim of the present study was to show the therapeutic effect of silibinin dihemisuccinate in a case of intoxication by mushrooms of Amanita gender. We report a clinical case of a 4-person family intoxicated by ingestion of mushrooms Amanita phalloides and admitted to the center for poisoning treatment of the Hospital “A. Cardarelli” in Naples. Although all were treated with standard therapy, there was a worsening of the clinical picture till the third day, when it was decided to add silibinin dihemisuccinate by the intravenous route to the therapy. After the beginning of silibinin administration the patients showed a favourable course with a rapid resolution of the clinical picture, although the prognosis appeared severe on the basis of hematochemical examination results. On day 9 silibinin dihemisuccinate was replaced with silibinin betacyclodextrine per os. All patients were discharged on day 10-13. After two months all hematological parameters are in the normal range also a hepatobiliopancreatic echography does not show any morphological alteration. As in the case of polytherapies and because of the lack of comparative studies, it seems difficult to establish which therapeutic component had the major role in the resolution of the clinical picture. However, on the basis of our experience, and of the literature data, we think that silibinin may play a significant role in protecting hepatic tissue not yet injured. However we believe that other studies are necessary to confirm our hypothesis

Opposite effects of linoleic acid and conjugated linoleic acid on human prostatic cancer in SCID mice.

Cesano A, Visonneau S, Scimeca JA, et al.

Anticancer Res. 1998 May; 18(3A):1429-34.

The relationship between dietary fat intake (level and type) and cancer development is a matter of concern in Western society. The purpose of this study was to determine the effect of three different diets on the local growth and metastatic properties of DU-145 human prostatic carcinoma cells in severe combined immunodeficient (SCID) mice. Animals were fed a standard diet or diets supplemented with 1% LA or 1% CLA for 2 weeks prior to subcutaneous (s.c.) inoculation of DU-145 cells and throughout the study (total of 14 weeks). Mice receiving LA-supplemented diet displayed significantly higher body weight, lower food intake and increased local tumor load as compared to the other two groups of mice. Mice fed the CLA-supplemented diet displayed not only smaller local tumors than the regular diet-fed group, but also a drastic reduction in lung metastases. These results support the view that dietary polyunsaturated fatty acids may influence the prognosis of prostatic cancer patients, thus opening the possibility of new therapeutic options

c-Jun N-terminal kinase activation by hydrogen peroxide in endothelial cells involves SRC-dependent epidermal growth factor receptor transactivation.

Chen K, Vita JA, Berk BC, et al.

J Biol Chem. 2001 May 11; 276(19):16045-50.

The phenotypic properties of the endothelium are subject to modulation by oxidative stress, and the c-Jun N-terminal kinase (JNK) pathway is important in mediating cellular responses to stress, although activation of this pathway in endothelial cells has not been fully characterized. Therefore, we exposed endothelial cells to hydrogen peroxide (H(2)O(2)) and observed rapid activation of JNK within 15 min that involved phosphorylation of JNK and c-Jun and induction of AP-1 DNA binding activity. Inhibition of protein kinase C and phosphoinositide 3-kinase did not effect JNK activation. In contrast, the tyrosine kinase inhibitors, genistein, herbimycin A, and 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) significantly attenuated H(2)O(2)-induced JNK activation as did endothelial cell adenoviral transfection with a dominant-negative form of Src, implicating Src as an upstream activator of JNK. Activation of JNK by H(2)O(2) was also inhibited by AG1478 and antisense oligonucleotides directed against the epidermal growth factor receptor (EGFR), implicating the EGFR in this process. Consistent with this observation, H(2)O(2) stimulated EGFR tyrosine phosphorylation and complex formation with Shc-Grb2 that was abolished by PP2, implicating Src in H(2)O(2)-induced EGFR activation. Tyrosine phosphorylation of the EGFR by H(2)O(2) did not involve receptor autophosphorylation at Tyr(1173) as assessed by an autophosphorylation-specific antibody. These data indicate that H(2)O(2)-induced JNK activation in endothelial cells involves the EGFR through an Src-dependent pathway that is distinct from EGFR ligand activation. These data represent one potential pathway for mediating oxidative stress-induced phenotypic changes in the endothelium

Effects of conjugated dienoic derivatives of linoleic acid and beta-carotene in modulating lymphocyte and macrophage function.

Chew BP, Wong TS, Shultz TD, et al.

Anticancer Res. 1997 Mar; 17(2A):1099-106.

The in vitro effects of conjugated dienoic derivatives of linoleic acid (CLA) in combination with beta-carotene on lymphocyte and macrophage function was studied. Porcine blood lymphocytes and murine peritoneal macrophages were incubated with 0 (control), 1.78 x 10(-5), 3.57 x 10(-5) and 7.14 x 10(-5) M CLA and 0 (control), 10(-9), 10(-8) and 10(-7) M beta-carotene. CLA alone stimulated mitogen-induced lymphocyte proliferation, lymphocyte cytotoxic activity and macrophage bactericidal activity. In contrast, CLA inhibited interleukin-2 production by lymphocytes and suppressed the phagocytic activity of macrophages. beta-Carotene alone stimulated the cytotoxicity of lymphocytes and increased superoxide production by peritoneal macrophages. When present together, CLA and beta-carotene interacted in an additive manner to further enhance lymphocyte cytotoxicity and spontaneous lymphocyte proliferation. In addition, beta-carotene was able to negate the inhibitory action of CLA on the phagocytic activity of macrophages. Also, CLA and beta-carotene together seemed to suppress mitogen-induced lymphocyte proliferation. Therefore, CLA and beta-carotene; alone and in concert, act to modulate different aspects of cellular host defense

Modulation of growth of human prostate cancer cells by the N-acetylcysteine conjugate of phenethyl isothiocyanate.

Chiao JW, Chung F, Krzeminski J, et al.

Int J Oncol. 2000 Jun; 16(6):1215-9.

There is growing evidence that thiol conjugates of isothiocyanates present in cruciferous vegetables are effective cancer chemopreventive and potentially active therapeutic agents. The effects of the N-acetylcysteine conjugate of phenethyl isothiocyanate (PEITC-NAC) on tumor cell growth were analyzed in human prostate cancer cell lines LNCaP, androgen-dependent, and DU-145, androgen-independent. Exposure of the cells to PEITC-NAC at high concentrations caused cytolysis, while at lower concentrations PEITC-NAC mediated a dose-dependent growth modulation, with reduction of DNA synthesis and growth rate, inhibition of clonogenicity and induction of apoptosis in both types of prostate cancer cells. PEITC-NAC decreased cells in S and G2M phases of cell cycle, blocking cells entering replicating phases. In parallel, a significant enhancement of cells expressing the cell cycle regulator p21 as well as its intensity was determined using a fluorescent antibody technique. The action of PEITC-NAC was time-dependent, with the magnitude of inhibition increasing to 50-65% after PEITC-NAC exposure for several days. Interaction of tumor cells with dissociation products of PEITC-NAC, PEITC and NAC, are proposed as the mechanism of growth regulation

Indole-3-carbinol (I3C) induced cell growth inhibition, G1 cell cycle arrest and apoptosis in prostate cancer cells.

Chinni SR, Li Y, Upadhyay S, et al.

Oncogene. 2001 May 24; 20(23):2927-36.

Prostate cancer is one of the most common cancers in men and it is the second leading cause of cancer related death in men in the United States. Recent dietary and epidemiological studies have suggested the benefit of dietary intake of fruits and vegetables in lowering the incidence of prostate cancer. A diet rich in fruits and vegetables provides phytochemicals, particularly indole-3-carbinol (I3C), which may be responsible for the prevention of many types of cancer, including hormone-related cancers such as prostate. Studies to elucidate the role and the molecular mechanism(s) of action of I3C in prostate cancer, however, have not been conducted. In the current study, we investigated whether I3C had any effect against prostate cancer cells and, if so, attempts were made to identify the potential molecular mechanism(s) by which I3C elicits its biological effects on prostate cancer cells. Here we report for the first time that I3C inhibits the growth of PC-3 prostate cancer cells. Induction of G1 cell cycle arrest was also observed in PC-3 cells treated with I3C, which may be due to the observed effects of I3C in the up-regulation of p21(WAF1) and p27(Kip1) CDK inhibitors, followed by their association with cyclin D1 and E and down-regulation of CDK6 protein kinase levels and activity. The induction of p21(WAF1) appears to be transcriptionally upregulated and independent of the p53 responsive element. In addition, I3C inhibited the hyperpohosphorylation of the Retinoblastoma (Rb) protein in PC-3 cells. Induction of apoptosis was also observed in this cell line when treated with I3C, as measured by DNA laddering and poly (ADP-ribose) polymersae (PARP) cleavage. We also found an up-regulation of Bax, and down-regulation of Bcl-2 in I3C-treated cells. These effects may also be mediated by the down-regulation of NF-kappaB observed in I3C treated PC-3 cells. From these results, we conclude that I3C inhibits the growth of PC-3 prostate cancer cells by inducing G1 cell cycle arrest leading to apoptosis, and regulates the expression of apoptosis-related genes. These findings suggest that I3C may be an effective chemopreventive or therapeutic agent against prostate cancer

Effects of thymosin in vitro in cancer patients and correlation with clinical course after thymosin immunotherapy.

Chretien PB, Lipson SD, Makuch RW, et al.

Ann N Y Acad Sci. 1979; 332:135-47.

Effects of berberine on arylamine N-acetyltransferase activity in human bladder tumour cells.

Chung JG, Wu LT, Chu CB, et al.

Food Chem Toxicol. 1999 Apr; 37(4):319-26.

Berberine was used to determine inhibition of arylamine N-acetyltransferase (NAT) activity in human bladder tumour cells. The NAT activity was measured by HPLC assaying for the amounts of N-acetyl-2-aminofluorene (AAF) and N-acetyl-p-aminobenzoic acid (N-Ac-PABA) and remaining 2-aminofluorene (AF) and p-aminobenzoic acid (PABA). Two assay systems were performed, one with cellular cytosols, the other with intact bladder tumour cell suspensions. The NAT activity in human bladder tumour cells was inhibited by berberine in a dose-dependent manner, that is, the higher the concentration of berberine, the higher the inhibition of NAT activity. The values of apparent Km and Vmax calculated from cytosol NAT and intact cells were also decreased by berberine. This report is the first demonstration to show berberine did affect human bladder tumour cell NAT activity

Synergistic cytotoxicity, apoptosis and protein-linked DNA breakage by etoposide and camptothecin in human U87 glioma cells: dependence on tyrosine phosphorylation.

Ciesielski MJ, Fenstermaker RA.

J Neurooncol. 1999 Feb; 41(3):223-34.

In this study, simultaneous administration of certain inhibitors of topoisomerase I and topoisomerase II produced synergistic cytotoxicity in a series of human glioma cell lines. Camptothecin (CPT) and etoposide (VP-16) produced combination indices (CI) <1.0 in all glioma cell lines tested, including those that were relatively resistant to the two topoisomerase inhibitors individually. In contrast, CPT and VP-16 produced additive cytotoxicity in HT-29 and SW-620 colon carcinoma cell lines. To explore the molecular basis for synergy in glioma cells, we focused on one glioma cell line (U87) in which even sub-cytotoxic doses of CPT potentiated the action of VP-16. Except for genistein (a topo II agent with tyrosine kinase inhibitory function), all topo II inhibitors tested (doxorubicin, ellipticine, and m-AMSA) were synergistic with CPT. While CPT and VP-16 produced cytotoxicity and protein-linked DNA breaks (PLDB) that were supra-additive in U87 glioma cells, CPT and genistein produced additive results. Pretreatment of U87 cells with the tyrosine kinase inhibitor tyrphostin-A23 or the tyrosine phosphatase activator O-phospho-L-tyrosine (OPLT) reduced combination PLDB from synergistic to additive levels, but had no effect on the formation of PLDB induced by either CPT or VP-16 alone. CPT and VP-16 also produced a synergistic accumulation of sub-G0 (apoptotic) cells which was blocked by tyrphostin-A23. No significant increase in topoisomerase protein levels could be detected in response to combination treatment. Thus, synergistic effects between topoisomerase I and topoisomerase II inhibitors in U87 glioma cells may depend upon phosphorylation of cellular proteins other than the topoisomerases themselves

Effect of curcumin on the aryl hydrocarbon receptor and cytochrome P450 1A1 in MCF-7 human breast carcinoma cells.

Ciolino HP, Daschner PJ, Wang TT, et al.

Biochem Pharmacol. 1998 Jul 15; 56(2):197-206.

We examined the interaction of curcumin, a dietary constituent and chemopreventive compound, with the carcinogen activation pathway mediated by the aryl hydrocarbon receptor (AhR) in MCF-7 mammary epithelial carcinoma cells. Curcumin caused a rapid accumulation of cytochrome P450 1A1 (CYP1A1) mRNA in a time- and concentration-dependent manner, and CYP1A1 monooxygenase activity increased as measured by ethoxyresorufin-O-deethylation. Curcumin activated the DNA-binding capacity of the AhR for the xenobiotic responsive element of CYP1A1 as measured by the electrophoretic-mobility shift assay (EMSA). Curcumin was able to compete with the prototypical AhR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin for binding to the AhR in isolated MCF-7 cytosol, indicating that it interacts directly with the receptor. Although curcumin could activate the AhR on its own, it partially inhibited the activation of AhR, as measured by EMSA, and partially decreased the accumulation of CYP1A1 mRNA caused by the mammary carcinogen dimethylbenzanthracene (DMBA). Curcumin competitively inhibited CYP1A1 activity in DMBA-treated cells and in microsomes isolated from DMBA-treated cells. Curcumin also inhibited the metabolic activation of DMBA, as measured by the formation of DMBA-DNA adducts, and decreased DMBA-induced cytotoxicity. These results suggest that the chemopreventive effect of curcumin may be due, in part, to its ability to compete with aryl hydrocarbons for both the AhR and CYP1A1. Curcumin may thus be a natural ligand and substrate of the AhR pathway

Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group.

Clark LC, Combs GF, Jr., Turnbull BW, et al.

JAMA. 1996 Dec 25; 276(24):1957-63.

OBJECTIVE: To determine whether a nutritional supplement of selenium will decrease the incidence of cancer. DESIGN: A multicenter, double-blind, randomized, placebo-controlled cancer prevention trial. SETTING: Seven dermatology clinics in the eastern United States. PATIENTS: A total of 1312 patients (mean age, 63 years; range, 18-80 years) with a history of basal cell or squamous cell carcinomas of the skin were randomized from 1983 through 1991. Patients were treated for a mean (SD) of 4.5 (2.8) years and had a total follow-up of 6.4 (2.0) years. INTERVENTIONS: Oral administration of 200 microg of selenium per day or placebo. MAIN OUTCOME MEASURES: The primary end points for the trial were the incidences of basal and squamous cell carcinomas of the skin. The secondary end points, established in 1990, were all-cause mortality and total cancer mortality, total cancer incidence, and the incidences of lung, prostate, and colorectal cancers. RESULTS: After a total follow-up of 8271 person-years, selenium treatment did not significantly affect the incidence of basal cell or squamous cell skin cancer. There were 377 new cases of basal cell skin cancer among patients in the selenium group and 350 cases among the control group (relative risk [RR], 1.10; 95% confidence interval [CI], 0.95-1.28), and 218 new squamous cell skin cancers in the selenium group and 190 cases among the controls (RR, 1.14; 95% CI, 0.93-1.39). Analysis of secondary end points revealed that, compared with controls, patients treated with selenium had a nonsignificant reduction in all-cause mortality (108 deaths in the selenium group and 129 deaths in the control group [RR; 0.83; 95% CI, 0.63-1.08]) and significant reductions in total cancer mortality (29 deaths in the selenium treatment group and 57 deaths in controls [RR, 0.50; 95% CI, 0.31-0.80]), total cancer incidence (77 cancers in the selenium group and 119 in controls [RR, 0.63; 95% CI, 0.47-0.85]), and incidences of lung, colorectal, and prostate cancers. Primarily because of the apparent reductions in total cancer mortality and total cancer incidence in the selenium group, the blinded phase of the trial was stopped early. No cases of selenium toxicity occurred. CONCLUSIONS: Selenium treatment did not protect against development of basal or squamous cell carcinomas of the skin. However, results from secondary end-point analyses support the hypothesis that supplemental selenium may reduce the incidence of, and mortality from, carcinomas of several sites. These effects of selenium require confirmation in an independent trial of appropriate design before new public health recommendations regarding selenium supplementation can be made

Chemopreventive agent resveratrol, a natural product derived from grapes, triggers CD95 signaling-dependent apoptosis in human tumor cells.

Clement MV, Hirpara JL, Chawdhury SH, et al.

Blood. 1998 Aug 1; 92(3):996-1002.

Resveratrol, a constituent of grapes and other food products, has been shown to prevent carcinogenesis in murine models. We report here that resveratrol induces apoptotic cell death in HL60 human leukemia cell line. Resveratrol-treated tumor cells exhibit a dose-dependent increase in externalization of inner membrane phosphatidylserine and in cellular content of subdiploid DNA, indicating loss of membrane phospholipid asymmetry and DNA fragmentation. Resveratrol-induced cell death is mediated by intracellular caspases as observed by the dose-dependent increase in proteolytic cleavage of caspase substrate poly (ADP-ribose) polymerase (PARP) and the ability of caspase inhibitors to block resveratrol cytotoxicity. We also show that resveratrol treatment enhances CD95L expression on HL60 cells, as well as T47D breast carcinoma cells, and that resveratrol-mediated cell death is specifically CD95-signaling dependent. On the contrary, resveratrol treatment of normal human peripheral blood lymphocytes (PBLs) does not affect cell survival for up to 72 hours, which correlates with the absence of a significant change in either CD95 or CD95L expression on treated PBLs. These data show specific involvement of the CD95-CD95L system in the anti-cancer activity of resveratrol and highlight the chemotherapeutic potential of this natural product, in addition to its recently reported chemopreventive activity

Assessment of hormonally active agents in the reproductive tract of female nonhuman primates.

Cline JM, Soderqvist G, Register TC, et al.

Toxicol Pathol. 2001 Jan; 29(1):84-90.

Using the ovariectomized macaque model of postmenopausal women’s health, we investigated the effects of long-term treatments (5 weeks-3 years) with estradiol, conjugated equine estrogens (CEE), esterified estrogens, progestins such as medroxyprogesterone acetate (MPA) and nomegestrol acetate, CEE + MPA, tamoxifen, soybean phytoestrogens (SPEs), a variety of putative selective estrogen receptor modulators (SERMs), and androgens. Agents tested were selected on the basis of beneficial effects on arteries and/or bone. Doses were scaled on a caloric or serum-concentration basis to approximate human clinical doses. We evaluated endometrial and mammary gland histopathology and morphometry and used immunohistochemistry to evaluate cell proliferation and expression of estrogen receptor alpha and progesterone receptor (PR). Both estradiol and CEE induced endometrial hyperplasia. MPA antagonized epithelial proliferation induced by CEE in endometrium and induced pseudodecidual stromal hyperplasia in some animals. Tamoxifen induced endometrial polyps, cystic hyperplasia, stromal fibrosis, and PR expression but not Ki-67 expression. SPEs were not estrogenic at dietary doses and antagonized estrogen-induced proliferation in the endometrium and breast. Nandrolone induced mucometra and an adenomyosis-like change. The potential SERM 17 alpha dihydroequilenin did not have uterotrophic or mammotrophic effects. In general, experimental findings in macaques have been predictive of outcomes in human clinical trials of the same agents

Garlic extracts stimulate proliferation of rat lymphocytes in vitro by increasing IL-2 and IL-4 production.

Colic M, Savic M.

Immunopharmacol Immunotoxicol. 2000 Feb; 22(1):163-81.

Garlic components are known to modulate certain immune functions. However, mechanisms of their action are not sufficiently elucidated. This study was, therefore, undertaken to examine the effects of aqueous and ethanolic extracts prepared from a garlic powder sample on proliferation of rat spleen lymphocytes in culture. Cells were stimulated with the combination of phorbol myristate acetate (PMA) and a Ca ionophore (A23187) or R73 monoclonal antibody (mAb) directed to the alphabeta chain of T cell receptor. It has been shown that both extracts significantly stimulated proliferation of lymphocytes. The effect correlated with upregulation of the Interleukin 2 receptor alpha (IL-2R alpha) expression and the increase in IL-2 production. Stimulation of IL-2 production by the extracts was higher in cultures with PMA/Ca ionophore than in cultures with R73 mAb. In contrast, both extracts stimulated production of IL-4 by splenocytes triggered by R73 mAb. The complete dependence of lymphocyte proliferation in cultures with R73 mAb and garlic extracts on IL-2 and IL-4 was demonstrated using neutralising mAbs to IL-2R alpha and IL-4. These results suggest that the potentiating effect of garlic extracts on lymphocyte proliferation in vitro differs depending on specific stimulators of cell proliferation and probably on the type of responding cells

Physicians want education about complementary and alternative medicine to enhance communication with their patients.

Corbin WL, Shapiro H.

Arch Intern Med. 2002 May 27; 162(10):1176-81.

BACKGROUND: More than one third of patients in the United States use complementary and alternative medicine (CAM); most also visit conventional physicians. There is little information about how physicians and patients discuss CAM. We hypothesized that physicians frequently fielded questions about CAM treatments but felt uncomfortable discussing them owing to a lack of education. OBJECTIVES: To survey physicians to see how they discussed CAM with their patients and what factors influenced discussions and referrals. METHODS: A total of 751 physicians in the Denver, Colo, area were asked about their experience with CAM and communication about CAM with patients. Analyses were conducted using the SAS system (version 6, 1989; SAS Institute Inc, Cary, NC). RESULTS: Of the 705 deliverable surveys, 302 (43%) were returned: 76% of physicians reported having patients using CAM; 59% had been asked about specific CAM treatments; 48% had recommended CAM to a patient; and 24% had personally used CAM. Physician recommendation of CAM was most strongly associated with physician self-use (odds ratio, 6.98; P<.001). Few physicians felt comfortable discussing CAM with their patients, and the overwhelming majority (84%) thought they needed to learn more about CAM to adequately address patient concerns. CONCLUSIONS: Education about CAM modalities is a significant unmet need among Denver physicians, and education may help alleviate the discomfort physicians have when answering patients’ questions about CAM. Physicians who use CAM treatments themselves are much more likely to recommend CAM for their patients than physicians who do not

Butter Enhanced with Natural Fatty Acids Reduces Breast Cancer Risk in Animals.

Cornell News.

Cornell News. 1999

Adriamycin cardiotoxicity: early detection by systolic time interval and possible prevention by coenzyme Q10.

Cortes EP, Gupta M, Chou C, et al.

Cancer Treat Rep. 1978 Jun; 62(6):887-91.

Recent work suggests that adriamycin (ADM) cardiotoxicity results from the depletion of coenzyme 10 (CoQ10) activity in myocardial mitochondria. CoQ10 is indispensable in the bioenergetics of coupled respiration of oxidative phosphorylation. It exists naturally in mitochondria, especially in the myocardium. Bertazzoli et al have reported a decrease in ADM-induced cardiotoxicity by CoQ10 both in vivo and in the in vitro isolated rabbit heart. The systolic time interval (ATI) (pre-ejection period/left ventricular ejection time ratio) has been shown to increase (indicating cardiac dysfunction) with increasing doses of ADM. We have noted a gradual increase in the STI in eight of ten patients receiving 200-500 mg/m2 of ADM. Two of these eight patients had congestive heart failure (CHF) at doses of 200 and 350 mg/m2. The continued daily oral administration of 50 mg of CoQ10 beginning with the first dose of ADM resulted in a decreased incidence of cardiac dysfunction, and a gradual increase in STI occurred in only two of eight patients receiving 200-400 mg/m2 of ADM. CHF was observed inone patient at a dose of 350 mg/m2. It is suggested that CoQ10 was nontoxic and did not affect the antitumor activity or modify the ADM-induced bone marrow toxicity. A prospective randomized study comparing ADM with and without CoQ10 is in progress

Indole-3-carbinol and tamoxifen cooperate to arrest the cell cycle of MCF-7 human breast cancer cells.

Cover CM, Hsieh SJ, Cram EJ, et al.

Cancer Res. 1999 Mar 15; 59(6):1244-51.

The current options for treating breast cancer are limited to excision surgery, general chemotherapy, radiation therapy, and, in a minority of breast cancers that rely on estrogen for their growth, antiestrogen therapy. The naturally occurring chemical indole-3-carbinol (I3C), found in vegetables of the Brassica genus, is a promising anticancer agent that we have shown previously to induce a G1 cell cycle arrest of human breast cancer cell lines, independent of estrogen receptor signaling. Combinations of I3C and the antiestrogen tamoxifen cooperate to inhibit the growth of the estrogen-dependent human MCF-7 breast cancer cell line more effectively than either agent alone. This more stringent growth arrest was demonstrated by a decrease in adherent and anchorage-independent growth, reduced DNA synthesis, and a shift into the G1 phase of the cell cycle. A combination of I3C and tamoxifen also caused a more pronounced decrease in cyclin-dependent kinase (CDK) 2-specific enzymatic activity than either compound alone but had no effect on CDK2 protein expression. Importantly, treatment with I3C and tamoxifen ablated expression of the phosphorylated retinoblastoma protein (Rb), an endogenous substrate for the G1 CDKs, whereas either agent alone only partially inhibited endogenous Rb phosphorylation. Several lines of evidence suggest that I3C works through a mechanism distinct from tamoxifen. I3C failed to compete with estrogen for estrogen receptor binding, and it specifically down-regulated the expression of CDK6. These results demonstrate that I3C and tamoxifen work through different signal transduction pathways to suppress the growth of human breast cancer cells and may, therefore, represent a potential combinatorial therapy for estrogen-responsive breast cancer

Selected micronutrient intake and thyroid carcinoma risk.

D’Avanzo B, Ron E, La Vecchia C, et al.

Cancer. 1997 Jun 1; 79(11):2186-92.

BACKGROUND: Protection from thyroid carcinoma due to certain dietary factors was suggested by several studies, but the findings were relatively inconsistent. The role of micronutrients has not yet been systematically analyzed. To investigate the relationship between micronutrient intake and thyroid carcinoma risk, the authors used data from a case-control study conducted in northern Italy between 1986 and 1992. METHODS: The study included 399 incident, histologically confirmed thyroid carcinoma cases and 617 controls admitted to the hospital for acute, nonneoplastic, nonhormone-related diseases. RESULTS: Retinol intake showed a direct association with thyroid carcinoma risk, with odds ratios (ORs) of 1.39 (95% confidence Interval [CI], 0.9-2.0) in the third quartile of consumption and 1.52 (95% CI, 1.0-2.3) in the highest quartile, whereas beta-carotene had an inverse relationship, with ORs of 0.63 (95% CI, 0.4-0.9) in the third quartile of consumption and 0.58 (95% CI, 0.4-0.9) in the highest quartile compared with the lowest quartile. Some protection was observed for measures of vitamin C intake (with an OR of 0.72) and vitamin E (with an OR of 0.67) for the highest quartile of consumption, although the estimates were not statistically significant, and were reduced after adjustment for beta-carotene intake. No clear pattern in risk appeared for vitamin D, lolate, calcium, thiamin, or riboflavin. The inverse relationship between beta-carotene and thyroid carcinoma was observed in both papillary and follicular carcinomas. CONCLUSIONS: In this study, a significant inverse association between beta-carotene and thyroid carcinoma was observed, and some protection against thyroid carcinoma from vitamins C and E was also suggested

Inhibition of tumorigenic potential and prostate-specific antigen expression in LNCaP human prostate cancer cell line by 13-cis-retinoic acid.

Dahiya R, Park HD, Cusick J, et al.

Int J Cancer. 1994 Oct 1; 59(1):126-32.

Prostate-specific antigen (PSA) is a member of the kallikrein family and has been an important biological marker for prostate cancer. The mechanisms regulating PSA expression in prostatic cancer cells are unclear. The present study was designed to elucidate the role of 13-cis-retinoic acid (RA) in regulation of PSA and the tumorigenic potential of the human prostate cancer cell line LNCaP. The growth regulation of LNCaP cells was examined by DNA synthesis and doubling time. The tumorigenic potential of prostate cancer cells was analyzed by soft agar colony-forming assay, in vitro invasion assay, type IV collagenase assay and binding to extracellular matrix assay. The nuclear receptors for retinoic acid (RAR alpha, -beta, -gamma and RXR alpha, -beta, -gamma) as well as PSA mRNA were determined by Northern blot using specific oligonucleotide probes. Our results suggest that 13-cis-RA significantly inhibits PSA secretion and expression both at the mRNA and protein levels compared with untreated cells. Electron microscopic studies suggest that after 13-cis-RA treatment, cells become more differentiated as they contain lumina, lined by plasma membrane and microvilli. Prostate cancer cell growth and tumorigenic potential after 13-cis-RA treatment was significantly decreased compared with controls. Nude mice tumorigenicity studies showed that 13-cis-RA-treated cells produced significantly smaller tumors compared with untreated cell tumors. There was also a significant increase in the expression of RXRa mRNA after 13-cis-RA treatment compared with untreated cells

Population-based case-control study of soyfood intake and breast cancer risk in Shanghai.

Dai Q, Shu XO, Jin F, et al.

Br J Cancer. 2001 Aug 3; 85(3):372-8.

We evaluated the association of soyfood intake and breast cancer risk in a population-based case-control study among Chinese women in Shanghai. Included in the study were 1459 cases and 1556 age-matched controls, with respective response rates of 91.1% and 90.3%. Usual soyfood intake was assessed using a food frequency questionnaire (FFQ). Separate analyses were performed for all subjects and for the subset who reported no recent change in soyfood intake. The intake levels of soyfoods among women in Shanghai are high, with 96.6% women reporting soyfood consumption at least once a week. A statistically non-significant reduced risk (odds ratio (OR) = 0.78 95% CI = 0.52-1.16) of breast cancer was observed among those who reported eating soyfood at least once a week. Compared to those in the lowest decile intake group, women in the highest decile intake group had a 30% reduced risk of breast cancer (OR = 0.66, 95% CI = 0.46-0.95), but no monotonic dose-response relation was observed (P for trend, 0.28). Stratified analyses showed that the inverse association was restricted primarily among women who had a high body mass index (BMI), with an adjusted OR of 0.30 (95% CI = 0.10-0.94) observed for the highest intake group. The reduction in risk was stronger for breast cancer positive for both oestrogen receptor (ER) and progesterone receptor (PR) (OR = 0.44, 95% CI = 0.25-0.78) than those with other ER/PR status. More pronounced inverse associations were observed in analyses among those who reported no recent change in soyfood intake than those conducted in all subjects. A dose-response relation between soyfood intake and breast cancer risk was observed in this subset of women (P for trend, 0.02), with an OR of 0.46 (95%CI = 0.28-0.75) for those in the highest decile intake group. No clear monotonic dose-response relation was found between soyfood intake and breast cancer risk among regular soy eaters, but nevertheless the results suggest that regular soyfood consumption may reduce the risk of breast cancer, particularly for those positive for ER and PR; the effect may be modified by body mass index

Genistein, a component of soy, inhibits the expression of the EGF and ErbB2/Neu receptors in the rat dorsolateral prostate.

Dalu A, Haskell JF, Coward L, et al.

Prostate. 1998 Sep 15; 37(1):36-43.

BACKGROUND: Epidemiological reports suggest that Asians consuming a diet high in soy have a low incidence of prostate cancer. In animal models, soy and genistein have been demonstrated to suppress the development of prostate cancer. In this study, we investigate the mechanism of action, bioavailability, and potential for toxicity of dietary genistein in a rodent model. METHODS: Lobund-Wistar rats were fed a 0.025-1.0-mg genistein/g AIN-76A diet. The dorsolateral prostate was subjected to Western blot analysis for expression of tyrosine-phosphorylated proteins, and of the EGF and ErbB2/Neu receptors. Genistein concentrations were measured from serum and prostate using HPLC-mass spectrometry. Body and prostate weights, and circulating testosterone levels, were measured. RESULTS: Increasing concentrations of genistein in the diet inhibited tyrosine-phosphorylated proteins with molecular weights of 170,000 and 85,000 in the dorsolateral prostate. Western blot analysis revealed that the 1-mg genistein/g AIN-76A diet inhibited by 50% the expression of the EGF receptor and its phosphorylation. In rats fed this diet, serum-free and total genistein concentrations were 137 and 2,712 pmol/ml, respectively. The free and total genistein IC50 values for the EGF receptor were 150 and 600 pmol/g prostate tissue, respectively. Genistein in the diet also inhibited the ErbB2/Neu receptor. Body and dorsolateral prostate weights, and circulating testosterone concentrations, were not adversely effected from exposure to genistein in the diet for 3 weeks. CONCLUSIONS: We conclude that genistein in the diet can downregulate the EGF and ErbB2/Neu receptors in the rat prostate with no apparent adverse toxicity to the host. The concentration needed to achieve a 50% reduction in EGF receptor expression can be achieved by eating a diet high in soy products or with genistein supplementation. Genistein inhibition of the EGF signaling pathway suggests that this phytoestrogen may be useful in both protecting against and treating prostate cancer

Distinct Chk2 activation pathways are triggered by genistein and DNA-damaging agents in human melanoma cells.

Darbon JM, Penary M, Escalas N, et al.

J Biol Chem. 2000 May 19; 275(20):15363-9.

Genistein, a natural isoflavone found in soybeans, exerts a number of biological actions suggesting that it may have a role in cancer prevention. We have previously shown that it potently inhibits OCM-1 melanoma cell proliferation by inducing a G(2) cell cycle arrest. Here we show that genistein exerts this effect by impairing the Cdc25C-dependent Tyr-15 dephosphorylation of Cdk1, as the overexpression of this phosphatase allows the cells to escape G(2) arrest and enter an abnormal chromatin condensation stage. Caffeine totally overrides the genistein-induced G(2) arrest, whereas the block caused by etoposide is not bypassed and that caused by adriamycin is only partially abolished. We also report that genistein activates the checkpoint kinase Chk2 as efficiently as the two genotoxic agents and that caffeine may counteract the activation of Chk2 by genistein but not by etoposide. In contrast, caffeine abolishes the accumulation of p53 caused by all the compounds. Wortmannin does not suppress the Chk2 activation in any situation, suggesting that the ataxia telangiectasia-mutated kinase is not involved in this regulation. Finally, unlike etoposide and adriamycin, genistein induces only a weak response in terms of DNA damage in OCM-1 cells. Taken together, these results suggest that the G(2) checkpoints activated by genistein and the two genotoxic agents involve different pathways

[From cancers of the uterus and breast to cancers of the spirit (XVIII-XIX centuries)].

Darmon P.

Contracept Fertil Sex. 1993 Feb; 21(2):185-6.

Cancer, particularly uterus and breast cancer, is since Antiquity attributed to melancholy and psychological reasons. Testimonies become especially numerous at XVIII and XIX centuries

Effects of soy or rye supplementation of high-fat diets on colon tumour development in azoxymethane-treated rats.

Davies MJ, Bowey EA, Adlercreutz H, et al.

Carcinogenesis. 1999 Jun; 20(6):927-31.

Evidence is accumulating that a diet high in plant-derived foods may be protective against cancer. One class of plant component under increasing investigation is the phytoestrogens of which there are two main groups: the isoflavones, found mainly in soy products, and the lignans, which are more ubiquitous and are found in fruit, vegetables and cereals with high levels being found in flaxseed. In this study, we have used carefully balanced high-fat (40% energy) diets: a control diet (containing low isoflavone soy protein as the sole protein source), a rye diet (the control diet supplemented with rye bran) and a soy diet (containing as protein source a high isoflavone soy protein). The effect of these diets on the development of colonic cancer was studied in F-344 rats treated with the carcinogen, azoxymethane (two doses of 15 mg/kg given 1 week apart). Colons from treated animals were examined for aberrant crypt foci (ACF) and tumours after 12 and 31 weeks. Results after 12 weeks showed no differences in the total number of ACF in the control, soy or rye bran groups. However, the soy group had increased numbers of small ACF (less than four crypts/focus) while the rye group had decreased numbers of large ACF (greater than six crypts/focus). Examination of colons after 31 weeks gave similar low numbers of ACF in each group with no differences in multiplicity. There were no differences in the number of tumours between the control (1.36 tumours/rat) and soy (1.38 tumours/rat) groups. However, there was a significant decrease in the number of tumours in the rye group (0.17 tumours/rat). These results suggest that soy isoflavones have no effect on the frequency of colonic tumours in this model while rye bran supplementation decreases the frequency of colon cancer. This effect is due not to a decrease in early lesions but in their progression to larger multi-crypt ACF. The study also supports the hypothesis that larger ACF are more predictive of subsequent tumorigenicity

Selenium-enriched broccoli decreases intestinal tumorigenesis in multiple intestinal neoplasia mice.

Davis CD, Zeng H, Finley JW.

J Nutr. 2002 Feb; 132(2):307-9.

Multiple intestinal neoplasia (Min) mice are a good model for the investigation of the effects of dietary alterations in a genetic model for intestinal cancer. Previous studies have shown that selenium-enriched broccoli is protective against chemically induced colon cancer susceptibility. This study investigated whether selenium-enriched broccoli would be protective against intestinal cancer susceptibility in Min mice. Five-week-old heterozygotic male Min mice were fed an AIN-93-based diet containing either low-selenium broccoli or an equivalent amount of high-selenium broccoli for 10 wk. Mice fed the selenium-enriched broccoli had fewer (P < 0.02) small intestinal (46.4 +/- 3.7 vs. 65.6 +/- 6.1) and large intestinal (0.43 +/- 0.17 vs. 1.93 +/- 0.27) tumors than those fed an equivalent amount of unenriched broccoli. Min mice fed the selenium-enriched broccoli had small but significant (P < 0.0001) increases in plasma and liver selenium concentrations and red blood cell glutathione peroxidase activity. These results extend previous observations that selenium-enriched broccoli is protective against chemically induced mammary and colon cancer in rats

Soy isoflavone supplementation in healthy men prevents NF-kappa B activation by TNF-alpha in blood lymphocytes.

Davis JN, Kucuk O, Djuric Z, et al.

Free Radic Biol Med. 2001 Jun 1; 30(11):1293-302.

Dietary intake of soy has been associated with a decreased risk of cancer. Soy isoflavones have been postulated to be the protective compounds in soybeans; however, the precise mechanism by which soy isoflavones prevent human cancer is not known. The major soy isoflavones, genistein and daidzein, are antioxidant compounds, therefore one possible mechanism of action is through their antioxidant effect. We have previously demonstrated that the soy isoflavone, genistein, inhibits the activation of the redox-sensitive transcription factor, NF-kappa B, in prostate cancer cells in vitro. In this study, we have demonstrated that genistein, but not daidzein, inhibits TNF-alpha-induced NF-kappa B activation in cultured human lymphocytes. Additionally, we investigated the in vivo effect of soy isoflavone supplementation on NF-kappa B activation induced by TNF-alpha in vitro in peripheral blood lymphocytes of six healthy men. We show that healthy male subjects receiving 50 mg isoflavone mixture (Novasoy) twice daily for 3 weeks are protected from TNF-alpha induced NF-kappa B activation. Additionally, we observed a reduction of 5-hydroxymethyl-2′-deoxyuridine (5-OHmdU), a marker for oxidative DNA damage, following isoflavone supplementation. The inhibitory effect of soy isoflavones was no longer present 3 months after the supplementation. This preliminary study demonstrates that soy isoflavone supplementation may protect cells from oxidative stress-inducing agents by inhibiting NF-kappa B activation and decreasing DNA adduct levels

Metabolic, desmutagenic and anticarcinogenic effects of N-acetylcysteine.

De Flora S, Rossi GA, De Flora A.

Respiration. 1986; 50 Suppl 1:43-9.

N-acetylcysteine (NAC) is often administered to respiratory patients with histories of exposure to noxious agents (e.g. cigarette smoke and atmospheric pollutants), which are known to act as glutathione (GSH) depletors and as cancer initiators and/or promoters. Since NAC is a precursor of intracellular GSH, we investigated its effects on GSH metabolism and on the biotransformation of carcinogenic and/or mutagenic compounds. In vitro, NAC induced a significant increase in oxidized glutathione (GSSG) reductase activity in rat liver preparations and counteracted the mutagenicity of direct-acting compounds (such as epichlorohydrin, hydrogen peroxide, 4-nitroquinoline-N-oxide and dichromate), as a result of its reducing and scavenging properties. At high concentrations, the drug completely inhibited the mutagenicity of procarcinogens (cigarette smoke condensate, tryptophan pyrolysate, cyclophosphamide, 2-aminofluorene, benzo(a)pyrene and aflatoxin B1) by binding their electrophilic metabolites. In contrast, their metabolic activation was stimulated by decreasing NAC concentrations, especially when liver preparations from enzyme-induced rats were used. Lung and liver subcellular preparations of rats treated in vivo with NAC, in various combinations with enzyme inducers and/or GSH depletors, also affected the mutagenicity of a number of compounds. NAC generally increased intracellular GSH and restored its levels following depletion. It did not affect the levels nor the spectral properties of cytochromes P-450 in pulmonary and hepatic microsomes, whereas it stimulated, especially in Aroclor-pretreated animals, cytosolic enzyme activities involved in NADP or GSSG reduction (G6PD, 6PGD and GSSG reductase) and in the reductive detoxification of xenobiotics (DT diaphorase). When administered with the diet, at a nontoxic posology (120 mg/kg b.w.), NAC markedly inhibited the induction of lung tumors in mice by a potent carcinogen (urethane)

N-Acetylcysteine as antimutagen and anticarcinogen.

De Flora S.

Toxicol Lett. 1992; 53

W4/L2

Synergism between N-acetylcysteine and doxorubicin in the prevention of tumorigenicity and metastasis in murine models.

De Flora S, D’Agostini F, Masiello L, et al.

Int J Cancer. 1996 Sep 17; 67(6):842-8.

The thiol N-acetylcysteine (NAC) is a promising cancer chemopreventive agent which acts through a variety of mechanisms, including its nucleophilic and antioxidant properties. We have recently shown that NAC inhibits type-IV collagenase activity as well as invasion, tumor take and metastasis of malignant cells in mice. NAC is also known to attenuate the cardiotoxicity of the cytostatic drug doxorubicin (DOX, Adriamycin). The present study was designed to evaluate whether the combination of NAC and DOX treatments in mice injected with cancer cells could affect their tumorigenic and metastatic properties. Six separate experiments were carried out, using a total of 291 adult female mice. In experimental metastasis assays, in which B16-F10 melanoma cells were injected i.v. into (CD-1)BR nude mice, DOX significantly reduced the number of lung metastases when administered i.v. at a dose of 10 mg/kg body weight, 3 days after the i.v. injection of cancer cells. NAC inhibited lung metastases when added to the medium of cancer cells before their i.v. injection. The combined treatment with DOX and NAC, under various experimental conditions, was highly effective, showing a synergistic reduction in the number of mestastases. In tumorigenicity and spontaneous metastasis assays, in which B16-BL6 melanoma cells were injected s.c. into the footpad of C57BL/6 mice, DOX decreased the number of lung metastases when given i.p. at 2 mg/kg body weight. Oral NAC exerted significant protective effects, and considerably prolonged survival of mice. The combined treatment with DOX and NAC again showed synergistic effects on the frequency and weight of primary tumors and local recurrences, and completely prevented the formation of lung metastases in the experiment in which these end-points were evaluated at fixed times. While injection of DOX 7 days after implantation of cancer cells failed to improve the cancer-protective effects of NAC, its injection after I day resulted in a striking inhibition of lung metastases. These findings demonstrate an evident synergism between DOX (given parenterally) and NAC (given with drinking water) in preventing tumorigenicity and metastases. The indications of these animal studies warrant further evaluation in clinical trials

Dietary carotenoids and risk of gastric cancer: a case-control study in Uruguay.

De Stefani E, Boffetta P, Brennan P, et al.

Eur J Cancer Prev. 2000 Oct; 9(5):329-34.

In the period 1997-1999, 120 incident and histologically verified cases of stomach cancer were frequency matched on age, sex, residence and urban/rural status with 360 controls in order to study the role of diet in gastric cancer in Uruguay. Our attention was focused on the role of carotenoids in gastric carcinogenesis, after controlling for major confounders. According to the results, vitamin A, alpha-carotene and lycopene were associated with strong inverse relationships with stomach cancer (OR of stomach cancer for high alpha-carotene intake 0.34, 95% CI 0.17-0.65). Joint exposure to high intakes of alpha-carotene and vitamin C intakes were associated with a strong reduction in risk (OR 0.11, 95% CI 0.03-0.36). It was also suggested that high lycopene intake explained most of the reduction in risk of gastric cancer associated with vegetable intake, whereas no such effect was observed for fruit intake

Striking regression of radiation-induced fibrosis by a combination of pentoxifylline and tocopherol.

Delanian S.

Br J Radiol. 1998 Aug; 71(848):892-4.

Radiation-induced fibrosis (RIF) is a terminal sequela to irradiation that does not regress spontaneously. A preliminary study of a combination of pentoxifylline (PTX) and tocopherol (vit-E) has shown clinical activity with 50% superficial RIF regression at 6 months in half of the patients studied. The present report is of a 67-year-old woman presenting with bulky cervicothoracic RIF who, 10 years previously, had received radiochemotherapy for a small cell thyroid carcinoma to a dose of 50 Gy, with severe acute side-effects. She had palpable cervicosternal fibrosis measuring 10 x 8 cm, with local inflammatory signs and functional consequences (cough, restricted cervical movement, dyspnoea and bronchitis) with a SOMA scale for grading the long-term side effects of radiation therapy of 19/14. CT showed deep RIF extending from the vocal cords to the carina, with laryngotracheal compression but without cancer recurrence. PTX (800 mg d-1) and vit-E (1000 U d-1), orally administered daily for 18 months, were well tolerated. The patient exhibited clinical regression and functional improvement. The linear dimensions and SOMA scale were, respectively, 8 x 6 cm and 11 at 6 months; 4 x 4 cm and 7 at 12 months; and complete response with no measurable RIF and 1 at 18 months. This is the first time that the combination of PTX and vit-E has had a significant antifibrotic effect by completely reversing deep RIF as shown by CT scan normalization

Estradiol activation of human colon carcinoma-derived Caco-2 cell growth.

Di Domenico M, Castoria G, Bilancio A, et al.

Cancer Res. 1996 Oct 1; 56(19):4516-21.

This is the first report on estrogen-dependent growth of human-derived colon carcinoma cells. Under selected conditions, growth of subconfluent Caco-2 cells is triggered by estradiol. Cell growth is estradiol concentration dependent, with maximal effect occurring at about 0.4 nM. Growth is prevented by two different antiestrogens: the partial agonist, OH-Tamoxifen, and the pore antagonist, ICI 182,780. The growth effect is specific for estradiol since other hormonal steroids tested do not affect cell growth. The amount of estradiol receptor in subconfluent Caco-2 cells, detected by blot with monoclonal antibodies directed against the receptor as well as estradiol binding assays, is similar to that of the classical estradiol-responsive, human mammary cancer-derived MCF-7 cells. Estradiol treatment of subconfluent Caco-2 cells rapidly and reversibly stimulates four important intermediates in a signal transduction pathway that is known to trigger cell proliferation: two members of the large family of c-src-related tyrosine kinases, c-src and c-yes, and two serine/threonine kinases, the mitogen-activated protein (MAP) kinases, erk-1 and erk-2. Tyrosine kinases activated by estradiol are up-stream MAP kinases and Caco-2 cell proliferation. In fact, genistein, a specific tyrosine kinase inhibitor, abolishes the estradiol stimulatory effect on both erk-2 activity and cell proliferation. Our findings show that in subconfluent Caco-2 cells, the estradiol-receptor complex activates the c-src, c-yes/MAP kinase pathway and activates growth. This could have important implications for the understanding of human intestinal carcinogenesis

Effect of lactoferrin on Helicobacter felis induced gastritis.

Dial EJ, Lichtenberger LM.

Biochem Cell Biol. 2002; 80(1):113-7.

Lactoferrin possesses antibiotic, antiinflammatory, and immune-modulating properties that may be active against the gastritis-, ulcer- and cancer-inducing bacterium Helicobacter pylori. In vitro testing of bovine and human lactoferrin by several laboratories has shown significant bacteriostatic and bactericidal activity. Subsequent in vivo testing of bovine lactoferrin in animal models of H. pylori infection has shown beneficial effects of this agent. Our laboratory has utilized a mouse model that is infected with the feline strain of this bacterium, H. felis. The resulting gastritis that develops in this model and the effects of bovine lactoferrin and recombinant human lactoferrin (from Aspergillus niger var. awamori, Agennix Inc., Houston, Tex.) treatment were assessed by various measures. Infected animals treated with orally administered lactoferrin showed reversals in all parameters. In addition, when recombinant human lactoferrin was used in combination with low doses of amoxicillin or tetracycline, there was an enhancement in gastritis-reducing activity. Possible mechanisms for these effects of lactoferrin are discussed. Lactoferrin has significant, orally active in vivo actions and should be further investigated for clinical situations involving Helicobacter infections where it may have utility when administered alone and also when given in combination with established antibiotic agents

Reduction in new metastases in breast cancer with adjuvant clodronate treatment.

Diel IJ, Solomayer EF, Costa SD, et al.

N Engl J Med. 1998 Aug 6; 339(6):357-63.

BACKGROUND: Bisphosphonates are effective against the increased bone resorption caused by certain diseases because they inhibit the activity of osteoclasts. In patients who have breast cancer and metastatic bone disease, the bisphosphonate clodronate (clodronic acid) reduces the frequency of skeletal complications. Experiments in animals and preliminary clinical observations indicate that early clodronate therapy reduces the incidence of new bony metastases in breast cancer. We investigated the effects of clodronate on the incidence and extent of new metastases in patients with breast cancer. METHODS: Between 1990 and 1995, 302 patients with primary breast cancer and tumor cells in the bone marrow (the presence of which is a risk factor for the development of distant metastases) were randomly assigned to receive clodronate at a dose of 1600 mg per day orally for two years (157 patients) or standard follow-up (145 patients). The median length of observation was 36 months. All patients in both groups received standard surgical treatment and customary hormonal therapy or chemotherapy. RESULTS: Distant metastases were detected in 21 patients in the clodronate group and in 42 patients in the control group (P<0.001). The incidence of both osseous and visceral metastases was significantly lower in the clodronate group than in the control group (P=”0.003″ for both osseous and visceral metastases). Six patients in the clodronate group died, as did 22 in the control group (P=”0.001).” The mean number of bony metastases per patient in the clodronate group was roughly half that in the control group (3.1 vs. 6.3). CONCLUSIONS: Clodronate can reduce the incidence and number of new bony and visceral metastases in women with breast cancer who are at high risk for distant metastases

Differential sensitivity of various pediatric cancers and squamous cell carcinomas to lovastatin-induced apoptosis: therapeutic implications.

Dimitroulakos J, Ye LY, Benzaquen M, et al.

Clin Cancer Res. 2001 Jan; 7(1):158-67.

3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase is the rate-limiting enzyme of the mevalonate pathway, the diverse array of end products of which are vital for a variety of cellular functions, including cholesterol synthesis and cell cycle progression. We showed previously that this enzyme holds a critical role in regulating tumor cell fate, including cell death, as its expression is down-regulated in response to retinoic acid, a potent anticancer therapeutic. Indeed, direct inhibition of HMG-CoA reductase with lovastatin, a competitive inhibitor of this enzyme, induced a pronounced apoptotic response in neuroblastoma and acute myeloid leukemic cells. We have now extended this work and evaluated a wide variety and large number of tumor-derived cell lines for their sensitivity to lovastatin-induced apoptosis. These cell lines were exposed to a wide range (0-100 microM) of lovastatin for 2 days and assayed for cell viability using the 3,4,5-dimethyl thiazlyl-2,2,5-diphenyltetrazolium bromide assay and the induction of apoptosis by flow cytometric and ultrastructural analyses. Lovastatin induced a pronounced apoptotic response in cells derived from juvenile monomyelocytic leukemia, pediatric solid malignancies (rhabdomyosarcoma and medulloblastoma), and squamous cell carcinoma of the cervix and of the head and neck. Interestingly, the subset of malignancies that are particularly sensitive to lovastatin-induced apoptosis correspond to those tumor subtypes that are sensitive to the biological and antiproliferative effects of retinoids in vitro. The nature of the biologically active form of lovastatin has been challenged recently as the growth-inhibitory effects of this drug were attributed to its prodrug lactone form that does not inhibit HMG-CoA reductase function. In this report, we demonstrate that the apoptotic properties of lovastatin are triggered by the open ring acid form that is a potent inhibitor of HMG-CoA reductase activity. Thus, we have identified a subset of tumors that are sensitive to lovastatin-induced apoptosis and show HMG-CoA reductase as a potential therapeutic target of these cancers

Lipoxygenase inhibitors abolish proliferation of human pancreatic cancer cells.

Ding XZ, Iversen P, Cluck MW, et al.

Biochem Biophys Res Commun. 1999 Jul 22; 261(1):218-23.

Epidemiologic and animal studies have linked pancreatic cancer growth with fat intake, especially unsaturated fats. Arachidonic acid release from membrane phospholipids is essential for tumor cell proliferation. Lipoxygenases (LOX) constitute one pathway for arachidonate metabolism, but their role in pancreatic cancer growth is unknown. The expression of 5-LOX and 12-LOX as well as their effects on cell proliferation was investigated in four human pancreatic cancer cell lines (PANC-1, MiaPaca2, Capan2, and ASPC-1). Expression of 5-LOX and 12-LOX mRNA was measured by nested RT-PCR. Effects of LOX inhibitors and specific LOX antisense oligonucleotides on pancreatic cancer cell proliferation were measured by (3)H-thymidine incorporation. Our results showed that (1) 5-LOX and 12-LOX were expressed in all pancreatic cancer cell lines tested, while they were not detectable in normal human pancreatic ductal cells; (2) both LOX inhibitors and LOX antisense markedly inhibited cell proliferation in a concentration-dependent and time-dependent manner; (3) the 5-LOX and 12-LOX metabolites 5-HETE and 12-HETE as well as arachidonic and linoleic acids directly stimulated pancreatic cancer cell proliferation; (4) LOX inhibitor-induced growth inhibition was reversed by 5-HETE and 12-HETE. The current studies indicate that both 5-LOX and 12-LOX expression is upregulated in human pancreatic cancer cells and LOX plays a critical role in pancreatic cancer cell proliferation. LOX inhibitors may be valuable for the treatment of pancreatic cancer

Bisphosphonates in multiple myeloma.

Djulbegovic B, Wheatley K, Ross J, et al.

Cochrane Database Syst Rev. 2001;(4):CD003188.

BACKGROUND: Multiple myeloma is a disease characterized by the neoplastic proliferation of a clone of plasma cells that can lead to bone destruction. Bisphosphonates are specific inhibitors of osteoclastic activity. Therefore, there is a pharmacological basis for their use in multiple myeloma. However, the exact clinical role of bisphosphonates in multiple myeloma remains unclear. OBJECTIVES: Primary: to determine whether adding bisphosphonates to standard therapy in multiple myeloma decreases skeletal-related morbidity (pathological fractures), skeletal-related mortality and overall mortality. Secondary: to determine the effects of bisphosphonates on pain, quality of life and incidence of hypercalcemia. SEARCH STRATEGY: We searched MEDLINE (1

L-arginine inhibits apoptosis via a NO-dependent mechanism in Nb2 lymphoma cells.

Dodd F, Limoges M, Boudreau RT, et al.

J Cell Biochem. 2000 Apr; 77(4):624-34.

Prolactin (PRL) inhibits apoptosis and stimulates proliferation of the PRL-dependent rat Nb2 lymphoma cell line by divergent signaling pathways. Nitric oxide (NO) was recently identified as a downstream regulator of PRL action, and as an inhibitor of apoptosis in immune cells. In the present study, the role of NO in PRL-regulated Nb2 cell function was investigated. Nb2 cells expressed the endothelial nitric oxide synthase (eNOS) isoform, whereas neuronal NOS (nNOS) and inducible NOS (iNOS) mRNAs were undetectable. The eNOS mRNA was abundantly expressed in PRL-deprived, growth-arrested cells but decreased by at least 3-fold at 3-24 h following PRL treatment. Downregulation of eNOS was not accompanied by a corresponding decrease in the eNOS protein, the level of which remained constant for at least 24 h after PRL treatment. PRL had no effect on the phosphorylation state or subcellular redistribution of the eNOS enzyme, or on production of NO by Nb2 cells. However, increasing concentrations of L-arginine (NOS substrate) alone increased NO production in these cells and significantly enhanced PRL-stimulated cell proliferation. NO releasers (SNAP, DEA/NO, SIN-1) also significantly enhanced Nb2 cell proliferation in the presence of a submaximal dose of PRL (0.125 ng/ml). In the absence of PRL, the NO releasers alone promoted cell survival and maintained a viable cell density significantly higher than that of untreated PRL-deprived cells. L-arginine or the NO releaser DEA/NO alone significantly inhibited apoptosis in Nb2 cells deprived of PRL for 5 days. Expression of the anti-apoptotic gene bcl-2, which was stimulated within 1 h by PRL, was upregulated by L-arginine or DEA/NO alone at 2 h and 8 h, respectively. These findings suggest that NO produced by eNOS inhibits apoptosis and promotes the survival of growth-arrested Nb2 lymphoma cells via a prolactin-independent, Bcl-2-mediated pathway

Goitrogenic and estrogenic activity of soy isoflavones.

Doerge DR, Sheehan DM.

Environ Health Perspect. 2002 Jun; 110 Suppl 3:349-53.

Soy is known to produce estrogenic isoflavones. Here, we briefly review the evidence for binding of isoflavones to the estrogen receptor, in vivo estrogenicity and developmental toxicity, and estrogen developmental carcinogenesis in rats. Genistein, the major soy isoflavone, also has a frank estrogenic effect in women. We then focus on evidence from animal and human studies suggesting a link between soy consumption and goiter, an activity independent of estrogenicity. Iodine deficiency greatly increases soy antithyroid effects, whereas iodine supplementation is protective. Thus, soy effects on the thyroid involve the critical relationship between iodine status and thyroid function. In rats consuming genistein-fortified diets, genistein was measured in the thyroid at levels that produced dose-dependent and significant inactivation of rat and human thyroid peroxidase (TPO) in vitro. Furthermore, rat TPO activity was dose-dependently reduced by up to 80%. Although these effects are clear and reproducible, other measures of thyroid function in vivo (serum levels of triiodothyronine, thyroxine, and thyroid-stimulating hormone; thyroid weight; and thyroid histopathology) were all normal. Additional factors appear necessary for soy to cause overt thyroid toxicity. These clearly include iodine deficiency but may also include additional soy components, other defects of hormone synthesis, or additional goitrogenic dietary factors. Although safety testing of natural products, including soy products, is not required, the possibility that widely consumed soy products may cause harm in the human population via either or both estrogenic and goitrogenic activities is of concern. Rigorous, high-quality experimental and human research into soy toxicity is the best way to address these concerns. Similar studies in wildlife populations are also appropriate

Therapeutic potential of curcumin in human prostate cancer. III. Curcumin inhibits proliferation, induces apoptosis, and inhibits angiogenesis of LNCaP prostate cancer cells in vivo.

Dorai T, Cao YC, Dorai B, et al.

Prostate. 2001 Jun 1; 47(4):293-303.

BACKGROUND: Earlier work from our laboratory highlighted the therapeutic potential of curcumin (turmeric), used as a dietary ingredient and as a natural anti-inflammatory agent in India and other Southeast Asian countries. This agent was shown to decrease the proliferative potential and induce the apoptosis potential of both androgen-dependent and androgen-independent prostate cancer cells in vitro, largely by modulating the apoptosis suppressor proteins and by interfering with the growth factor receptor signaling pathways as exemplified by the EGF-receptor. To extend these observations made in vitro and to study the efficacy of this potential anti-cancer agent in vivo, the growth of LNCaP cells as heterotopically implanted tumors in nude mice was followed. METHODS: The androgen-dependent LNCaP prostate cancer cells were grown, mixed with Matrigel and injected subcutaneously into nude mice. Experimental group received a synthetic diet containing 2% curcumin for up to 6 weeks. At the end point, sections taken from the excised tumors were evaluated for pathology, cell proliferation, apoptosis, and vascularity. RESULTS: Curcumin causes a marked decrease in the extent of cell proliferation as measured by the BrdU incorporation assay and a significant increase in the extent of apoptosis as measured by an in situ cell death assay. Moreover, a significant decrease in the microvessel density as measured by the CD31 antigen staining was also seen. CONCLUSIONS: Curcumin could be a potentially therapeutic anti-cancer agent, as it significantly inhibits prostate cancer growth, as exemplified by LNCaP in vivo, and has the potential to prevent the progression of this cancer to its hormone refractory state

Combined effect of lipoic acid and doxorubicin in murine leukemia.

Dovinova I, Novotny L, Rauko P, et al.

Neoplasma. 1999; 46(4):237-41.

Our experiments indicate that administration of a toxic drug with high rate of free-radical formation (doxorubicin, DOX) combined with an antioxidant (alpha-lipoic acid, LA) may lead to a decrease in drug-toxicity. However, the effects of antioxidant may be concentration-dependent and it is therefore crucial to choose its appropriate dosage. LA at a low concentration (1 micromol/l) acts as a growth factor and at a higher concentration (100 micromol/l) acts as an antiproliferation agent. Both concentrations of LA in combination with DOX were examined in cytotoxic and antitumor effects in L1210 mouse leukemia cells employing a MTT chemosensitivity assay. In most concentration combinations, DOX and LA effect were antagonistic and synergistic action was only found at the higher concentration of both agents (DOX 2.5 micromol/l and LA 100 micromol/l). Use of LA in doxorubicin therapy lead to an increase (though marginally significant) in survival of animals. Combined single-dose administration of DOX (5 mg/kg) and LA (16 mg/kg) lead to super-additive effect of the combination on survival of leukemic mice

A 2-week pretreatment with 13-cis-retinoic acid + interferon-alpha-2a prior to definitive radiation improves tumor tissue oxygenation in cervical cancers.

Dunst J, Hansgen G, Krause U, et al.

Strahlenther Onkol. 1998 Nov; 174(11):571-4.

BACKGROUND: We have evaluated the tumor tissue pO2 in cervical cancers in patients treated with 13-cis-retinoic acid and interferon-alpha-2a prior to and during radiotherapy. PATIENTS AND METHODS: From June 1995 through April 1997, 22 patients with squamous cell carcinoma FIGO IIB/III of the cervix who were scheduled for definitive radiotherapy with curative intent received additional treatment with 13-cis-retinoic acid (cRA, isotretinoin) plus interferon-alpha-2a (IFN-alpha-2a) as part of a phase-II protocol. cRA/IFN-alpha-2a started 14 days prior to radiotherapy (1 mg per kilogramme body weight cRA orally daily plus 6 x 10(6) IU IFN-alpha-2a subcutaneously daily). After this induction period, standard radiotherapy was administered (external irradiation with 50.4 Gy in 28 fractions of 1.8 Gy plus HDR-brachytherapy). During radiotherapy, cRA/IFN-alpha-2a treatment was continued with 50% of the daily doses. Tumor tissue pO2-measurements were performed prior to and after the cRA/IFN-induction period as well as at 20 Gy and at the end of radiotherapy with an Eppendorf-pO2-histograph. RESULTS: In 11 out of the 22 patients, pO2-measurements were performed prior to the cRA/IFN-induction therapy. The median pO2 of these untreated tumors was 17.7 +/- 16.3 mm Hg. The relative frequency of hypoxic readings with pO2-values below 5 mm Hg ranged from 0% to 60.6% (mean 24.3 +/- 21.0%). After the 2-week induction period with cRA/IFN, the median pO2 had increased from 17.7 +/- 16.3 mm Hg to 27.6 +/- 19.1 mm Hg (not significant). In all 5 patients with hypoxic tumors prior to cRA/IFN (median pO2 of 10 mm Hg or less), the median pO2 was above 20 mm Hg after the 2-week cRA/IFN-induction. In this subgroup of hypoxic tumors, the median pO2 increased from 6.3 +/- 2.7 mm Hg to 27.0 +/- 5.6 mm Hg (p = 0.004, t-test for paired samples). The frequency of hypoxic readings (pO2-values < 5 mm Hg) decreased from 44.7 +/- 17.1% to 2.0 +/- 2.5% (p = “0.012,” t-test for paired samples). There was, however, no obvious volume reduction after 14 weeks of cRA/IFN on clinical examination. A complete clinical remission of the local tumor was observed in 19/22 patients after radiotherapy and additional cRA/IFN-alpha-2a-treatment. In primarily hypoxic tumors (with a median pO2 below 10 mm Hg prior to treatment), 4/5 achieved complete remission. CONCLUSIONS: Pretreatment with cRA/IFN improves oxygenation of primarily hypoxic cervical cancers. The mechanisms of action remain unclear and further investigation of the combination regimen is recommended

Oxygenation of cervical cancers during radiotherapy and radiotherapy + cis-retinoic acid/interferon.

Dunst J, Hansgen G, Lautenschlager C, et al.

Int J Radiat Oncol Biol Phys. 1999 Jan 15; 43(2):367-73.

PURPOSE: We have evaluated the tumor tissue pO2 in cervical cancers during radiotherapy with special emphasis on the course of the pO2 in primarily hypoxic tumors and in patients treated with radiotherapy plus 13-cis-retinoic acid/interferon-alpha-2a. METHODS AND MATERIALS: From June 1995 through April 1997, 49 patients with squamous cell carcinoma FIGO IIB-IVA of the cervix who were treated with definitive radiotherapy with curative intent underwent polarographic measurement of tumor tissue pO2 with an Eppendorf pO2-histograph prior to and during radiation treatment. Radiotherapy consisted of external irradiation with 50.4 Gy in 28 fractions of 1.8 Gy plus high dose rate (HDR) brachytherapy. Twenty-two patients had additional treatment with 13-cis-retinoic acid (cRA, isotretinoin) and interferon-alpha-2a (IFN-alpha-2a). Therapy with cRA/IFN in these patients started 2 weeks before radiotherapy; during this induction period, cRA was administered in a dosage of 1 mg per kilogram body weight orally daily and IFN-alpha-2a in a dosage of 6×10(6) I.U. subcutaneously daily. After start of external radiotherapy (XRT), cRA/IFN was continued concomitantly with radiotherapy in reduced doses (0.5 mg cRA per kg body weight orally daily plus 3×10(6) I.U. IFN-alpha-2a subcutaneously three times weekly until the end of the radiation treatment). PO2 measurements were performed prior to radiotherapy, at 20 Gy, and at the end of radiotherapy. RESULTS: A poor oxygenation defined as a median pO2 of 10 mm Hg or less was present in 15/38 tumors (39%) in which measurements prior to any treatment were done. Low pO2 readings below 5 mm Hg were present in 70% of all tumors prior to treatment. In 13 of 15 hypoxic tumors, pO2 measurements at 19.8 Gy were performed. In these tumors, a significant increase of the median pO2 from 6.0+/-3.1 mm Hg to 20.7+/-21.2 mm Hg was found, p10 mm Hg), 20/23 (87%) achieved a clinically complete response. In patients with primarily hypoxic tumors, 6/6 patients whose primarily hypoxic tumors showed an increase of the median pO2 above 10 mm Hg at 19.8 Gy achieved a complete remission (CR). In contrast, only 4/7 patients with a low pretreatment and persisting low median pO2 achieved a CR. CONCLUSIONS: There are evident changes in the oxygenation of cervical cancers during a course of fractionated radiotherapy. In primarily hypoxic tumors, a significant increase of the median pO2 was found. An additional treatment with cis-retinoic acid/interferon further improved the oxygenation. An impact of the different patterns of oxygenation on local control is to be evaluated

Oxygenation of cervical cancers during radiotherapy and radiotherapy + cis-retinoic acid/interferon.

Dunst J, Hansgen G, Lautenschlager C, et al.

Int J Radiat Oncol Biol Phys. 1999 Jan 15; 43(2):367-73.

PURPOSE: We have evaluated the tumor tissue pO2 in cervical cancers during radiotherapy with special emphasis on the course of the pO2 in primarily hypoxic tumors and in patients treated with radiotherapy plus 13-cis-retinoic acid/interferon-alpha-2a. METHODS AND MATERIALS: From June 1995 through April 1997, 49 patients with squamous cell carcinoma FIGO IIB-IVA of the cervix who were treated with definitive radiotherapy with curative intent underwent polarographic measurement of tumor tissue pO2 with an Eppendorf pO2-histograph prior to and during radiation treatment. Radiotherapy consisted of external irradiation with 50.4 Gy in 28 fractions of 1.8 Gy plus high dose rate (HDR) brachytherapy. Twenty-two patients had additional treatment with 13-cis-retinoic acid (cRA, isotretinoin) and interferon-alpha-2a (IFN-alpha-2a). Therapy with cRA/IFN in these patients started 2 weeks before radiotherapy; during this induction period, cRA was administered in a dosage of 1 mg per kilogram body weight orally daily and IFN-alpha-2a in a dosage of 6×10(6) I.U. subcutaneously daily. After start of external radiotherapy (XRT), cRA/IFN was continued concomitantly with radiotherapy in reduced doses (0.5 mg cRA per kg body weight orally daily plus 3×10(6) I.U. IFN-alpha-2a subcutaneously three times weekly until the end of the radiation treatment). PO2 measurements were performed prior to radiotherapy, at 20 Gy, and at the end of radiotherapy. RESULTS: A poor oxygenation defined as a median pO2 of 10 mm Hg or less was present in 15/38 tumors (39%) in which measurements prior to any treatment were done. Low pO2 readings below 5 mm Hg were present in 70% of all tumors prior to treatment. In 13 of 15 hypoxic tumors, pO2 measurements at 19.8 Gy were performed. In these tumors, a significant increase of the median pO2 from 6.0+/-3.1 mm Hg to 20.7+/-21.2 mm Hg was found, p10 mm Hg), 20/23 (87%) achieved a clinically complete response. In patients with primarily hypoxic tumors, 6/6 patients whose primarily hypoxic tumors showed an increase of the median pO2 above 10 mm Hg at 19.8 Gy achieved a complete remission (CR). In contrast, only 4/7 patients with a low pretreatment and persisting low median pO2 achieved a CR. CONCLUSIONS: There are evident changes in the oxygenation of cervical cancers during a course of fractionated radiotherapy. In primarily hypoxic tumors, a significant increase of the median pO2 was found. An additional treatment with cis-retinoic acid/interferon further improved the oxygenation. An impact of the different patterns of oxygenation on local control is to be evaluated

The inhibitory effect of curcumin, genistein, quercetin and cisplatin on the growth of oral cancer cells in vitro.

Elattar TM, Virji AS.

Anticancer Res. 2000 May; 20(3A):1733-8.

Epidemiological evidence indicates that plant derived flavonoids and other phenolic antioxidants protect against heart disease and cancer. In the current investigation utilizing human oral squamous carcinoma cell line (SCC-25), we have evaluated the potency of three different plant phenolics, viz., curcumin, genistein and quercetin in comparison with that of cisplatin on growth and proliferation of SCC-25. Test agents were dissolved in DMSO and incubated in triplicates in 25 cm2 flasks in DMEM- HAM’s F-12 (50:50)supplemented with 10% calf serum and antibiotics in an atmosphere 5% CO2 in air for 72 hours cell growth was determined by counting the number of cells in a hemocytometer. Cell proliferation was determined by measuring DNA synthesis by the incorporation of [3H]-thymidine in nuclear DNA. Cisplatin (0.1, 1.0, 10.0 microM) and curcumin (0.1, 1.0, 10.0 microM) induced significant dose-dependent inhibition in both cell growth as well as cell proliferation. Genistein and quercetin (1.0, 10.0, 100.0 microM) had biphasic effect, depending on their concentrations, on cell growth as well as cell proliferation. Based on these findings, it is concluded that curcumin is considerably more potent than genistein and quercetin, but cisplatin is five fold more potent than curcumin in inhibition of growth and DNA synthesis in SCC-25

Activation of c-Neu tyrosine kinase by o,p’-DDT and beta-HCH in cell-free and intact cell preparations from MCF-7 human breast cancer cells.

Enan E, Matsumura F.

J Biochem Mol Toxicol. 1998; 12(2):83-92.

It has been suggested that there is a positive correlation between increased incidence of breast cancer and the presence of organochlorine residues such as DDT and HCH in breast tissues in the United States. To study possible biochemical links between these two parameters, we have examined the effect of o,p’-DDT, the most estrogenic congener of the DDT family of chemicals and beta-HCH on protein phosphorylation activities in MCF-7, a line derived from human breast cancer cells. Both of these organochlorine chemicals were found to be potent activators of protein kinases. Among kinases activated, protein tyrosine kinases (PTK) appear to be most affected as judged by the antagonistic action of genistein, a class-specific PTK inhibitor. Moreover, these organochlorines were found to activate PTK even under cell-free conditions, indicating that they are likely to interact directly with the target protein tyrosine kinase. As a result of immunoprecipitation with specific antibodies, and testing on the action of these organochlorines, we could show that the major kinase activated by o,p’-DDT is c-Neu (= c-erbB2 product protein). The concentrations of these organochlorines required to activate c-Neu were extremely low (0.1-1 nM range), whereas an inactive analog p,p’-DDT showed no stimulatory property even at 100 nM. Such an action of these organochlorine compounds were not antagonized by the presence of 1 microM tamoxifen, indicating that it is not mediated through the estrogen receptor. In addition, their c-Neu activating actions were specifically antagonized by a c-Neu antibody known to interact with the extracellular domain of c-Neu only without affecting the EGF receptor. Moreover, these chemicals did not cause downregulation of the EGF receptor during the 72 hour test period. Together these data indicate that the action of these chemicals on c-Neu kinase is very specific

Ubiquinol: an endogenous antioxidant in aerobic organisms.

Ernster L, Forsmark-Andree P.

Clin Investig. 1993; 71(8 Suppl):S60-S65.

Ubiquinone (coenzyme Q), in addition to its function as an electron and proton carrier in mitochondrial and bacterial electron transport linked to ATP synthesis, acts in its reduced form (ubiquinol) as an antioxidant, preventing the initiation and/or propagation of lipid peroxidation in biological membranes and in serum low-density lipoprotein. The antioxidant activity of ubiquinol is independent of the effect of vitamin E, which acts as a chain-breaking antioxidant inhibiting the propagation of lipid peroxidation. In addition, ubiquinol can efficiently sustain the effect of vitamin E by regenerating the vitamin from the tocopheroxyl radical, which otherwise must rely on water-soluble agents such as ascorbate (vitamin C). Ubiquinol is the only known lipid-soluble antioxidant that animal cells can synthesize de novo, and for which there exist enzymic mechanisms that can regenerate the antioxidant from its oxidized form resulting from its inhibitory effect of lipid peroxidation. These features, together with its high degree of hydrophobicity and its widespread occurrence in biological membranes and in low-density lipoprotein, suggest an important role of ubiquinol in cellular defense against oxidative damage. Degenerative diseases and aging may be manifestations of a decreased capacity to maintain adequate ubiquinol levels

Treatment of 32 cervico-uterine cancer patients with 13-cis-retinoic acid and interferon alpha.

Espinoza P.

Rev Invest Clin. 1994; 46(2):105-11.

Therapeutic potential of glutathione.

Exner R, Wessner B, Manhart N, et al.

Wien Klin Wochenschr. 2000 Jul 28; 112(14):610-6.

Reactive oxygen species, formed in various biochemical reactions, are normally scavenged by antioxidants. Glutathione in its reduced form (GSH) is the most powerful intracellular antioxidant, and the ratio of reduced to oxidised glutathione (GSH:GSSG) serves as a representative marker of the antioxidative capacity of the cell. Several clinical conditions are associated with reduced GSH levels which as a consequence can result in a lowered cellular redox potential. GSH and the redox potential of the cell are components of the cell signaling system influencing the translocation of the transcription factor NF kappa B which regulates the synthesis of cytokines and adhesion molecules. Therefore, one possibility to protect cells from damage caused by reactive oxygen species is to restore the intracellular glutathione levels. Cellular GSH concentration can be influenced by exogenous administration of GSH (as intravenous infusion or as aerosol), of glutathione esters or of GSH precursors such as glutamine or cysteine (in form of N-acetyl-L-cysteine, alpha-lipoic acid). The modulation of GSH metabolism might present a useful adjuvant therapy in many pathologies such as intoxication, diabetes, uremia, sepsis, inflammatory lung processes, coronary disease, cancer and immunodeficiency states

Broccoli sprouts: an exceptionally rich source of inducers of enzymes that protect against chemical carcinogens.

Fahey JW, Zhang Y, Talalay P.

Proc Natl Acad Sci U S A. 1997 Sep 16; 94(19):10367-72.

Induction of phase 2 detoxication enzymes [e.g., glutathione transferases, epoxide hydrolase, NAD(P)H: quinone reductase, and glucuronosyltransferases] is a powerful strategy for achieving protection against carcinogenesis, mutagenesis, and other forms of toxicity of electrophiles and reactive forms of oxygen. Since consumption of large quantities of fruit and vegetables is associated with a striking reduction in the risk of developing a variety of malignancies, it is of interest that a number of edible plants contain substantial quantities of compounds that regulate mammalian enzymes of xenobiotic metabolism. Thus, edible plants belonging to the family Cruciferae and genus Brassica (e.g., broccoli and cauliflower) contain substantial quantities of isothiocyanates (mostly in the form of their glucosinolate precursors) some of which (e.g., sulforaphane or 4-methylsulfinylbutyl isothiocyanate) are very potent inducers of phase 2 enzymes. Unexpectedly, 3-day-old sprouts of cultivars of certain crucifers including broccoli and cauliflower contain 10-100 times higher levels of glucoraphanin (the glucosinolate of sulforaphane) than do the corresponding mature plants. Glucosinolates and isothiocyanates can be efficiently extracted from plants, without hydrolysis of glucosinolates by myrosinase, by homogenization in a mixture of equal volumes of dimethyl sulfoxide, dimethylformamide, and acetonitrile at -50 degrees C. Extracts of 3-day-old broccoli sprouts (containing either glucoraphanin or sulforaphane as the principal enzyme inducer) were highly effective in reducing the incidence, multiplicity, and rate of development of mammary tumors in dimethylbenz(a)anthracene-treated rats. Notably, sprouts of many broccoli cultivars contain negligible quantities of indole glucosinolates, which predominate in the mature vegetable and may give rise to degradation products (e.g., indole-3-carbinol) that can enhance tumorigenesis. Hence, small quantities of crucifer sprouts may protect against the risk of cancer as effectively as much larger quantities of mature vegetables of the same variety

Effect of eicosapentaenoic acid and other fatty acids on the growth in vitro of human pancreatic cancer cell lines.

Falconer JS, Ross JA, Fearon KC, et al.

Br J Cancer. 1994 May; 69(5):826-32.

A number of polyunsaturated fatty acids have been shown to inhibit the growth of malignant cells in vitro. To investigate whether fatty acids modify the growth of human pancreatic cancer, lauric, stearic, palmitic, oleic, linoleic, alpha-linolenic, gamma-linolenic, arachidonic, docosahexaenoic and eicosapentaenoic (EPA) acids were each incubated with the cells lines MIA PaCa-2, PANC-1 and CFPAC at concentrations ranging from 1.25 microM to 50 microM and the effect of each fatty acid on cell growth was examined. All the polyunsaturated fatty acids tested had an inhibitory effect, with EPA being the most potent (ID50 2.5-5 microM). Monounsaturated or saturated fatty acids were not inhibitory. The action of EPA could be reversed with the anti-oxidant vitamin E acetate or with oleic acid. The cyclo-oxygenase inhibitors indomethacin and piroxicam had no effect on the action of EPA. The action of EPA appeared to be associated with the generation of lipid peroxides, although the level of lipid peroxidation did not always appear to correlate directly with the extent of cell death. The ability of certain fatty acids to inhibit significantly the growth of three human pancreatic cancer cell lines in vitro at concentrations which could be achieved in vivo suggests that administration of such fatty acids may be of therapeutic benefit in patients with pancreatic cancer

Isoflavonoids inhibit catabolism of vitamin D in prostate cancer cells.

Farhan H, Wahala K, Adlercreutz H, et al.

J Chromatogr B Analyt Technol Biomed Life Sci. 2002 Sep 25; 777(1-2):261-8.

The high ingestion of soybean products in Asian countries has been suggested to be responsible for a reduced incidence of prostate cancer. The mechanism of action, however, is unknown. Our data demonstrate that genistein and some isoflavone metabolites reduce the activity of 25-D3-24-hydroxylase (CYP24) in the human prostate cancer-derived cell line DU-145. CYP24 is also responsible for degradation of the active vitamin D metabolite 1,25-dihydroxyvitamin D3 which is known to be antimitotic and prodifferentiating in prostate cancer cells. High levels of CYP24 frequently found in prostate cancer cells may thus degrade the active metabolite. This could be prevented by ingestion of genistein-containing food such as soybeans

Effect of Gutamine on the Initiation and Promotion Phases of DMBA-Induced Mammary Tumor Development 1997.

Feng Z.

2004

Modulatory effects of selenium and zinc on the immune system.

Ferencik M, Ebringer L.

Folia Microbiol (Praha). 2003; 48(3):417-26.

Almost all nutrients in the diet play a crucial role in maintaining an “optimal” immune response, and both insufficient and excessive intakes can have negative consequences on the immune status and susceptibility to a variety of pathogens. We summarize the evidence for the importance of two micronutrients, selenium and zinc, and describe the mechanisms through which they affect the immune status and other physiological functions. As a constituent of selenoproteins, selenium is needed for the proper functioning of neutrophils, macrophages, NK cells, T lymphocytes and some other immune mechanisms. Elevated selenium intake may be associated with reduced cancer risk and may alleviate other pathological conditions including oxidative stress and inflammation. Selenium appears to be a key nutrient in counteracting the development of virulence and inhibiting HIV progression to AIDS. It is required for sperm motility and may reduce the risk of miscarriage. Selenium deficiency has been linked to adverse mood states and some findings suggest that selenium deficiency may be a risk factor in cardiovascular diseases. Zinc is required as a catalytic, structural and regulatory ion for enzymes, proteins and transcription factors, and is thus a key trace element in many homeostatic mechanisms of the body, including immune responses. Low zinc ion bioavailability results in limited immunoresistance to infection in aging. Physiological supplementation of zinc for 1-2 months restores immune responses, reduces the incidence of infections and prolongs survival. However, in every single individual zinc supplementation of food should be adjusted to the particular zinc status in views of the great variability in habitat conditions, health status and dietary requirements

Host circadian clock as a control point in tumor progression.

Filipski E, King VM, Li X, et al.

J Natl Cancer Inst. 2002 May 1; 94(9):690-7.

BACKGROUND: The circadian timing system controlled by the suprachiasmatic nuclei (SCN) of the hypothalamus regulates daily rhythms of motor activity and adrenocortical secretion. An alteration in these rhythms is associated with poor survival of patients with metastatic colorectal or breast cancer. We developed a mouse model to investigate the consequences of severe circadian dysfunction upon tumor growth. METHODS: The SCN of mice were destroyed by bilateral electrolytic lesions, and body activity and body temperature were recorded with a radio transmitter implanted into the peritoneal cavity. Plasma corticosterone levels and circulating lymphocyte counts were measured (n = 75 with SCN lesions, n = 64 sham-operated). Complete SCN destruction was ascertained postmortem. Mice were inoculated with implants of Glasgow osteosarcoma (n = 16 with SCN lesions, n = 12 sham-operated) or pancreatic adenocarcinoma (n = 13 with SCN lesions, n = 13 sham-operated) tumors to determine the effects of altered circadian rhythms on tumor progression. Time series for body temperature and rest-activity patterns were analyzed by spectral analysis and cosinor analysis. Parametric data were compared by the use of analysis of variance (ANOVA) and survival curves with the log-rank test. All statistical tests were two-sided. RESULTS: The 24-hour rest-activity cycle was ablated and the daily rhythms of serum corticosterone level and lymphocyte count were markedly altered in 75 mice with complete SCN destruction as compared with 64 sham-operated mice (two-way ANOVA for corticosterone: sampling time effect P<.001, lesion effect P =”.001,” and time x lesion interaction P<.001; for lymphocytes P =”.001,.002,” and.002 respectively). Body temperature rhythm was suppressed in 60 of the 75 mice with SCN lesions (P<.001). Both types of tumors grew two to three times faster in mice with SCN lesions than in sham-operated mice (two-way ANOVA: P<.001 for lesion and for tumor effects; P =”.21″ for lesion x tumor effect interaction). Survival of mice with SCN lesions was statistically significantly shorter compared with that of sham-operated mice (log-rank P =”.0062).” CONCLUSIONS: Disruption of circadian rhythms in mice was associated with accelerated growth of malignant tumors of two types, suggesting that the host circadian clock may play an important role in endogenous control of tumor progression

Growth inhibition, cell-cycle arrest and apoptosis in human T-cell leukemia by the isothiocyanate sulforaphane.

Fimognari C, Nusse M, Cesari R, et al.

Carcinogenesis. 2002 Apr; 23(4):581-6.

Glucosinolates (GL) can inhibit, retard or reverse experimental multistage carcinogenesis. When brassica plant tissue is broken, GLs are hydrolyzed by the endogenous enzyme myrosinase (Myr), releasing many products including isothiocyanates (ITC). Synthetic ITCs like sulforaphane exert chemopreventive effects against chemically induced tumors in animals, modulating enzymes required for carcinogens’ activation/detoxification and/or the induction of cell-cycle arrest and apoptosis in tumor cell lines. To investigate the chemopreventive potential of ITCs while reproducing the circumstances of dietary contact with sulforaphane, we studied proliferation, apoptosis induction and p53, bcl-2 and bax protein expression in Jurkat T-leukemia cells by sulforaphane, the ITC generated in situ in a quantitative manner by Myr starting from glucoraphanin (GRA). Jurkat cells were treated with different doses of GRA-Myr mixture. Effects on cell growth or survival were evaluated by counting trypan blue-excluding cells. Cell-cycle progression, apoptosis and expression of p53, bax and bcl-2 proteins were analyzed by flow cytometry. Results were analyzed by two-sided Fisher’s exact test. Sulforaphane, but not GRA, caused G(2)/M-phase arrest (P = 0.028) and increase of apoptotic cell fraction (P < 0.0001) in a time- and dose-dependent manner. Necrosis was observed after prolonged exposure to elevated sulforaphane doses. Moreover, it markedly increased p53 and bax protein expression, and slightly affected bcl-2 expression. These findings indicate that sulforaphane but not the native GL GRA can exert both protective and toxic effects inhibiting leukemic cell growth. Sulforaphane therefore deserves study as a potential chemopreventive/chemotherapeutic antileukemic agent

Effect of histamine and the H2 antagonist cimetidine on the growth and migration of human neoplastic glia.

Finn PE, Purnell P, Pilkington GJ.

Neuropathol Appl Neurobiol. 1996 Aug; 22(4):317-24.

Histamine is known to act, at least in part, as a growth factor, as production of this neurotransmitter has been found to accelerate the rate of tissue proliferation in wound repair, embryogenesis and malignant growth. Histamine favours in vivo tumour cell proliferation via H2 receptors. Cimetidine is an H2 blocker and has been shown to inhibit tumour cell growth. In the present study, the growth modulating effects of histamine and cimetidine were assessed on five cell lines derived from human brain tumours of different histological types and grades of malignancy. Each cell line was treated with either cimetidine or histamine for 24 h before kinetic analyses, with PCNA, or motility assays, using Transwell migration chambers incorporating a microporous membrane, were carried out. Cimetidine significantly inhibited cell proliferation in three out of the five cell lines, which may indicate the dependence of proliferation of these cell lines on stimulation of the H2 receptor. With regard to migration, it was observed that in the majority of cell lines, cimetidine induced migration whilst histamine inhibited it. It was concluded that the link between effects of histamine on proliferation and its effects on migration must be clarified using a larger sample of cell lines

Milk thistle (Silybum marianum) for the therapy of liver disease.

Flora K, Hahn M, Rosen H, et al.

Am J Gastroenterol. 1998 Feb; 93(2):139-43.

Silymarin, derived from the milk thistle plant, Silybum marianum, has been used for centuries as a natural remedy for diseases of the liver and biliary tract. As interest in alternative therapy has emerged in the United States, gastroenterologists have encountered increasing numbers of patients taking silymarin with little understanding of its purported properties. Silymarin and its active constituent, silybin, have been reported to work as antioxidants scavenging free radicals and inhibiting lipid peroxidation. Studies also suggest that they protect against genomic injury, increase hepatocyte protein synthesis, decrease the activity of tumor promoters, stabilize mast cells, chelate iron, and slow calcium metabolism. In this article we review silymarin’s history, pharmacology, and properties, and the clinical trials pertaining to patients with acute and chronic liver disease

Lovastatin decreases coenzyme Q levels in quantitative review of primary prevention trials.

Folkers K.

Br J Med. 1990; 301:309-14.

Coenzyme Q10 increases T4/T8 ratios of lymphocytes in ordinary subjects and relevance to patients having the AIDS related complex.

Folkers K, Hanioka T, Xia LJ, et al.

Biochem Biophys Res Commun. 1991 Apr 30; 176(2):786-91.

Coenzyme Q10 (CoQ10) is indispensable to biochemical mechanisms of bioenergetics, and it has a non-specific role as an antioxidant. CoQ10 has shown a hematological activity for the human and has shown an influence on the host defense system. The T4/T8 ratios of lymphocytes are known to be low in patients with AIDS, ARC and malignancies. Our two patients with ARC have survived four-five years without any symptoms of adenopathy or infection on continuous treatment with CoQ10. We have newly found that 14 ordinary subjects responded to CoQ10 by increases in the T4/T8 ratios and an increase in blood levels of CoQ10; both by p less than 0.001. This knowledge and survival of two ARC patients for four-five years on CoQ10 without symptoms, and new data on increasing ratios of T4/T8 lymphocytes in the human by treatment with CoQ10 constitute a rationale for new double blind clinical trials on treating patients with AIDS, ARC and diverse malignancies with CoQ10

Survival of cancer patients on therapy with coenzyme Q10.

Folkers K, Brown R, Judy WV, et al.

Biochem Biophys Res Commun. 1993 Apr 15; 192(1):241-5.

Over ca. 25 years, assays in animal models established the hematopoietic activities of coenzyme Q’s in rhesus monkeys, rabbits, poultry, and children having kwashiorkor. Surprisingly, a virus was found to cause a deficiency of CoQ9. Patients with AIDS showed a-”striking”-clinical response to therapy with CoQ10. The macrophage potentiating activity of CoQ10 was recorded by the carbon clearance method. CoQ10 significantly increased the levels of IgG in patients. Eight new case histories of cancer patients plus two reported cases support the statement that therapy of cancer patients with CoQ10, which has no significant side effect, has allowed survival on an exploratory basis for periods of 5-15 years. These results now justify systematic protocols

Activities of vitamin Q10 in animal models and a serious deficiency in patients with cancer.

Folkers K, Osterborg A, Nylander M, et al.

Biochem Biophys Res Commun. 1997 May 19; 234(2):296-9.

New data on blood levels of vitamin Q10 in 116 cancer patients reveal an incidence of 23.1% of patients (N=17) with breast cancer whose blood levels were below 0.5 microg/ml. The incidence of breast cancer cases with levels below 0.6 microg/ml was 38.5%. The incidence is higher (p<0.05) than that for a group of ordinary people. Patients (N=”15)” with myeloma showed a mean blood level of 0.67 +/- 0.17 microg/ml. The incidence of a vitamin Q10 blood level below 0.7 microg/ml for these 15 cases of myeloma was 53.3%, which is higher (p<0.05) than the 24.5% found for a group of ordinary people

Dietary genistein down-regulates androgen and estrogen receptor expression in the rat prostate.

Fritz WA, Wang J, Eltoum IE, et al.

Mol Cell Endocrinol. 2002 Jan 15; 186(1):89-99.

The incidence of clinically manifested prostate cancer is higher in the United States and Europe than in Asian countries. One of the major differences in lifestyle between these populations is the diet, with Asians consuming a greater amount of soy. Soy and genistein, the predominant isoflavone found in soy, inhibit prostate tumor development in animal models. The purpose of this study was to investigate the effect of dietary genistein on sex steroid receptor expression in the dorsolateral prostate, on circulating androgens, and the potential for toxicity in the male rat reproductive tract. Male Sprague-Dawley rats were fed 25 and 250 mg genistein/kg diet from conception until day 70 postpartum, or 250 and 1000 mg genistein/kg diet from day 56 to 70 postpartum. Exposure to genistein in the diet, starting at conception, resulted in down-regulated androgen receptor (AR), and estrogen receptors (ER)-alpha and -beta mRNA expression in the dorsolateral prostate in a dose-dependent manner. Also, genistein fed to adult rats for 2 weeks reduced mRNA expression of AR, ER-alpha and ER-beta in the dorsolateral prostate. ER-alpha protein levels were significantly reduced in animals fed 1000 mg genistein/kg diet compared to control animals. There were no significant alterations to male reproductive tract histomorphology or weights. We conclude that dietary genistein down-regulated expression of the AR and ER-alpha and -beta in the rat prostate at concentrations comparable to those found in humans on a soy diet. Down-regulated sex steroid receptor expression may be responsible for the lower incidence of prostate cancer in populations on a diet containing high levels of phytoestrogens

Bisphosphonates induce breast cancer cell death in vitro.

Fromigue O, Lagneaux L, Body JJ.

J Bone Miner Res. 2000 Nov; 15(11):2211-21.

Breast cancer frequently spreads to bone and is almost always associated with osteolysis. This tumor-induced osteolysis is caused by increased osteoclastic bone resorption. Bisphosphonates are used successfully to inhibit bone resorption in tumor bone disease and may prevent development of new osteolytic lesions. The classical view is that bisphosphonates only act on bone cells. We investigated their effects on breast cancer cells using three human cell lines, namely, MCF-7, T47D, and MDA.MB.231, and we tested four structurally different bisphosphonates: clodronate, pamidronate, ibandronate, and zoledronate. We performed time course studies for each bisphosphonate at various concentrations and found that all four compounds induced a nonreversible growth inhibition in both MCF-7 and T47D cell lines in a time- and dose-dependent manner. The MDA.MB.231 cell line was less responsive. Bisphosphonates induced apoptosis in MCF-7 and cell necrosis in T47D cells. The inhibition of MCF-7 cell proliferation could be reverted almost completely by the benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethyl ketone (z-VAD-fmk) inhibitor of caspases, suggesting that the apoptotic process observed in the MCF-7 cell line is mediated, at least partly, by the caspase system. Caspase activity was little changed by bisphosphonates in T47D cells and the inhibitor of caspase did not modify bisphosphonates effects. In summary, we found that bisphosphonates inhibit breast cancer cell growth by inducing cell death in vitro. Such effects could contribute to the beneficial role of bisphosphonates in the treatment and the prevention of tumor-induced osteolysis

Lung cancer prevention with (-)-epigallocatechin gallate using monitoring by heterogeneous nuclear ribonucleoprotein B1.

Fujimoto N, Sueoka N, Sueoka E, et al.

Int J Oncol. 2002 Jun; 20(6):1233-9.

Considering the problems involved in prevention of human lung cancer, growth inhibition of human lung cancer cell line A549 was studied with emphasis on two parameters: green tea polyphenols, such as (-)-epigallocatechin gallate (EGCG) and (-)-epicatechin gallate (ECG); and heterogeneous nuclear ribonucleoprotein B1 (hnRNP B1), a new biomarker of human lung cancer which is highly expressed in the very early stages of human lung cancer. The inhibitory potencies of green tea polyphenols were compared with those of genistein as a control. EGCG or ECG and genistein as a control dose-dependently inhibited the growth of A549 cells, which strongly elevated hnRNP B1 protein, and increased G2/M phase cells associated with induction of apoptotic cells. The results were confirmed by previous evidence with human lung cancer cell line PC-9. Some larger differences in mechanisms of action between green tea polyphenols and genistein were presented. Treatment of A549 cells with EGCG, ECG or genistein significantly inhibited the expression levels of hnRNP B1 mRNA and the elevated levels of hnRNP B1 protein, both of which are constitutively elevated in cancer cells. Furthermore, both EGCG and genistein inhibited the promoter activity of hnRNP A2/B1 gene expression, with IC50 values 29 microM for EGCG and 66 microM for genistein, suggesting the interaction of EGCG or genistein with the transcriptional complex. Looking at our results here, and those of previously reported epidemiological studies with green tea, we discuss the steadily accumulating evidence that clinical trials with green tea extract would be an efficient means of lung cancer prevention

Inhibition by berberine of cyclooxygenase-2 transcriptional activity in human colon cancer cells.

Fukuda K, Hibiya Y, Mutoh M, et al.

J Ethnopharmacol. 1999 Aug; 66(2):227-33.

The enzyme cyclooxygenase-2 (COX-2) is abundantly expressed in colon cancer cells and plays a key role in colon tumorigenesis. Compounds inhibiting COX-2 transcriptional activity have therefore potentially a chemopreventive property against colon tumor formation. An assay method for estimating COX-2 transcriptional activity in human colon cancer cells was established using a beta-galactosidase reporter gene system, and examination was made of various medicinal herbs and their ingredients for an inhibitory effect on COX-2 transcriptional activity. We found that berberine, an isoquinoline alkaloid present in plants of the genera Berberis and Coptis, effectively inhibits COX-2 transcriptional activity in colon cancer cells in a dose- and time-dependent manner at concentrations higher than 0.3 microM. The present findings may further explain the mechanism of anti-inflammatory and anti-tumor promoting effects of berberine

Detoxification.

Galland L.

Presented at Comprehensive Cancer Care 2000, Arlington, VA, June 7-11, 2000. 2000;June 7-11, 2000

Immunomodulatory activity of resveratrol: suppression of lymphocyte proliferation, development of cell-mediated cytotoxicity, and cytokine production.

Gao X, Xu YX, Janakiraman N, et al.

Biochem Pharmacol. 2001 Nov 1; 62(9):1299-308.

trans-Resveratrol, a phytoalexin found in grapes, wine, and other plant products, has been shown to have anti-inflammatory, antioxidant, and antitumor activities. Many of these beneficial effects of resveratrol require participation of the cells of the immune system; however, the effect of resveratrol on the development of immunological responses remains unknown. We have investigated the effect of resveratrol on mitogen/antigen-induced proliferation of splenic lymphocytes, induction of cytotoxic T lymphocytes (CTLs) and lymphokine activated killer (LAK) cells, and the production of the cytokines interferon (IFN)-gamma, interleukin (IL)-2, tumor necrosis factor (TNF)-alpha, and IL-12. We found that mitogen-, IL-2-, or alloantigen-induced proliferation of splenic lymphocytes and the development of antigen-specific CTLs were suppressed significantly at 25-50 microM resveratrol. The generation of LAK cells at similar concentrations was less sensitive to the suppressive effect of resveratrol. The suppression of cell proliferation and CTL generation by resveratrol was not only reversible, but in some cases the response (mitogen/IL-2-induced proliferation and CTL generation) was actually enhanced following pretreatment of cells with resveratrol. Resveratrol also inhibited the production of IFN-gamma and IL-2 by splenic lymphocytes, and the production of TNF-alpha and IL-12 by peritoneal macrophages. The inhibition of cytokine production by resveratrol was irreversible. Further, resveratrol blocked the activation of the transcription factor NF-kappaB without affecting basal NF-kappaB activity. The latter result suggests that resveratrol inhibits cell proliferation, cell-mediated cytotoxicity, and cytokine production, at least in part through the inhibition of NF-kappaB activation

Genistein inhibits the growth of human-patient BPH and prostate cancer in histoculture.

Geller J, Sionit L, Partido C, et al.

Prostate. 1998 Feb 1; 34(2):75-9.

BACKGROUND: There is strong epidemiological evidence that prostate disease is significantly less prevalent in the Orient, where the intake of soy products is very high, than in the United States. We therefore undertook a study of the effects of genistein, a major component of soy, on growth of human-patient benign prostatic hypertrophy (BPH) and prostate cancer tissue in three-dimensional collagen gel-supported histoculture. METHODS: Surgical specimens of human BPH and cancer were histocultured for 5 days to study the effects of genistein on growth, as measured by inhibition of 3H-thymidine incorporation per microgram protein on day 5. RESULTS: Genistein in doses of 1.25-10 micrograms/ml decreased the growth of BPH tissue in histoculture in a dose-dependent manner, with little additional effect at higher doses. Prostate cancer tissue in histoculture was similarly inhibited by these doses of genistein. CONCLUSIONS: Genistein decreases the growth of both BPH and prostate cancer tissue in histoculture. The data suggest that genistein has potential as a therapeutic agent for BPH and prostate cancer

Enhancement of human natural killer cell activity by modified arabinoxylan from rice brain (MGN-3).

Ghoneum M.

Int J Immunother. 1998; 14(2):89-99.

Synergistic Effect of Modified Arabinoxylan (MGN-3) and Low Dose of Recombinant IL-2 on Human NK cell Activity and TNF-A Production 1998 Aug. East Rutherford, NJ: American Academy of Anti-Aging Medicine; (Abstract) see also – Production of tumor necrosis factor-alpha and interferon-gamma from human peripheral blood lymphocytes by MGN-3, a modified arabinoxylan from rice bran, and its synergy with interleukin-2 in vitro.

Ghoneum M, Jewett A.

Cancer Detect Prev. 1998; 24(4):314-24.

Effect of MGN-3 on human natural killer cell activity and interferon-? synthesis in vitro.

Ghoneum M.

FASEB. 1996; 10(6):26-32.

Inhibition of arachidonate 5-lipoxygenase triggers massive apoptosis in human prostate cancer cells.

Ghosh J, Myers CE.

Proc Natl Acad Sci U S A. 1998 Oct 27; 95(22):13182-7.

Diets high in fat are associated with an increased risk of prostate cancer, although the molecular mechanism is still unknown. We have previously reported that arachidonic acid, an omega-6 fatty acid common in the Western diet, stimulates proliferation of prostate cancer cells through production of the 5-lipoxygenase metabolite, 5-HETE (5-hydroxyeicosatetraenoic acid). We now show that 5-HETE is also a potent survival factor for human prostate cancer cells. These cells constitutively produce 5-HETE in serum-free medium with no added stimulus. Exogenous arachidonate markedly increases the production of 5-HETE. Inhibition of 5-lipoxygenase by MK886 completely blocks 5-HETE production and induces massive apoptosis in both hormone-responsive (LNCaP) and -nonresponsive (PC3) human prostate cancer cells. This cell death is very rapid: cells treated with MK886 showed mitochondrial permeability transition between 30 and 60 min, externalization of phosphatidylserine within 2 hr, and degradation of DNA to nucleosomal subunits beginning within 2-4 hr posttreatment. Cell death was effectively blocked by the thiol antioxidant, N-acetyl-L-cysteine, but not by androgen, a powerful survival factor for prostate cancer cells. Apoptosis was specific for 5-lipoxygenase-programmed cell death was not observed with inhibitors of 12-lipoxygenase, cyclooxygenase, or cytochrome P450 pathways of arachidonic acid metabolism. Exogenous 5-HETE protects these cells from apoptosis induced by 5-lipoxygenase inhibitors, confirming a critical role of 5-lipoxygenase activity in the survival of these cells. These findings provide a possible molecular mechanism by which dietary fat may influence the progression of prostate cancer

Vitamin C mediated protection on cisplatin induced mutagenicity in mice.

Giri A, Khynriam D, Prasad SB.

Mutat Res. 1998 Nov 3; 421(2):139-48.

In present studies the development of chromosomal aberrations, micronuclei in bone marrow cells and sperm head abnormalities were used as mutagenic bioassay in Swiss albino mice treated with cisplatin alone or ascorbic plus cisplatin. It was noted that in the combined treated hosts the frequency of all the mutagenic parameters were always significantly less than that treated with cisplatin alone. These findings suggest a protective role of ascorbic acid against cisplatin induced mutagenic potentials. Interestingly, in combined treated hosts glutathione (GSH) level in bone marrow cells increased significantly which may suggest a possible mechanism of ascorbic acid mediated protection against cisplatin induced mutagenic potentials in the hosts

Effects of Thomsen-Friedenreich antigen-specific peptide P-30 on beta-galactoside-mediated homotypic aggregation and adhesion to the endothelium of MDA-MB-435 human breast carcinoma cells.

Glinsky VV, Huflejt ME, Glinsky GV, et al.

Cancer Res. 2000 May 15; 60(10):2584-8.

Both the ability of malignant cells to form multicellular aggregates via homotypic or heterotypic aggregation and their adhesion to the endothelium are important if not critical during early stages of cancer metastasis. The tumor-associated carbohydrate Thomsen-Friedenreich antigen (T antigen) and beta-galactoside binding lectins (galectins) have been implicated in tumor cell adhesion and tissue invasion. In this study, we demonstrate the involvement of T antigen in both homotypic aggregation of MDA-MB-435 human breast carcinoma cells and their adhesion to the endothelium. The T antigen-specific peptide P-30 (HGRFILPWWYAFSPS) selected from a bacteriophage display library was able to inhibit spontaneous homotypic aggregation of MDA-MB-435 cells up to 74% in a dose-dependent manner. Because T antigen has beta-galactose as a terminal sugar, the expression profile of beta-galactoside-binding lectins (galectins) in MDA-MB-435 cells was studied. Our data indicated the abundant expression of [35S]methionine/cysteine-labeled galectin-1 and galectin-3 in this cell line, which suggested possible interactions between galectins and T antigen. As revealed by laser confocal microscopy, both galectin-1 and galectin-3 also participate in the adhesion of the MDA-MB-435 cells to the endothelium. We observed the clustering of galectin-3 on endothelial cells at the sites of the contact with tumor cells, consistent with its possible interaction with T antigen on cancer cells The galectin-1 signal, however, strongly accumulated at the sites of cell-cell contacts predominantly on tumor cells. The T antigen-specific P-30 significantly (50%) inhibited this adhesion, which indicated that T antigen participates in the adhesion of MDA-MB-435 breast cancer cells to the endothelium. The ability of synthetic P-30 to inhibit both the spontaneous homotypic aggregation of MDA-MB-435 cells and their adhesion to the endothelium (>70 and 50%, respectively) suggests its potential functional significance for antiadhesive therapy of cancer metastasis

Stress and hopelessness in the promotion of cervical intraepithelial neoplasia to invasive squamous cell carcinoma of the cervix.

Goodkin K, Antoni MH, Blaney PH.

J Psychosom Res. 1986; 30(1):67-76.

Stress and hopelessness have been associated with the development of invasive cervical cancer by previous research. Subjects in this study were recruited from a colposcopy clinic awaiting work-up of an abnormal pap smear and from those admitted to an in-patient gynecology ward for cone biopsy of the cervix or hysterectomy to treat a symptomatic pelvic mass thought to be uterine leiomyomas. After data collection, pathology reports and colposcopic findings were used to determine group assignment independent of subjects’ knowledge of their diagnosis. A modest stress-promotion correlation was derived, which was greatly enhanced by significant interactions with low levels of cooperative coping style and for high levels of premorbid pessimism, future despair, somatic anxiety, and life threat reactivity. These stress-moderator interactions are discussed in terms of immune system deficit with concomitant enhancement of promotion of CIN to invasive squamous cell cervical cancer

Germanium-The Health and Life Enhancer.

Goodman S.

2004

[The treatment of cutaneous radiation-induced fibrosis with pentoxifylline and vitamin E. An empirical report].

Gottlober P, Krahn G, Korting HC, et al.

Strahlenther Onkol. 1996 Jan; 172(1):34-8.

BACKGROUND: Radiation fibrosis represents a severe complication of radiation therapy; standardized treatment protocols are lacking so far. Surgical excision rarely results in complete healing. PATIENT AND METHODS: We report on a 58-year-old female patient who developed a squamous cell carcinoma within the fibrotic area of the irradiation field on the right chest, resulting from a radiotherapy following mastectomy for breast cancer 17 years ago. After surgical excision of the carcinoma a combined treatment with pentoxifylline tablets (3 x 400 mg/d p.o.) and vitamin-E capsules (1 x 400 mg/d p.o.) was initiated. Skin thickness was quantified by 20 MHz-ultrasound before and during treatment. RESULTS: The patient noted an increasing improvement of the condition of the affected skin starting from 4 months. A continuing decrease of skin thickness as documented by 20 MHz-ultrasound could be demonstrated from the 6th month on. The treatment was tolerated well, no side effects were observed. CONCLUSION: The data indicate a beneficial therapeutic effect of pentoxifylline and vitamin E on radiation-induced fibrosis. Little is known about the mechanism of action of this combined treatment protocol including pentoxifylline and vitamin E. Controlled clinical trials should be performed to confirm this observation

Effects of exogenous inositol hexakisphosphate (InsP(6)) on the levels of InsP(6) and of inositol trisphosphate (InsP(3)) in malignant cells, tissues and biological fluids.

Grases F, Simonet BM, Vucenik I, et al.

Life Sci. 2002 Aug 16; 71(13):1535-46.

InsP(6) is abundant in cereals and legumes. InsP(6) and lower inositol phosphates, in particular InsP(3), participate in important intracellular processes. In addition, InsP(6) possess significant health benefits, such as anti-cancer effect, kidney stones prevention, lowering serum cholesterol. Because of the insensitivity of existing methods for determination of non-radiolabeled inositol phosphates, little is known about the natural occurrence, much less on the concentrations of InsP(6) and InsP(3) in biological samples. Using gas chromatography-mass detection analysis of HPLC chromatographic fractions, we report a measurement of unlabeled total InsP(3) and InsP(6) (a) as they occur within cells culture, tissues, and plasma, and (b) their changes depending on the presence of exogenous InsP(6). When rats were fed on a purified diet in which InsP(6) was undetectable (AIN-76A) the levels of InsP(6) in brain were 3.35 +/- 0.57 (SE) micromol.kg(-1) and in plasma 0.023 +/- 0.008 (SE) micromol.l(-1). The presence of InsP(6) in diet dramatically influenced its levels in brain and in plasma. When rats were given an InsP(6)-sufficient diet (AIN-76A + 1% InsP(6)), the levels of InsP(6) were about 100-fold higher in brain tissues (36.8 +/- 1.8 (SE)) than in plasma (0.29 +/- 0.02 (SE)); InsP(6) concentrations were 8.5-fold higher than total InsP(3) concentrations in either plasma (0.033 +/- 0.012 (SE)) and brain (4.21 +/- 0.55 (SE)). When animals were given an InsP(6)-poor diet (AIN-76A only), there was a 90% decrease in InsP(6) content in both brain tissue and plasma (p < 0.001); however, there was no change in the level of total InsP(3). In non-stimulated malignant cells (MDA-MB 231 and K562) the InsP(6) contents were 16.2 +/- 9.1 (SE) micromol.kg(-1) for MDA-MB 231 cells and 15.6 +/- 2.7 (SE) for K 562 cells. These values were around 3-fold higher than those of InsP(3) (4.8 +/- 0.5 micromol.kg(-1) and 6.9 +/- 0.1 (SE) for MDA-MB 231 and K562 cells respectively). Treatment of malignant cells with InsP(6) resulted in a 2-fold increase in the intracellular concentrations of total InsP(3) (9.5 +/- 1.3 (SE) and 10.8 +/- 1.0 (SE) micromol.kg(-1) for MDA-MB 231 and K562 cells respectively, p < 0.05), without changes in InsP(6) levels. These results indicate that exogenous InsP(6) directly affects its physiological levels in plasma and brain of normal rats without changes on the total InsP(3) levels. Although a similar fluctuation of InsP(6) concentration was not seen in human malignant cell lines following InsP(6) treatment, an increased intracellular levels of total InsP(3) was clearly observed

Modified citrus pectin (MCP) increases the prostate-specific antigen doubling time in men with prostate cancer: a phase II pilot study.

Guess BW, Scholz MC, Strum SB, et al.

Prostate Cancer Prostatic Dis. 2003; 6(4):301-4.

This trial investigated the tolerability and effect of modified citrus pectin (Pecta-Sol((R))) in 13 men with prostate cancer and biochemical prostate-specific antigen (PSA) failure after localized treatment, that is, radical prostatectomy, radiation, or cryosurgery. A total of 13 men were evaluated for tolerability and 10 for efficacy. Changes in the prostate-specific antigen doubling time (PSADT) of the 10 men were the primary end point in the study. We found that the PSADT increased (P-value<0.05) in seven (70%) of 10 men after taking MCP for 12 months compared to before taking MCP. This study suggests that MCP may lengthen the PSADT in men with recurrent prostate cancer.Prostate Cancer and Prostatic Diseases (2003) 6, 301-304. doi:10.1038/sj.pcan.4500679

Insulin: a novel factor in carcinogenesis.

Gupta K, Krishnaswamy G, Karnad A, et al.

Am J Med Sci. 2002 Mar; 323(3):140-5.

Cancer is a leading cause of mortality in the United States. Despite much research on specific carcinogens, the cause of many cancers remains unclear. The identification of novel causative agents offers the potential for cancer prevention. Diseases such as obesity and diabetes mellitus, characterized by hyperinsulinemia, are associated with increased risk of endometrial, colorectal, and breast carcinomas. There is increasing evidence that insulin is a growth factor for tumor formation. The mechanisms underlying insulin-mediated neoplasia may include enhanced DNA synthesis with resultant tumor cell growth, inhibition of apoptosis, and altered sex hormone milieu. The reduced insulin levels seen with physical activity, weight loss, and a high fiber diet may account for decreased cancer risk. The role of newer drugs that restore sensitivity to insulin, thereby reducing hyperinsulinemia, is an exciting potential area of cancer prevention. In this review, we discuss the potential role of insulin as a tumor growth factor

Inhibition of proliferation of estrogen receptor-negative MDA-MB-435 and -positive MCF-7 human breast cancer cells by palm oil tocotrienols and tamoxifen, alone and in combination.

Guthrie N, Gapor A, Chambers AF, et al.

J Nutr. 1997 Mar; 127(3):544S-8S.

Tocotrienols are a form of vitamin E, having an unsaturated isoprenoid side-chain rather than the saturated side-chain of tocopherols. The tocotrienol-rich fraction (TRF) from palm oil contains alpha-tocopherol and a mixture of alpha-, gamma- and delta-tocotrienols. Earlier studies have shown that tocotrienols display anticancer activity. We previously reported that TRF, alpha-, gamma- and delta-tocotrienols inhibited proliferation of estrogen receptor-negative MDA-MB-435 human breast cancer cells with 50% inhibitory concentrations (IC50) of 180, 90, 30 and 90 microg/mL, respectively, whereas alpha-tocopherol had no effect at concentrations up to 500 microg/mL. Further experiments with estrogen receptor-positive MCF-7 cells showed that tocotrienols also inhibited their proliferation, as measured by [3H] thymidine incorporation. The IC50s for TRF, alpha-tocopherol, alpha-, gamma- and delta-tocotrienols were 4, 125, 6, 2 and 2 microg/mL, respectively. Tamoxifen, a widely used synthetic antiestrogen inhibits the growth of MCF-7 cells with an IC50 of 0.04 microg/mL. We tested 1:1 combinations of TRF, alpha-tocopherol and the individual tocotrienols with tamoxifen in both cell lines. In the MDA-MB-435 cells, all of the combinations were found to be synergistic. In the MCF-7 cells, only 1:1 combinations of gamma- or delta-tocotrienol with tamoxifen showed a synergistic inhibitory effect on the proliferative rate and growth of the cells. The inhibition by tocotrienols was not overcome by addition of excess estradiol to the medium. These results suggest that tocotrienols are effective inhibitors of both estrogen receptor-negative and -positive cells and that combinations with tamoxifen should be considered as a possible improvement in breast cancer therapy

Vitamin D and vitamin D analogs as cancer chemopreventive agents.

Guyton KZ, Kensler TW, Posner GH.

Nutr Rev. 2003 Jul; 61(7):227-38.

Epidemiologic studies have associated vitamin D, attained through nutrition and sun exposure, with reduced cancer risk. Although dose-limiting hypercalcemia has limited the use of natural vitamin D in cancer prevention, several promising new synthetic vitamin D analogs (deltanoids) are under development. Examples are KH-1060, EB-1089, 1alpha-hydroxyvitamin D5, vitamin D2, and QW-1624F2-2. Clinical targets for deltanoids include colon, prostate, and breast. Studies to elucidate the molecular mechanisms underlying the observed efficacy of deltanoids are ongoing. The vitamin D receptor, a steroid/thyroid receptor superfamily member, appears to control most deltanoid effects on proliferation, apoptosis, differentiation, and angiogenesis

Three percent dietary fish oil concentrate increased efficacy of doxorubicin against MDA-MB 231 breast cancer xenografts.

Hardman WE, Avula CP, Fernandes G, et al.

Clin Cancer Res. 2001 Jul; 7(7):2041-9.

Omega 3 polyunsaturated fatty acids (the type of fat found in fish oil) have been used to kill or slow the growth of cancer cells in culture and in animal models and to increase the effectiveness of cancer chemotherapeutic drugs. An AIN-76 diet containing 5% corn oil (CO) was modified to contain 3% w/w fish oil concentrate (FOC) and 2% CO to test whether a clinically applicable amount of FOC is beneficial during doxorubicin (DOX) treatment of cancer xenografts in mice. Compared with the diet containing 5% CO, consumption of FOC increased omega 3 polyunsaturated fatty acids and lipid peroxidation in tumor and liver, significantly decreased the ratio of glutathione peroxidase activity to superoxide dismutase activity (a putative indicator of increased oxidative stress) in tumor but not in the liver, and significantly decreased the tumor-growth rate. The decreased glutathione peroxidase:superoxide dismutase ratio, indicating an altered redox state, in the tumor of FOC-fed mice was significantly correlated with decreased tumor-growth rate. Assay of the body weight change, blood cell counts, and number of micronuclei in peripheral erythrocytes indicated that the toxicity of DOX to the host mouse was not increased in mice fed FOC. Thus, a small amount of FOC increased the effectiveness of DOX but did not increase the toxicity of DOX to the host mouse. These positive results justify clinical testing of FOC in conjunction with cancer chemotherapy

Lowering cholesterol with Lovastatin. The wrong approach. A survey of usually overlooked literature.

Hattersley JG.

J Orthomolecular Med. 2004; 9(1):54-7.

Coenzyme Q10 and cancer.

Hattersley JG.

J Orthomolecular Med. 1996; 11(1)

Identification of melatonin in plants and its effects on plasma melatonin levels and binding to melatonin receptors in vertebrates.

Hattori A, Migitaka H, Iigo M, et al.

Biochem Mol Biol Int. 1995 Mar; 35(3):627-34.

Twenty-four edible plants were investigated for the presence of melatonin, heretofore considered to be a molecule found only in the animal kingdom. The amount of melatonin in different plants varied greatly with highest melatonin being present in plants of the rice family. Melatonin was identified by radioimmunoassay and verified by high performance liquid chromatography with fluorescence detection. Feeding a diet containing plant products rich in melatonin to chicks increased radioimmunoassayable levels of melatonin in their blood. Likewise, melatonin extracted from plants inhibited binding of [125I]iodomelatonin to rabbit brain. Thus, melatonin ingested in foodstuffs enters the blood and is capable of binding to melatonin binding sites in the brain of mammals

Inhibition of hepatocarcinogenic responses to 1,2-dimethylhydrazine by diallyl sulfide, a component of garlic oil.

Hayes MA, Rushmore TH, Goldberg MT.

Carcinogenesis. 1987 Aug; 8(8):1155-7.

The mechanisms by which diallyl sulfide (DAS), a component of garlic oil, inhibits hepatocarcinogenicity of 1,2-dimethylhydrazine (DMH) were examined in male Fischer 344 rats. Rats were subjected to partial hepatectomy to stimulate hepatocellular proliferation required for initiation by DMH (50-200 mg/kg i.p.) given 12 h later. Initiation was assessed by the numbers of foci and nodules of hepatocytes that were positive for gamma-glutamyl transpeptidase (gamma-GT) or glutathione-S-transferase-P (GST-P) after 6 weeks promotion by orotic acid (1% in semi-purified diet). DAS at doses above 50 mg/kg (by gavage) administered 1 h before DMH (50 mg/kg) partially reduced the numbers of gamma-GT and GST-P-positive foci. By comparison, all doses of DAS (25-100 mg/kg) completely prevented liver necrosis by DMH (200 mg/kg). DAS substantially reduced macromolecular binding of [14C]DMH in cultured liver cells, but had no effect on their levels of glutathione-S-transferase, glutathione reductase or glutathione peroxidase at 18 h. These findings suggest that low dosages of DAS which reduce DMH binding appear more likely to inhibit hepatocarcinogenicity by reducing the promoting influences of post-necrotic regeneration than by preventing initiation

[Role of sodium selenite as an adjuvant in radiotherapy of rectal carcinoma].

Hehr T, Hoffmann W, Bamberg M.

Med Klin (Munich). 1997 Sep 15; 92 Suppl 3:48-9.

BACKGROUND: In various epidemiologic studies an association of low selenium blood levels and reduced glutathione peroxidase with an increased risk of cancer incidence was described. The antitumoral therapy and a suboptimal nutrition could intensify this deficiency. Every reduction of disease related and therapeutic caused symptoms may improve life quality. APPLICATION: We report our preliminary experiences in the adjuvant radiochemotherapy of advanced rectal cancer (UICC II/III) corresponding to the NCl recommendation. An oral selenium supplementation was carried out with 2000 micrograms Na2SeO3 after every course of fluorouracil chemotherapy and daily 400 micrograms Na2SeO3 after irradiation of tumor region and lymph nodes. A weekly life quality assessment was explored with special interest in diarrhea, dysurie, pain, appetite, nausea and emesis. CONCLUSION: Damages to normal tissue specially to DNA enzymes and membranes caused by free radicals is one mechanism in tumorgenesis, tumor progression and therapeutic consequence. A radioprotective effect of selenium is verified by in vitro and in vivo data. Our data show that oral selenium intake in rectal cancer patients is easily tolerated with no side effects. Improving life quality and secondary cancer prevention with supplementation of selenium has to be proven in prospective randomized studies

Association between alpha-tocopherol, gamma tocopherol, selenium, and subsequent prostate cancer.

Helzlsourer KJ.

J Natl Cancer Inst. 2000; 92(24):2018-23.

Dietary supplementation with L-arginine: modulation of tumour-infiltrating lymphocytes in patients with colorectal cancer.

Heys SD, Segar A, Payne S, et al.

Br J Surg. 1997 Feb; 84(2):238-41.

BACKGROUND: Dietary supplementation with L-arginine enhances natural cytotoxicity in peripheral blood lymphocytes but its effect on infiltrating lymphoreticular cells within a tumour microenvironment is unknown. The effects of dietary supplementation with L-arginine on tumour-infiltrating lymphocytes (TILs) in patients with colorectal cancer were evaluated. METHODS: Eighteen patients received either a standard hospital diet (controls) or a standard diet supplemented with 30 g per day of L-arginine for 3 days before surgery. Tumour biopsies were taken at surgery and lymphocyte subsets (CD antigens) and macrophages examined immunohistochemically. RESULTS: Tumours from patients receiving L-arginine contained increased numbers of specific cell subsets within the tumour which expressed CD16 (P = 0.004) and CD56 (P = 0.001) surface markers, when compared with tumours from control patients. There were no differences in the total number of T and B cells, T helper and T suppressor cells. CONCLUSION: Dietary supplementation with L-arginine significantly alter the spectrum of TILs in human colorectal cancers in vivo. These findings have important implications for new strategies in anticancer treatment

1,1-Diphenyl-2-picrylhydrazyl radical-scavenging compounds from soybean miso and antiproliferative activity of isoflavones from soybean miso toward the cancer cell lines.

Hirota A, Taki S, Kawaii S, et al.

Biosci Biotechnol Biochem. 2000 May; 64(5):1038-40.

Guided by their DPPH radical-scavenging activity, nine compounds were isolated from soybean miso. Of these, 8-hydroxydaidzein, 8-hydroxygenistein and syringic acid had as high DPPH radical-scavenging activity as that of alpha-tocopherol. The antiproliferative activity of four of the isolated isoflavones toward three cancer cell lines was examined. 8-Hydroxygenistein showed the highest activity (IC50=5.2 microM) toward human promyelocytic leukemia cells (HL-60)

Lycopene lowers PSA in prostate cancer patients.

Holzman D.

Life Extension Magazine 2002 Jan. 2004 8(1):25.

Comparative study of concentration of isoflavones and lignans in plasma and prostatic tissues of normal control and benign prostatic hyperplasia.

Hong SJ, Kim SI, Kwon SM, et al.

Yonsei Med J. 2002 Apr; 43(2):236-41.

OBJECTIVE: Isoflavones and lignans are phytoestrogens that have recently gained interest as dietary factors related to prostatic diseases. However, no data on the concentrations in prostate tissue in humans is available. Therefore, the concentrations of isoflavones and lignans in plasma and prostatic tissues according to the prostate volume were compared to determine their possible effect on the benign prostatic growth. METHODS: Fasting plasma and prostatic tissue specimens were acquired from 25 men over 50 years of age with similar normal dietary habits and no previous history of drug intake that could affect the isoflavones and lignans levels. The tissue was acquired either during a transurethral resection of the prostate in 15 patients with benign prostatic hyperplasia (BPH) with prostate volume over 40 ml or during a radical cystoprostatectomy in 10 patients with bladder cancer with a prostate volume < 25 ml, who were used as the controls. Quantitative analysis of the isoflavones, specifically equol, daidzein and genistein and lignans, particularly enterodiol and enterolactone, was performed by gas chromatography-mass spectrometry. RESULTS: The mean prostatic concentrations of enterodiol, enterolactone, equol and daidzein in the BPH and the control groups were similar. However, the mean prostatic concentration of genistein was significantly lower in the BPH group than in the control group (65.43 +/- 17.05 vs 86.96 +/- 37.75 ng/ ml, respectively, p=”0.032).” The plasma concentration of isoflavones and lignans in the two groups were comparable. CONCLUSION: Isoflavones, but not lignans, have some influence the benign prostatic growth, and the prostatic concentration of genistein possibly has the closest association among them. More studies to further clarify the roles and mechanisms of isoflavone action on BPH including pharmacokinetic studies are recommended

Effects of allyl sulfur compounds and garlic extract on the expression of Bcl-2, Bax, and p53 in non small cell lung cancer cell lines.

Hong YS, Ham YA, Choi JH, et al.

Exp Mol Med. 2000 Sep 30; 32(3):127-34.

Allyl sulfur compounds play a major role in the chemoprevention against carcinogenesis. The present study compared the antiproliferative effects of diallyl sulfide (DAS), diallyl disulfide (DADS) and garlic extract on p53-wild type H460 and p53-null type H1299 non small cell lung cancer cells (NSCLC). The DAS and DADS treatment of both H460 and H1299 cells resulted in the highest numbers of cells in apoptotic state as measured by acridine orange staining, however, garlic extract treatment did not induce any significant apoptotic cells by MTT assay. DADS was found to be more effective in inducing apoptosis on NSCLC. The level of p53 protein in H460 cell was increased following DADS treatment. DAS and garlic extract treatment of H460 cells induced a rise in the level of Bax and a fall of Bcl-2 level. These results demonstrate that DAS, DADS and garlic extract are effective in reduction of anti-proliferative gene in NSCLC and suggest that modulation of apoptosis-associated cellular proteins by DAS, DADS and garlic extract may be the mechanism for apoptosis which merit further investigation as potential chemoprevention agents

Phytoestrogens and thyroid cancer risk: the San Francisco Bay Area thyroid cancer study.

Horn-Ross PL, Hoggatt KJ, Lee MM.

Cancer Epidemiol Biomarkers Prev. 2002 Jan; 11(1):43-9.

Epidemiological and pathological data suggest that thyroid cancer may well be an estrogen-dependent disease. The relationship between thyroid cancer risk and dietary phytoestrogens, which can have both estrogenic and antiestrogenic properties, has not been previously studied. We present data from a multiethnic population-based case-control study of thyroid cancer conducted in the San Francisco Bay Area. Of 817 cases diagnosed between 1995 and 1998 (1992 and 1998 for Asian women), 608 (74%) were interviewed. Of 793 controls identified through random-digit dialing, 558 (70%) were interviewed. Phytoestrogen consumption was assessed via a food-frequency questionnaire and a newly developed nutrient database. The consumption of traditional and nontraditional soy-based foods and alfalfa sprouts were associated with reduced risk of thyroid cancer. Consumption of “western” foods with added soy flour or soy protein did not affect risk. Of the seven specific phytoestrogenic compounds examined, the isoflavones, daidzein and genistein [odds ratio (OR), 0.70; 95% confidence interval (CI), 0.44-1.1; and OR, 0.65, 95% CI, 0.41-1.0, for the highest versus lowest quintile of daidzein and genistein, respectively] and the lignan, secoisolariciresinol (OR, 0.56; 95% CI, 0.35-0.89, for the highest versus lowest quintile) were most strongly associated with risk reduction. Findings were similar for white and Asian women and for pre- and postmenopausal women. Our findings suggest that thyroid cancer prevention via dietary modification of soy and/or phytoestrogen intake in other forms may be possible but warrants further research at this time

Effect of cimetidine on development of gastric cancer in rats after gastrojejunostomy.

Hortemo GS, Maartmann-Moe H, Rokke O, et al.

Eur J Surg. 1999 Mar; 165(3):259-61.

OBJECTIVE: To find out if cimetidine has an immunomodulating effect on gastric carcinogenesis in rats. DESIGN: Experimental prospective study. SETTING: Teaching hospital, Norway. ANIMALS: 132 male PGV/Mol rats given gastrojejunostomies. INTERVENTION: Half the rats were given cimetidine in their drinking water postoperatively for a minimum of 38 weeks. They were killed after 52 weeks observation and the stomach was investigated macroscopically and microscopically. MAIN OUTCOME MEASURE: In the cimetidine fed group 19/48 animals developed cancer (49%), versus 12/43 (28%) in the control group (p = 0.24). CONCLUSION: Cimetidine had no immunomodulatory effect on the development of gastric cancer in rats

Prostate cancer risk and serum levels of insulin and leptin: a population-based study.

Hsing AW, Chua S Jr, Gao YT, et al.

J Natl Cancer Inst. 2001 May 16; 93(10):783-9.

BACKGROUND: In a previous study of Chinese men, we found that men with a higher waist-to-hip ratio (WHR) have a higher prostate cancer risk. Because leptin and insulin are related to body fat distribution, we examined whether leptin and insulin were associated with prostate cancer risk. METHODS: Blood samples were collected from 128 case patients with incident prostate cancer and from 306 healthy control subjects randomly selected from residents of Shanghai, CHINA: Epidemiologic information and anthropometric measurements were collected in personal interviews. Serum leptin, insulin, and sex hormone levels were measured by radioimmunoassay, and insulin-like growth factor-I (IGF-I) was measured by enzyme-linked immunosorbent assay. Multiple logistic regression analyses were used to estimate odds ratios for prostate cancer in relation to serum insulin and leptin levels. All statistical tests were two-sided. RESULTS: After adjustment for body mass index, WHR, IGF-I, and sex hormone levels, higher serum insulin levels were associated with a statistically significantly elevated risk of prostate cancer (P0.900) and insulin (>8.83 microU/mL) had 8.55 times (95% CI = 2.80 to 26.10) the prostate cancer risk of men in the lowest tertiles of both, and those in the lowest tertile of WHR (<0.873) and highest tertile of insulin had 4.30 times (95% CI = “1.17″ to 15.70) the risk. By contrast, the association between leptin levels and prostate cancer risk was not statistically significant. CONCLUSION: Our results suggest that serum insulin levels may influence the risk of prostate cancer in Chinese men. Further research, especially prospective studies, is needed to confirm these findings in high-risk populations and to clarify the underlying mechanisms involved

Inhibitory effects of topical application of low doses of curcumin on 12-O-tetradecanoylphorbol-13-acetate-induced tumor promotion and oxidized DNA bases in mouse epidermis.

Huang MT, Ma W, Yen P, et al.

Carcinogenesis. 1997 Jan; 18(1):83-8.

The effects of topical applications of very low doses of curcumin (the major yellow pigment in turmeric and the Indian food curry) on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced oxidation of DNA bases in the epidermis and on tumor promotion in mouse skin were investigated. CD-1 mice were treated topically with 200 nmol of 7,12-dimethylbenz[a]anthracene followed one week later by 5 nmol of TPA alone or together with 1, 10, 100 or 3000 nmol of curcumin twice a week for 20 weeks. Curcumin-mediated effects on TPA-induced formation of the oxidized DNA base 5-hydroxymethyl-2′-deoxyuridine (HMdU) and tumor formation were determined. All dose levels of curcumin inhibited the mean values of TPA-induced HMdU formation in epidermal DNA (62-77% inhibition), but only the two highest doses of curcumin strongly inhibited TPA-induced tumor promotion (62-79% inhibition of tumors per mouse and tumor volume per mouse). In a second experiment, topical application of 20 or 100 nmol (but not 10 nmol) of curcumin together with 5 nmol TPA twice a week for 18 weeks markedly inhibited TPA-induced tumor promotion. Curcumin had a strong inhibitory effect on DNA and RNA synthesis (IC50 = 0.5-1 microM) in cultured HeLa cells, but there was little or no effect on protein synthesis

1,25-dihydroxyvitamin D3 regulates estrogen metabolism in cultured keratinocytes.

Hughes SV, Robinson E, Bland R, et al.

Endocrinology. 1997 Sep; 138(9):3711-8.

Local estrogen metabolism may play an important role in modulating cell development in peripheral tissues such as breast, adipose, and bone. C19 androgens are converted to C18 estrogens by the enzyme aromatase, overexpression of which is associated with breast cancer. Interconversion of active estradiol (E2) to inactive estrone is controlled by various isoforms of the enzyme 17beta-hydroxysteroid dehydrogenase (17betaHSD). We have studied the expression of these two enzymes in human keratinocytes and report rapid changes in 17betaHSD activity in response to treatment with 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]. Keratinocytes cultured in serum-free medium showed aromatase activity of 2.5 fmol/h x mg cell protein, which was unaffected by any culture treatment. A much higher level of 17betaHSD activity was observed in the keratinocytes, predominantly conversion of E2 to estrone (approximately 120 pmol/h x mg cell protein). This inactivation of E2 increased in a dose-dependent fashion after treatment of the cells with antiproliferative doses of 1,25-(OH)2D3 (0.1-200 nM). The effect of 1,25-(OH)2D3 on 17betaHSD activity was enhanced by simultaneous treatment with dexamethasone, which also increased the antiproliferative action of 1,25-(OH)2D3. Reverse transcription-PCR and Northern analysis showed that keratinocytes expressed messenger RNA for three 17betaHSD isoenzymes (types I, II, and IV). Treatment with 1,25-(OH)2D3 (10 nM for 20 h) resulted in the up-regulation of messenger RNA levels for type 2 17betaHSD. Further RNA studies combined with E2 binding experiments demonstrated the presence of estrogen receptors in the cultured keratinocytes. These data indicate that keratinocytes are potential targets for systemically or locally produced estrogens, which may, in turn, play a key role in the development of normal skin. In particular, we propose that 17betaHSD isoenzymes are key target genes for 1,25-(OH)2D3 in keratinocytes and may be an important feature of the antipsoriatic effects of vitamin D and its analogs

Carotenoids, alpha-tocopherols, and retinol in plasma and breast cancer risk in northern Sweden.

Hulten K, Van Kappel AL, Winkvist A, et al.

Cancer Causes Control. 2001 Aug; 12(6):529-37.

OBJECTIVE: Using a nested case-referent design we evaluated the relationship between plasma levels of six carotenoids, alpha-tocopherol, and retinol, sampled before diagnosis, and later breast cancer risk. METHODS: In total, 201 cases and 290 referents were selected from three population-based cohorts in northern Sweden, where all subjects donated blood samples at enrolment. All blood samples were stored at -80 degrees C. Cases and referents were matched for age, age of blood sample, and sampling centre. Breast cancer cases were identified through the regional and national cancer registries. RESULTS: Plasma concentrations of carotenoids were positively intercorrelated. In analysis of three cohorts as a group none of the carotenoids was found to be significantly related to the risk of developing breast cancer. Similarly, no significant associations between breast cancer risk and plasma levels of alpha-tocopherol or retinol were found. However, in postmenopausal women from a mammography cohort with a high number of prevalent cases, lycopene was significantly associated with a decreased risk of breast cancer. A significant trend of an inverse association between lutein and breast cancer risk was seen in premenopausal women from two combined population-based cohorts with only incident cases. A non-significant reduced risk with higher plasma alpha-carotene was apparent throughout all the sub-analyses. CONCLUSION: In conclusion, no significant associations were found between plasma levels of carotenoids, alpha-tocopherol or retinol and breast cancer risk in analysis of three combined cohorts. However, results from stratified analysis by cohort membership and menopausal status suggest that lycopene and other plasma-carotenoids may reduce the risk of developing breast cancer and that menopausal status has an impact on the mechanisms involved

Dietary beta-carotene intake and the risk of epithelial ovarian cancer: a meta-analysis of 3,782 subjects from five observational studies.

Huncharek M, Klassen H, Kupelnick B.

In Vivo. 2001 Jul; 15(4):339-43.

OBJECTIVE: The etiology of epithelial ovarian cancer is unknown. Prior work suggests that high dietary beta-carotene intake is associated with a decreased risk of this tumor although this association remains speculative. A meta-analysis was performed to evaluate this suspected relationship. METHODS: Using previously described methods, a protocol was developed for a meta-analysis examining the association between high dietary beta-carotene intake versus low intake and the risk of epithelial ovarian cancer. Literature search techniques, study inclusion criteria and statistical procedures were prospectively defined. Data from observational studies were pooled using a general variance based meta-analytic method employing confidence intervals previously described by Greenland. The outcome of interest was a summary relative risk (RRs) reflecting the risk of ovarian cancer associated with high beta-carotene intake versus low dietary intake. Sensitivity analyses were performed when necessary to evaluate any observed statistical heterogeneity. RESULTS: Five observational studies enrolling 3,782 subjects were initially pooled in a meta-analysis subsequent to an analysis showing a lack of statistical heterogeneity. The meta-analysis showed a summary relative risk of 0.84 with a 95% confidence interval of 0.75-0.94, a statistically significant result. These data suggest that high (versus low) dietary intake of beta-carotene is associated with a sixteen percent decrease in ovarian cancer risk. Sensitivity analyses showed no impact of study design or differences in quantitative measure of beta-carotene intake across studies on the summary relative risk. CONCLUSIONS: High dietary intake of beta-carotene appears to represent a protective factor for the development of ovarian cancer although its magnitude is modest. Further work is needed to clarify factors that may modify the effects of beta-carotene in vivo

Inhibition of the expression of inducible cyclooxygenase and proinflammatory cytokines by sesquiterpene lactones in macrophages correlates with the inhibition of MAP kinases.

Hwang D, Fischer NH, Jang BC, et al.

Biochem Biophys Res Commun. 1996 Sep 24; 226(3):810-8.

In our previous studies (Refs. 1 and 2), it was shown that protein tyrosine kinase (PTK) inhibitors, radicicol and herbimycin A, inhibit the expression of the mitogen-inducible cyclooxygenase (COX-2) and proinflammatory cytokines. Radicicol and herbimycin A possess polarized double bonds which can conjugate sulphydryl groups of proteins. Parthenolide, the predominant sesquiterpene lactone in European feverfew (Tanacetum parthenium), contains alpha-methylene-gamma-lactone (MGL) and an epoxide in its structure. These moieties can interact with biological nucleophiles such as a sulfhydryl group. Parthenolide inhibited the expression of COX-2 and proinflammatory cytokines (TNF alpha and IL-1) in lipopolysaccharide (LPS)-stimulated macrophages. The structure-function relationship indicates that the MGL moiety confers the inhibitory effect. Parthenolide suppressed LPS-stimulated protein tyrosine phosphorylation in the murine macrophage cell line (RAW 264.7). This suppression was correlated with its inhibitory effect on the expression of COX-2 and the cytokines. Among tyrosine phosphorylated proteins, mitogen-activated protein kinases (MAPKs) exhibited the most dramatic inhibition

Chemoprevention by curcumin during the promotion stage of tumorigenesis of mammary gland in rats irradiated with gamma-rays.

Inano H, Onoda M, Inafuku N, et al.

Carcinogenesis. 1999 Jun; 20(6):1011-8.

We have evaluated the chemopreventive effects of curcumin on diethylstilbestrol (DES)-induced tumor promotion of rat mammary glands initiated with radiation. Sixty-four pregnant rats received whole body irradiation with 2.6 Gy gamma-rays from a 60Co source at day 20 of pregnancy and were divided into two groups after weaning. In the control group of 39 rats fed a basal diet and then implanted with a DES pellet for 1 year, 33 (84.6%) developed mammary tumors. Twenty-five rats were fed diet containing 1% curcumin immediately after weaning and received a DES pellet, as for the control. The administration of dietary curcumin significantly reduced the incidence (28.0%) of mammary tumors. Multiplicity and Iball’s index of mammary tumors were also decreased by curcumin. Rats fed the curcumin diet showed a reduced incidence of the development of both mammary adenocarcinoma and ER(+)PgR(+) tumors in comparison with the control group. On long-term treatment with curcumin, body weight and ovarian weight were reduced, but liver weight was increased. Compared with the control rats, the curcumin-fed rats showed a significant reduction in serum prolactin, whereas estradiol-17beta and progesterone concentrations were not significantly different between the two groups. Curcumin did not have any effect on the concentration of free cholesterol, cholesterol ester and triglyceride. Feeding of the curcumin diet caused a significant increase in the concentrations of tetrahydrocurcumin, arachidonic acid and eicosapentaenoic acid and a significant decrease in thiobarbituric acid-reactive substance concentration in serum. Whole mounts of the mammary glands showed that curcumin yielded morphologically indistinguishable proliferation and differentiation from the glands of the control rats. These findings suggest that curcumin has a potent preventive activity during the DES-dependent promotion stage of radiation-induced mammary tumorigenesis

Tea and coffee consumption and the risk of digestive tract cancers: data from a comparative case-referent study in Japan.

Inoue M, Tajima K, Hirose K, et al.

Cancer Causes Control. 1998 Mar; 9(2):209-16.

OBJECTIVES: The purpose of this study was to examine the hypothesis that tea and coffee consumption have a protective effect against development of digestive tract cancers. METHODS: A comparative case-referent study was conducted using Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC) data from 1990 to 1995 in Nagoya, Japan. This study comprised 1,706 histologically diagnosed cases of digestive tract cancers (185 esophagus, 893 stomach, 362 colon, 266 rectum) and a total of 21,128 non-cancer outpatients aged 40 years and over. Logistic regression was used to analyze the data, adjusting for gender; age; year and season at hospital-visit; habitual smoking and alcohol drinking; regular physical exercise; fruit, rice, and beef intake; and beverage intake. RESULTS: The odds ratio (OR) of stomach cancer decreased to 0.69 (95 percent confidence interval [CI] = 0.48-1.00) with high intake of green tea (seven cups or more per day). A decreased risk was also observed for rectal cancer with three cups or more daily intake of coffee (OR = 0.46, CI = 0.26-0.81). CONCLUSIONS: The results suggest the potential for protective effect against site-specific digestive tract cancer by consumption of green tea and coffee, although most associations are limited only to the upper category of intake and have no clear explanation for site-specificity

Induction of apoptosis by conjugated linoleic acid in cultured mammary tumor cells and premalignant lesions of the rat mammary gland.

Ip C, Ip MM, Loftus T, et al.

Cancer Epidemiol Biomarkers Prev. 2000 Jul; 9(7):689-96.

Conjugated linoleic acid (CLA) is an effective agent in preventing mammary cancer in rats treated with a carcinogen. The appearance of a tumor mass is the net result of cell proliferation minus cell death. Thus, apoptosis could be an important mechanism in controlling clonal expansion of the early premalignant lesions. The overall objective of this report was to determine whether CLA stimulated apoptosis. In the first part of the study, CLA was found to increase chromatin condensation (visualized through fluorescent 4′,6-diamidino-2-phenylindole staining to DNA) and to induce DNA laddering, both evidence of apoptosis, in a rat mammary tumor cell line. The second part was to investigate the effect of CLA feeding on the development of histologically identifiable premalignant lesions in the rat mammary gland, as well as on the quantification of apoptosis (by terminal uridyltransferase nick end labeling assay) and the expression by immunohistochemistry of apoptosis regulatory proteins (bcl-2, bak, and bax) in normal versus premalignant mammary structures. CLA inhibited the formation of premalignant lesions by approximately 50%. It also significantly increased apoptosis and reduced the expression of bcl-2 in these lesions, but it did not modulate the levels of bak or bax. In contrast, neither apoptosis nor any of the apoptosis regulatory proteins was affected by CLA in normal mammary gland alveoli or terminal end buds. The data suggest that early pathological lesions may be particularly sensitive to CLA. In addition to providing a molecular basis for elucidating the mechanism of action of CLA in cancer prevention, the research on CLA-responsive biomarkers also has a practical side because these assays can be applied to biopsied human tissue samples in future CLA intervention trials

Conjugated linoleic acid inhibits proliferation and induces apoptosis of normal rat mammary epithelial cells in primary culture.

Ip MM, Masso-Welch PA, Shoemaker SF, et al.

Exp Cell Res. 1999 Jul 10; 250(1):22-34.

The trace fatty acid conjugated linoleic acid (CLA) inhibits rat mammary carcinogenesis when fed prior to carcinogen during pubertal mammary gland development or during the promotion phase of carcinogenesis. The following studies were done to investigate possible mechanisms of these effects. Using a physiological model for growth and differentiation of normal rat mammary epithelial cell organoids (MEO) in primary culture, we found that CLA, but not linoleic acid (LA), inhibited growth of MEO and that this growth inhibition was mediated both by a reduction in DNA synthesis and a stimulation of apoptosis. The effects of CLA did not appear to be mediated by changes in epithelial protein kinase C (PKC) since neither total activity nor expression nor localization of PKC isoenzymes alpha, beta II, delta, epsilon, eta, or zeta were altered in the epithelium of CLA-fed rats. In contrast, PKCs delta, epsilon, and eta were specifically upregulated and associated with a lipid-like, but acetone-insoluble, fibrillar material found exclusively in adipocytes from CLA-fed rats. Taken together, these observations demonstrate that CLA can act directly to inhibit growth and induce apoptosis of normal MEO and may thus prevent breast cancer by its ability to reduce mammary epithelial density and to inhibit the outgrowth of initiated MEO. Moreover, the changes in mammary adipocyte PKC expression and lipid composition suggest that the adipose stroma may play an important in vivo role in mediating the ability of CLA to inhibit mammary carcinogenesis

Quantitative analysis of estrogen receptor-alpha and -beta messenger RNA expression in breast carcinoma by real-time polymerase chain reaction.

Iwao K, Miyoshi Y, Egawa C, et al.

Cancer. 2000 Oct 15; 89(8):1732-8.

BACKGROUND: Estrogen action is mediated not only through a classic estrogen receptor (ER) (ER-alpha) but also through a second ER (ER-beta) that has a structure and function similar to ER-alpha. A correlation between ER-beta mRNA expression with ER and progesterone receptor (PR) protein levels as well as prognostic factors remains to be established in breast carcinoma. METHODS: The authors conducted a quantitative analysis of ER-alpha and ER-beta mRNA expression in 116 breast tumors using real-time polymerase chain reaction (PCR), and investigated a possible correlation between ER-alpha and ER-beta mRNA expression and ER and PR status as determined by enzyme immunoassay as well as with various prognostic factors. RESULTS: ER-alpha mRNA levels were significantly (P < 0.01) higher in ER positive compared with ER negative tumors. Conversely, ER-beta mRNA levels were significantly (P < 0.01) lower in ER positive compared with ER negative tumors. Accordingly, the ratio of ER-beta to ER-alpha was significantly (P < 0.01) higher in ER negative compared with ER positive tumors. A subset analysis based on ER and PR status showed that ER-beta mRNA levels as well as the ratios of ER-beta to ER-alpha mRNA level were highest in ER negative and PR negative tumors (P < 0.05). ER-alpha mRNA levels were significantly (P < 0.05) higher in postmenopausal compared with premenopausal tumors. Histologic Grade 3 tumors showed a significant decrease in ER-alpha mRNA levels compared with Grade 1 and 2 tumors (P < 0.01 and P < 0.05, respectively). No significant correlation between ER-alpha and ER-beta mRNA levels and histologic type, tumor size, or lymph node status was observed. CONCLUSIONS: An absolute and relative increase in ER-beta mRNA levels in ER negative and PR negative breast tumors, which rarely respond to endocrine therapy, suggests the possible involvement of up-regulation of ER-beta mRNA in the development of estrogen-independent tumors

DNA fragmentation, DNA-protein crosslinks, postlabeled nucleotidic modifications, and 8-hydroxy-2′-deoxyguanosine in the lung but not in the liver of rats receiving intratracheal instillations of chromium(VI). Chemoprevention by oral N-acetylcysteine.

Izzotti A, Bagnasco M, Camoirano A, et al.

Mutat Res. 1998 May 25; 400(1-2):233-44.

An in vivo study was carried out with the objectives of evaluating (a) the localization of DNA lesions resulting from exposure to chromium(VI) by the respiratory route, (b) the molecular nature of DNA alterations, and (c) modulation of DNA damage by a known chemopreventive agent. To this purpose, Sprague-Dawley rats received intratracheal instillations of sodium dichromate (0.25 mg/kg body weight) for three consecutive days, and the day after the last treatment lung and liver were removed for DNA purification. The results showed a selective localization of DNA lesions in the lung but not in the liver, which can be ascribed to toxicokinetics and metabolic characteristics of chromium(VI). DNA alterations included DNA-protein crosslinks, DNA fragmentation, nucleotidic modifications, and 8-hydroxy-2′-deoxyguanosine. The last two endpoints were evaluated, for the first time in chromium toxicology, by means of postlabeling procedures. This methodology was adapted to the detection of the DNA damage produced by those reactive oxygen species which result from the intracellular reduction of chromium(VI). The oral administration of the thiol N-acetylcysteine completely prevented any induction of DNA lesions in lung cells

Milk thistle for the treatment of liver disease: a systematic review and meta-analysis.

Jacobs BP, Dennehy C, Ramirez G, et al.

Am J Med. 2002 Oct 15; 113(6):506-15.

PURPOSE: Milk thistle, an herbal compound, is the dietary supplement taken most frequently by patients with chronic liver disease. We performed a systematic review of the literature to determine the efficacy and safety of this herb for the treatment of liver disease. METHODS: We searched English and non-English reports through July 1999 using thirteen databases and reference lists, and contacting manufacturers and technical experts. Reviewers independently screened all reports to identify randomized placebo-controlled trials that evaluated milk thistle for the treatment of liver disease. Outcomes of primary interest included mortality, histological findings on liver biopsy specimens, serum aminotransferase and albumin levels, and prothrombin times. RESULTS: Fourteen trials met inclusion criteria. Four trials reported outcomes for mortality among 433 participants. The overall summary odds ratio for mortality in the milk thistle group compared with placebo was 0.8 (95% confidence interval [CI]: 0.5 to 1.5; P = 0.6). Three trials assessed histology on liver biopsy; study quality was inversely associated with the likelihood of histological benefit for milk thistle compared with placebo. There were no differences in serum alanine aminotransferase, aspartate aminotransferase, or albumin levels, or prothrombin times, among participants assigned to milk thistle compared with those assigned to placebo. The only statistically significant difference was a greater reduction in alanine aminotransferase levels among patients with chronic liver disease assigned to milk thistle (-9 IU/L, 95% CI: -18 to -1 IU/L; P = 0.05), but this reduction was of negligible clinical importance and no longer statistically significant after limiting analyses to studies of longer duration or of higher quality. The frequency of adverse effects was low and, in clinical trials, indistinguishable from placebo. CONCLUSION: Treatment with milk thistle appears to be safe and well tolerated. We found no reduction in mortality, in improvements in histology at liver biopsy, or in biochemical markers of liver function among patients with chronic liver disease. Data are too limited to exclude a substantial benefit or harm of milk thistle on mortality, and also to support recommending this herbal compound for the treatment of liver disease

Does high soy milk intake reduce prostate cancer incidence? The Adventist Health Study (United States).

Jacobsen BK, Knutsen SF, Fraser GE.

Cancer Causes Control. 1998 Dec; 9(6):553-7.

OBJECTIVES: Recent experimental studies have suggested that isoflavones (such as genistein and daidzein) found in some soy products may reduce the risk of cancer. The purpose of this study was to evaluate the relationship between soy milk, a beverage containing isoflavones, and prostate cancer incidence. METHODS: A prospective study with 225 incident cases of prostate cancer in 12,395 California Seventh-Day Adventist men who in 1976 stated how often they drank soy milk. RESULTS: Frequent consumption (more than once a day) of soy milk was associated with 70 per cent reduction of the risk of prostate cancer (relative risk = 0.3, 95 percent confidence interval 0.1-1.0, p-value for linear trend = 0.03). The association was upheld when extensive adjustments were performed. CONCLUSIONS: Our study suggests that men with high consumption of soy milk are at reduced risk of prostate cancer. Possible associations between soy bean products, isoflavones and prostate cancer risk should be further investigated

The Effect of MGN-3 on Cisplatin and Adriamycin Induced Toxicity in the Rat 2000.

Jacoby H.

2004

Risk reduction for DDT toxicity and carcinogenesis through dietary modification.

Jaga K, Duvvi H.

J R Soc Health. 2001 Jun; 121(2):107-13.

Organochlorine pesticides, including dichlorodiphenyltrichloroethane (DDT), are an environmental hazard due to their persistent nature and potential health effects. DDT and 1,1,dichloro-2,2,bis(p-chlorophenyl)ethylene (DDE) are lipid-soluble pesticides which accumulate in fatty tissues and are, therefore, more present in fat-containing foods such as meat, fish, milk, cheese and oil than in fruit, vegetables and grain. Scientists have for some time been concerned about the human exposure to DDT and the potential risk of breast cancer due to its oestrogenic activity. The introduction of foods containing chemopreventive agents in the diet could inhibit the oestrogenic effects of DDT and the risk of developing cancer. Phytooestrogens are weak oestrogens found in certain plants such as soybean. They compete with DDT for oestrogen receptors and inhibit the oestrogenic effect of DDT on cultured human breast (MCF) cells. Curcumin, a spice widely used in Indian dishes, has anti-carcinogenic and anti-inflammatory properties. It also inhibits the oestrogenic effects of DDT and is synergistic with phytooestrogens. Indole-3-carbinol, a compound naturally found in cruciferous vegetables, stimulates oestrogen metabolism towards 2-hydroxyoestrone which reduces the oestrogenic response in MCF cells and the risk of breast cancer. Since DDT is lipid soluble and accumulates in adipose tissue it could have a role in lipid metabolism. Would a low fat diet reduce DDT bioaccumulation? A reduction in calories can decrease oestrogen levels and possibly reduce the risk of breast cancer. A dietary modification with the introduction of soy products, curcumin, cruciferous vegetables and low fat could be beneficial in reducing the risk of developing cancer and possibly the effects of DDT

Dietary polyunsaturated fatty acids and inflammatory mediator production.

James MJ, Gibson RA, Cleland LG.

Am J Clin Nutr. 2000 Jan; 71(1 Suppl):343S-8S.

Many antiinflammatory pharmaceutical products inhibit the production of certain eicosanoids and cytokines and it is here that possibilities exist for therapies that incorporate n-3 and n-9 dietary fatty acids. The proinflammatory eicosanoids prostaglandin E(2) (PGE(2)) and leukotriene B(4) (LTB(4)) are derived from the n-6 fatty acid arachidonic acid (AA), which is maintained at high cellular concentrations by the high n-6 and low n-3 polyunsaturated fatty acid content of the modern Western diet. Flaxseed oil contains the 18-carbon n-3 fatty acid alpha-linolenic acid, which can be converted after ingestion to the 20-carbon n-3 fatty acid eicosapentaenoic acid (EPA). Fish oils contain both 20- and 22-carbon n-3 fatty acids, EPA and docosahexaenoic acid. EPA can act as a competitive inhibitor of AA conversion to PGE(2) and LTB(4), and decreased synthesis of one or both of these eicosanoids has been observed after inclusion of flaxseed oil or fish oil in the diet. Analogous to the effect of n-3 fatty acids, inclusion of the 20-carbon n-9 fatty acid eicosatrienoic acid in the diet also results in decreased synthesis of LTB(4). Regarding the proinflammatory ctyokines, tumor necrosis factor alpha and interleukin 1beta, studies of healthy volunteers and rheumatoid arthritis patients have shown < or = “90%” inhibition of cytokine production after dietary supplementation with fish oil. Use of flaxseed oil in domestic food preparation also reduced production of these cytokines. Novel antiinflammatory therapies can be developed that take advantage of positive interactions between the dietary fats and existing or newly developed pharmaceutical products

Cancer chemopreventive activity of resveratrol.

Jang M, Pezzuto JM.

Drugs Exp Clin Res. 1999; 25(2-3):65-77.

Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a naturally occurring compound shown to inhibit carcinogen-induced preneoplastic lesion formation in mouse mammary organ culture and tumorigenesis in the two-stage mouse skin model. Cancer chemopreventive potential was also suggested in various assays reflective of the three major stages of carcinogenesis. Anti-initiation activity was indicated by its antioxidant and antimutagenic effects, inhibition of the hydroperoxidase function of cyclooxygenase (COX), and induction of phase II drug-metabolizing enzymes. Antipromotion activity was indicated by antiinflammatory effects, inhibition of production of arachidonic acid metabolites catalyzed by either COX-1 or COX-2, and chemical carcinogen-induced neoplastic transformation of mouse embryo fibroblasts. Antiprogression activity was demonstrated by its ability to induce human promyelocytic leukemia (HL-60) cell differentiation. Moreover, pretreatment of mouse skin with resveratrol significantly counteracted 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced oxidative stress, as evidenced by numerous biochemical responses. Resveratrol reduced the generation of hydrogen peroxide, and normalized levels of myeloperoxidase and oxidized-glutathione reductase activities. It also restored glutathione levels and superoxide dismutase activity. As judged by the reverse transcriptase-polymerase chain reaction, resveratrol selectively inhibited TPA-induced expression of c-fos and transforming growth factor-beta 1 (TGF-beta 1), but did not affect other TPA-induced gene products including COX-1, COX-2, c-myc, c-jun, and tumor necrosis factor-alpha. These data indicate that resveratrol may interfere with reactive oxidant pathways and/or modulate the expression of c-fos and TGF-beta 1 to inhibit tumorigenesis in mouse skin. As reported herein, in addition to the activities described above, resveratrol inhibited the de novo formation of inducible nitric oxide synthase (iNOS) in mouse macrophages stimulated with lipopolysaccharide. This finding suggests an additional mechanism by which resveratrol may function as a cancer chemopreventive agent

An eicosapentainoic acid (EPA)-enriched supplement versus megestrol acetate (MA) versus both for patients with cancer-associated wasting.

Jatoi A RKLC.

Proc Am Soc Clin Oncol. 2003;(22):743.

2987

Curcumin induces a p53-dependent apoptosis in human basal cell carcinoma cells.

Jee SH, Shen SC, Tseng CR, et al.

J Invest Dermatol. 1998 Oct; 111(4):656-61.

Curcumin, a potent antioxidant and chemopreventive agent, has recently been found to be capable of inducing apoptosis in human hepatoma and leukemia cells by way of an elusive mechanism. Here, we demonstrate that curcumin also induces apoptosis in human basal cell carcinoma cells in a dose- and time-dependent manner, as evidenced by internucleosomal DNA fragmentation and morphologic change. In our study, consistent with the occurrence of DNA fragmentation, nuclear p53 protein initially increased at 12 h and peaked at 48 h after curcumin treatment. Prior treatment of cells with cycloheximide or actinomycin D abolished the p53 increase and apoptosis induced by curcumin, suggesting that either de novo p53 protein synthesis or some proteins synthesis for stabilization of p53 is required for apoptosis. In electrophoretic mobility gel-shift assays, nuclear extracts of cells treated with curcumin displayed distinct patterns of binding between p53 and its consensus binding site. Supportive of these findings, p53 downstream targets, including p21(CIP1/WAF1) and Gadd45, could be induced to localize on the nucleus by curcumin with similar p53 kinetics. Moreover, we immunoprecipitated extracts from basal cell carcinoma cells with different anti-p53 antibodies, which are known to be specific for wild-type or mutant p53 protein. The results reveal that basal cell carcinoma cells contain exclusively wild-type p53; however, curcumin treatment did not interfere with cell cycling. Similarly, the apoptosis suppressor Bcl-2 and promoter Bax were not changed with the curcumin treatment. Finally, treatment of cells with p53 antisense oligonucleotide could effectively prevent curcumin-induced intracellular p53 protein increase and apoptosis, but sense p53 oligonucleotide could not. Thus, our data suggest that the p53-associated signaling pathway is critically involved in curcumin-mediated apoptotic cell death. This evidence also suggests that curcumin may be a potent agent for skin cancer prevention or therapy

Effect of soy protein foods on low-density lipoprotein oxidation and ex vivo sex hormone receptor activity–a controlled crossover trial.

Jenkins DJ, Kendall CW, Garsetti M, et al.

Metabolism. 2000 Apr; 49(4):537-43.

Plant-derived estrogen analogs (phytoestrogens) may confer significant health advantages including cholesterol reduction, antioxidant activity, and possibly a reduced cancer risk. However, the concern has also been raised that phytoestrogens may be endocrine disrupters and major health hazards. We therefore assessed the effects of soy foods as a rich source of isoflavonoid phytoestrogens on LDL oxidation and sex hormone receptor activity. Thirty-one hyperlipidemic subjects underwent two 1-month low-fat metabolic diets in a randomized crossover study. The major differences between the test and control diets were an increase in soy protein foods (33 g/d soy protein) providing 86 mg isoflavones/2,000 kcal/d and a doubling of the soluble fiber intake. Fasting blood samples were obtained at the start and at weeks 2 and 4, with 24-hour urine collections at the end of each phase. Soy foods increased urinary isoflavone excretion on the test diet versus the control (3.8+/-0.7 v 0.0+/-0.0 mg/d, P < .001). The test diet decreased both oxidized LDL measured as conjugated dienes in the LDL fraction (56+/-3 v 63+/-3 micromol/L, P < .001) and the ratio of conjugated dienes to LDL cholesterol (15.0+/-1.0 v 15.7+/-0.9, P = “.032),” even in subjects already using vitamin E supplements (400 to 800 mg/d). No significant difference was detected in ex vivo sex hormone activity between urine samples from the test and control periods. In conclusion, consumption of high-isoflavone foods was associated with reduced levels of circulating oxidized LDL even in subjects taking vitamin E, with no evidence of increased urinary estrogenic activity. Soy consumption may reduce cardiovascular disease risk without increasing the risk for hormone-dependent cancers

Anti-angiogenic potential of a cancer chemopreventive flavonoid antioxidant, silymarin: inhibition of key attributes of vascular endothelial cells and angiogenic cytokine secretion by cancer epithelial cells.

Jiang C, Agarwal R, Lu J.

Biochem Biophys Res Commun. 2000 Sep 16; 276(1):371-8.

In recent studies, we have shown that silymarin, a naturally occurring flavonoid antioxidant, exhibits anti-cancer effects against several epithelial cancers. Here, we assessed its potential as an anti-angiogenic agent employing human umbilical vein endothelial cells (HUVEC) and human prostate and breast cancer epithelial cells. When sub-confluent HUVEC were treated for 48 h, adherent cell number decreased by 50 and 90% at 50 and 100 microg/ml doses, respectively. Apoptotic cell death principally accounted for cell loss at >50 microg/ml doses. In biochemical analysis, silymarin treatment of HUVEC for 6 h resulted in a concentration-dependent decrease in the secretion and cellular content of matrix metalloproteinase (MMP)-2/gelatinase A. Silymarin also inhibited HUVEC tube formation (in vitro capillary differentiation) on a reconstituted extracellular matrix, Matrigel. In other studies, 5 to 6 h exposure of DU145 prostate, and MCF-7 and MDA-MB-468 breast cancer cells to silymarin resulted in a dose-dependent decrease in the secreted vascular endothelial growth factor (VEGF) level in conditioned media without any visible change in cell morphology. The inhibitory effect of silymarin on VEGF secretion occurred as early as 1 h. These observations indicate a rapid inhibitory action of silymarin on the secretion of this primary angiogenic cytokine by cancer epithelial cells. Taken together, the results of this study support the hypothesis that silymarin possesses an anti-angiogenic potential that may critically contribute to its cancer chemopreventive efficacy

gamma-tocopherol, the major form of vitamin E