Archive for the ‘Gemcitabine’ Category

Scientists Break Through Pancreas Cancer Treatment Barrier

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Posted 19 Mar 2012 — by James Street
Category Gemcitabine, Pancreatic
Released: 3/14/2012 11:15 AM EDT
Embargo expired: 3/19/2012 12:00 PM EDT
Source: Fred Hutchinson Cancer Research Center

Research study reports extending survival in mice by 70 percent; initial studies in humans are under way

Newswise — SEATTLE – Pancreas cancer tumors spread quickly and are notoriously resistant to treatment, making them among the deadliest of malignancies. Their resistance to chemotherapy stems in part from a unique biological barrier the tumor builds around itself. Now scientists at Fred Hutchinson Cancer Research Center have found a way to break through that defense, and their research represents a potential breakthrough in the treatment of pancreas cancer.

In a paper to be published in the March 20 issue of Cancer Cell, senior author Sunil Hingorani, M.D., Ph.D., an associate member of the Hutchinson Center’s Clinical Research and Public Health Sciences divisions, and colleagues describe the biological mechanisms of how the tumor barrier is formed and detail a newly discovered way to break it down. Their research significantly increased the length of survival in a genetically engineered mouse model of the disease. Early clinical trials in humans are under way at a few sites in the U.S. and Europe, including Seattle Cancer Care Alliance, the Hutchinson Center’s patient treatment arm. Details about the open clinical trial can be found here: http://clinicaltrials.gov/show/NCT01453153

Using a mouse model developed by Hingorani, the scientists combined gemcitabine, the current standard chemotherapy used to treat pancreatic ductal adenocarcinomas, with an enzyme called PEGPH20. When they infused the combination into specially engineered mice whose pancreas tumors mimic those of human pancreas cancer, the combination broke down the matrix barrier within the tumors and allowed the chemotherapy to permeate freely and spread throughout the cancerous tissue. The result was a 70 percent increase in survival time of the mice after the start of treatment, from 55 to 92 days.

“This represents the largest survival increase we’ve seen in any of the studies done in a preclinical model, and it rivals the very best results reported in humans,” Hingorani said.

Unlike most solid tumors, pancreas tumors use a two-pronged defense to keep small molecules, such as those contained in chemotherapy, from entering: a vastly reduced blood supply and the creation of a strong fibroinflammatory response. The latter includes the production of fibroblasts, immune cells and endothelial cells that become embedded within a dense and complex extracellular matrix throughout the tumor. One major component of this matrix is a substance called hyaluronan, or hyaluronic acid (HA). HA is a glycosaminoglycan, a complex sugar that occurs naturally in the body and is secreted at extremely high levels by pancreas cancer cells.

Hingorani and colleagues discovered that the fibroinflammatory response creates unusually high interstitial fluid pressures that collapse the tumor’s blood vessels. This in turn prevents chemotherapy agents from entering the tumors. The researchers found that HA is the main biological cause of the elevated pressures that leads to blood vessel collapse.

“That’s the primary reason pancreas cancers are resistant to everything we’ve thrown at them: because none of the drugs get into the tumor. It’s physics first, before we even get to the intrinsic biology,” Hingorani said.

Administering the enzyme/gemcitabine combination degrades HA in the tumor barrier and results in rapid reduction of the interstitial fluid pressure. This in turn opens the blood vessels and permits high concentrations of chemotherapy to reach the tumor.

“Being able to deliver the drugs effectively into the tumor resulted in improved survival as well as the realization that pancreas cancer may be more sensitive to conventional chemotherapy than we previously thought,” Hingorani said.

Pancreatic ductal adenocarcinoma is the fourth leading cause of cancer-related death in the United States. Overall five-year survival is less than 5 percent with a median survival of four to six months.

Grants from the National Cancer Institute, the Giles W. and Elise G. Mead Foundation, Safeway and several individuals supported the research. Collaborators from the University of Washington and the Translational Genomics Research Institute in Scottsdale, Ariz., contributed to the study.

Note for media only: Please contact Dean Forbes to schedule interviews with Hingorani. He is available on Friday, March 16 and next Monday and Tuesday, March 19 and 20. Please contact the Cell Press office at 617-397-2802 or moleary@cell.com to obtain a copy of the Cancer Cell paper, “Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma.”

At Fred Hutchinson Cancer Research Center, our interdisciplinary teams of world-renowned scientists and humanitarians work together to prevent, diagnose and treat cancer, HIV/AIDS and other diseases. Our researchers, including three Nobel laureates, bring a relentless pursuit and passion for health, knowledge and hope to their work and to the world. For more information, please visit fhcrc.org.

Curcumin found safe with Docetaxol and found to enhance gemcitabine

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Posted 30 Jul 2011 — by James Street
Category CURCUMIN, docetaxel, Gemcitabine
INTEGRATIVE ONCOLOGY

Turmeric (Curcuma longa, Curcuma domestica)

Complementary Therapies, Herbs, and other OTC Agents

By Guest Editor Barrie Cassileth, PhD1 | May 13, 2010
1 Laurance S. Rockefeller Chair and Chief, Integrative Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York

 

Turmeric, a perennial herb prevalent in South Asia, is ubiquitous in Asian and Middle Eastern cooking. It is also used in Ayurveda and traditional Chinese medicine to treat inflammation, burns, and disorders of the digestive system.

Turmeric was found useful in relieving symptoms associated with irritable bowel syndrome, ulcerative colitis, and osteoarthritis. Epidemiological data indicate that it may improve cognitive performance, but a randomized trial did not find any benefit.

Current evidence from preclinical studies suggests strong chemopreventive potential of curcumin, the active constituent of turmeric, against a variety of tumors. Clinical trials are underway.

Curcumin was shown to interfere with cyclophosphamide(Drug information on cyclophosphamide) in vitro, but a combination of curcumin and docetaxel(Drug information on docetaxel) was found to be safe in a Phase I study. In addition, curcumin enhanced the effects of gemcitabine(Drug information on gemcitabine) both in vitro and in vivo. Until definitive data become available, cancer patients should avoid taking turmeric supplements during treatment.

—Barrie Cassileth, PhD

ALSO KNOWN AS: Indian saffron, curcumin, jiang huang.

TurmericSUMMARY: Turmeric, a perennial plant native to South Asia, is a key ingredient in Asian and Middle Eastern cuisines. It has also been used in Ayurveda and traditional Chinese medicine to treat bacterial infections, inflammation, burns, and digestive disorders. It is available in supplemental form for gastrointestinal discomfort and as an antiseptic.

Extensive research over the last two decades suggests that it helps to alleviate symptoms of irritable bowel syndrome,[1] ulcerative colitis,[2] and osteoarthritis.[3] Curcumin, a hydrophilic polyphenol constituent of turmeric, elicits strong anti-inflammatory and antioxidant properties and is thought to be responsible for turmeric’s beneficial effects. Data from epidemiologic studies suggest that turmeric may improve cognitive performance,[4] but a randomized trial of patients with Alzheimer’s disease found no such benefits.[5]

Curcumin has been shown to be a promising anticancer agent in several in vitro and animal studies. Proposed mechanisms of action include regulation of transcription factors, growth-regulatory molecules, and growth factor receptors, protein kinase, and tumor suppressor pathways.[6]

In clinical studies, curcumin was well tolerated by cancer patients.[7] While it was shown to significantly inhibit cyclophosphamide-induced tumor regression in a human breast cancer model,[8] results from a phase I trial found a combination of curcumin and docetaxel (Taxotere) to be safe.[9] Curcumin also potentiated the antitumor effects of gemcitabine (Gemzar) in pancreatic cancer.[10] Clinical trials are under way to determine the efficacy of curcumin in patients with pancreatic cancer.

HERB-DRUG INTERACTIONS: Anticoagulants/antiplatelets: Turmeric may increase risk of bleeding.[11]

Camptothecin: Turmeric inhibits campto-thecin-induced apoptosis of breast cancer cell lines in vitro.[8]

Mechlorethamine: Turmeric inhibits me-chlorethamine-induced apoptosis of breast cancer cell lines in vitro.[8]

Doxorubicin: Turmeric inhibits doxorubicin(Drug information on doxorubicin)-induced apoptosis of breast cancer cell lines in vitro.[8]

Cyclophosphamide: Dietary turmeric inhibits cyclophosphamide-induced tumor regression in animal studies.[8]

Norfloxacin: Pretreatment with curcumin increased plasma elimination half-life, reducing the dosage of norfloxacin(Drug information on norfloxacin).[12]

Drugs metabolized by CYP3A4 enzyme: Curcumin inhibits cytochrome 3A4 enzyme, altering the metabolism of certain prescription drugs.[13]

Celiprolol and midazolam: Curcumin was shown to downregulate intestinal P-glycoprotein levels, thereby increasing the concentrations of celiprolol(Drug information on celiprolol) and midazolam(Drug information on midazolam).[14]

For additional information, visit the Memorial Sloan-Kettering Cancer Center Integrative Medicine Service website, “About Herbs,” at http://www.mskcc.org/AboutHerbs.

REFERENCES

1. Bundy R, et al: Turmeric extract may improve irritable bowel syndrome symptomology in otherwise healthy adults: A pilot study. J Altern Complement Med 10:1015-1018, 2004.

2. Hanai H, et al: Curcumin maintenance therapy for ulcerative colitis: Randomized, multicenter, double-blind, placebo-controlled trial. Clin Gastroenterol Hepatol 4:1502-1506, 2006.

3. Kuptniratsaikul V, et al: Efficacy and safety of Curcuma domestica extracts in patients with knee osteoarthritis. J Altern Complement Med 15:891-897, 2009.

4. Ng TP, et al: Curry consumption and cognitive function in the elderly. Am J Epidemiol 164:898-906, 2006.

5. Baum L, et al: Six-month randomized, placebo-controlled, double-blind, pilot clinical trial of curcumin in patients with Alzheimer disease. J Clin Psychopharmacol 28:110-113, 2008.

6. Ravindran J, et al: Curcumin and cancer cells: How many ways can curry kill tumor cells selectively? AAPS J 11:495-510, 2009.

7. Dhillon N, et al: Phase II trial of curcumin in patients with advanced pancreatic cancer. Clin Cancer Res 14:4491-4499, 2008.

8. Somasundaram S, et al: Dietary curcumin inhibits chemotherapy-induced apoptosis in models of human breast cancer. Cancer Res 62:3868-3875, 2002.

9. Bayet-Robert M, et al: Phase I dose escalation trial of docetaxel plus curcumin in patients with advanced and metastatic breast cancer. Cancer Biol Ther 9:8-14, 2010.

10. Kunnynajjara AB, et al: Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation, angiogenesis, and inhibition of nuclear factor-kappaB-regulated gene products. Cancer Res 67:3853-3861, 2007.

11. Brinker F: Herbal Contraindications and Drug Interactions, 2nd ed. Sandy, OR, Eclectic Medical Publications, 1998.

12. Pavithra BH, et al: Modification of pharmacokinetics of norfloxacin following oral administration of curcumin in rabbits. J Vet Sci 10:293-297, 2009.

13. Zhang W, Lim LY: Effects of spice constituents on P-glycoprotein-mediated transport and CYP3A4-mediated metabolism in vitro. Drug Metab Dispos 36:1283-1290, 2008.

14. Zhang W, et al: Impact of curcumin-induced changes in P-glycoprotein and CYP3A expression on the pharmacokinetics of peroral celiprolol and midazolam in rats. Drug Metab Dispos 35:110-115, 2007.

Tumeric-curcumin Sloan-Kettering

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Posted 20 Jun 2011 — by James Street
Category Chemotherapy, CURCUMIN, docetaxel, Drug Interactions, Gemcitabine

Turmeric

Scientific Name

Curcuma longa, Curcuma domestica

Common Name

Indian saffron, curcumin, jiang huang

Clinical Summary

Derived from the rhizome and root, turmeric is used as a spice and coloring agent, and in traditional medicine in Asia. The active constituents are thought to be turmerone oil and water soluble curcuminoids, including curcumin. Turmeric may help alleviate symptoms of irritable bowel syndrome (9) as well as quiescent ulcerative colitis (10). Data from an epidemiological study are suggestive of improved cognitive performance in elderly Asians who consume turmeric in the form of curry powder (11); however, no benefits of curcumin supplementation were detected in patients with Alzheimer’s (12). In another study, turmeric extract was found to be safe and equally effective as a non-steroidal anti-inflammatory drug for the treatment of osteoarthritis of knee (34).

In vitro studies suggest that curcumin acts as a weak phytoestrogen (43), exhibits neuroprotective (42), antiproliferative and preventative effects against cancer (3) (4) (5) (6) (7) (8) (35). Furthermore, curcumin was shown to induce apoptosis in human colon cancer (14) and promyelocytic leukemia cells (15). Curcumin potentiated gemcitabine action in both in vitro and in vivo studies of pancreatic cancer (17). In a phase II trial in pancreatic cancer patients, down-regulation of NF-kappa B and cyclooxygenase-2 were observed (29).
Oral administration is well tolerated, but bioavailability is relatively low (1) (2) (29). Following absorption, curcuminoids are rapidly metabolized. But a recent study in rats shows that bioavailability of curcumin can be increased when coadministered with piperine (38).

Animal studies indicate that curcumin may inhibit cyclophosphamide in treating breast cancer (16), but results from a recent, phase I trial found a combination of curcumin and docetaxel to be safe (36). More research is necessary, but it is advisable for cancer patients undergoing chemotherapy to limit intake of turmeric. Patients with gastrointestinal disorders or those predisposed to kidney stone formation (13) should use this supplement with caution.

Purported uses

  • Cancer prevention
  • Infections
  • Inflammation
  • Kidney stones
  • Stomach and intestinal gas

    • Constituents

  • Curcuminoids (mainly curcumin)
  • ar-turmerone
  • Ascorbic acid, carotene
  • Polysaccharides
    (19)

    • Mechanism of Action

    Turmeric has anti-inflammatory and choleretic actions. Both curcuminoids (curcumin) and volatile oils are responsible for the anti-inflammatory activity, which may be due to leukotriene inhibition. Curcuminoids induce glutathione S-transferase and are potent inhibitors of cytochrome P450. Turmeric acts as a free radical scavenger and antioxidant, inhibiting lipid peroxidation and oxidative DNA damage. It also inhibits activation of NF-kB 17, 20, c-jun/AP-1 function, and activation of the c-Jun NH2-terminal kinase (JNK) pathway. In vitro and animal models of breast cancer show that turmeric may inhibit chemotherapy-induced apoptosis via inhibition of the JNK pathway and generation of reactive oxygen species (ROS). Studies also suggest that curcumin induces apoptosis in human colon cancer cells independent of p21 expression (14). In addition, in vitro and in vivo studies report that NF-kB-mediated resistance of cancer cells to gemcitabine and ɣ-radiation was repressed by curcumin administration (17) (21). In laboratory tests, curcumin’s antitumor actions appear to be due to interactions with arachidonate metabolism and its in vivo antiangiogenic properties (16) (22). Another possible chemopreventive mechanism of curcumin maybe via binding and activating the vitamin D receptor (VDR), thereby protecting tissues such as small intestine and colon where VDRs are expressed and vitamin D is known to serve anticancer function (30).

    Pharmacokinetics

    Bioavailability of curcumin is approximately 60-65% following oral administration. Metabolism is primarily via glucuronidation to glucuronide and glucuronide/sulfate metabolites (20). In vitro studies indicate inhibition of Cytochrome P450s (CYPs) such as CYP1A1, CYP1A2, CYP3A4, CYP2D6, CYP2C9, and CYP2B6 (23). Excretion of parent compound is primarily in the feces with metabolites present in the urine (2).

    Warnings

    Recent laboratory findings indicate that dietary turmeric may inhibit the anti-tumor action of chemotherapeutic agents such as cyclophosphamide in treating breast cancer. More research is necessary, but it is advisable for cancer patients undergoing chemotherapy to limit intake of turmeric and turmeric-containing foods. (3)

    Contraindications

    Patients with bile duct obstruction, gallstones, and GI disorders (including stomach ulcers and hyperacidity disorders) should not take this supplement (24).

    Adverse Reactions

    Case Reports
    Allergic dermatitis has been reported with curcumin (39) (40).
    Two cases of contact urticaria from curcumin were reported (41).

    Herb-Drug Interactions

    Anticoagulants / Antiplatelets: Turmeric may increase risk of bleeding (25).
    Camptothecin: Turmeric inhibits camptothecin-induced apoptosis of breast cancer cell lines in vitro (16).
    Mechlorethamine: Turmeric inhibits mechlorethamine-induced apoptosis of breast cancer cell lines in vitro (16).
    Doxorubicin: Turmeric inhibits doxorubicin-induced apoptosis of breast cancer cell lines in vitro (16).
    Cyclophosphamide: Dietary turmeric inhibits cyclophosphamide-induced tumor regression in animal studies (16).
    Norfloxacin: Pretreatment with curcumin resulted in increased plasma elimination half-life, thereby reducing the dosage of norfloxacin (31).
    Drugs metabolized by CYP3A4 enzyme: Curcumin inhibits cytochrome 3A4 enzyme, altering the metabolism of some prescription drugs (32).
    Drugs metabolized by CYP1A2 enzyme: Curcumin inhibits cytochrome 1A2 enzyme, affecting the metabolism of certain prescription medicines (37).
    Drugs metabolized by CYP2A6 enzyme: Curcumin enhances cytochrome 2A6 enzyme, and can affect the metabolism of certain prescription drugs (37).
    Celiprolol and Midazolam: Curcumin was shown to downregulate intestinal P-Glycoprotein levels, thereby increasing the concentrations of Celiprolol and midazolam (33).

    Literature Summary and Critique

    Baum L, Cheung SK, Mok VC, et al. Curcumin effects on blood lipid profile in a 6-month human study. Pharmacol Res 2007 Dec;56(6):509-14.
    The effects of curcumin on blood lipid profiles were assessed in this randomized, double-blind study of 36 elderly participants. Subjects were separated into a control or curcumin-treated groups (1 or 4 g/day), and serum lipid profiles were measured at baseline, 1 month, and 6 months. The side effects were similar between the groups. No significant differences in serum lipid profiles were detected upon curcumin administration; however, levels of absorbed curcumin were modestly associated with increased cholesterol concentration. Larger studies are required to determine if curcumin supplementation may increase cholesterol levels.

    James J. Curcumin: clinical trial finds no antiviral effect. AIDS Treat News 1996;242:1.
    A randomized study of 38 patients to either high-dose or low-dose turmeric powder. Following 8 weeks of treatment, there was no demonstrated effect of turmeric on HIV viral load. A small increase in CD4 cells in the high-dose group and a consistent fall of CD4 cells in the low-dose group were documented, but neither result was statistically significant. This report of an abstract presented at the third annual Conference on Retroviruses and Opportunistic Infections demonstrated no efficacy of turmeric in treating HIV.

    Animal / In vitro data:
    Li JK, et al. Mechanisms of cancer chemoprevention by curcumin. Proc Natl Sci Counc Repub China B 2001;25:59-66.
    Curcumin has shown anti-carcinogenic activity in animals as indicated by its ability to block colon tumor initiation by azoxymethane and skin tumor promotion induced by phorbol ester TPA. Recently, curcumin has been considered by oncologists as a potential third-generation cancer chemopreventive agent, and clinical trials using it have been carried out in several laboratories. Curcumin possesses anti-inflammatory activity and is a potent inhibitor of reactive oxygen-generating enzymes, such as lipoxygenase/cyclooxygenase, xanthine dehydrogenase/oxidase and inducible nitric oxide synthase. Curcumin is also a potent inhibitor of protein kinase C and EGF-receptor tyrosine kinase. It is proposed that curcumin may suppress tumor promotion by blocking signal transduction pathways in the target cells.

    Venkatesan N. Curcumin prevents adriamycin nephrotoxicity in rats. Br J Pharmacol 2000;129:231-4.
    This study investigated the effect of curcumin on Adriamycin (ADR) nephrosis in rats. The results indicate that ADR-induced kidney injury was remarkably well prevented by treatment with curcumin. Treatment with curcumin markedly protected against ADR-induced proteinuria, albuminuria, hypoalbuminemia and hyperlipidemia. Curcumin restored renal function in ADR rats, as judged by the increase in GFR. The data also demonstrate that curcumin protects against ADR-induced renal injury by suppressing oxidative stress and increasing kidney glutathione content and glutathione peroxidase activity. This suggests that administration of curcumin is a promising approach in the treatment of nephrosis caused by ADR.

    Kawamori T, et al. Chemopreventive effect of curcumin, a naturally occurring anti-inflammatory agent, during the promotion/progression stages of colon cancer. Cancer Res 1999;59:597-601.
    This study was designed to investigate the chemopreventive action of curcumin when administered (late in the premalignant stage) during the promotion/progression stage of colon carcinogenesis in male F344 rats. The study also monitored the modulating effect of this agent on apoptosis in the tumors. The results showed that the administration of 0.2% curcumin during both the initiation and post initiation periods significantly inhibited colon tumorigenesis. In addition, administration of 0.2% and of 0.6% synthetic curcumin in the diet during the promotion/progression stage significantly suppressed the incidence and multiplicity of noninvasive adenocarcinomas and also strongly inhibited the multiplicity of invasive adenocarcinomas of the colon.

    Mehta K, et al. Antiproliferative effect of curcumin (diferuloylmethane) against human breast tumor cell lines. Anticancer Drugs 1997;8:470-81.
    The antiproliferative effects of curcumin against several breast tumor cell lines, including hormone-dependent, hormone-independent, and multidrug lines, were studied. Curcumin preferentially arrested cells in the G2/S phase of the cell cycle. Curcumin-induced cell death was due neither to apoptosis nor to a significant change in the expression of apoptosis-related genes, including Bcl-2 p53, cyclin B and transglutaminase.

    Rao CV, et al. Chemoprevention of colon carcinogenesis by dietary curcumin, a naturally occurring plant phenolic compound. Cancer Res 1995;55:259-66.
    This study was designed to investigate the chemopreventive action of dietary curcumin on azoxymethane-induced colon carcinogenesis and the modulating effect of curcumin on the colonic mucosal and tumor phospholipase A2, phospholipase C gamma 1, lipoxygenase, and cyclooxygenase activities in male F344 rats. The results indicate that the administration of curcumin significantly inhibited incidence of colon adenocarcinomas (p<0.004) and the multiplicity of invasive, non-invasive, and total adenocarcinomas. Curcumin also significantly suppressed the colon tumor volume by more than 57% compared to the control diet. Although the precise mechanism by which curcumin inhibits colon tumorigenesis remains to be elucidated, it is likely that the chemopreventive action, at least in part, may be related to the modulation of arachidonic acid metabolism.

    References

    1. Garcea G, et al. Consumption of the putative chemopreventive agent curcumin by cancer patients: assessment of curcumin levels in the colorectum and their pharmacodynamic consequences. Cancer Epidemiol Biomarkers Prev. 2005 Jan;14(1):120-5.
    2. Ravindranath V, Chandrasekhara N. Absorption and tissue distribution of curcumin in rats. Toxicology 1980;16:259-65.
    3. Kawamori T, et al. Chemopreventive effect of curcumin, a naturally occurring anti-inflammatory agent, during the promotion/progression stages of colon cancer. Cancer Res 1999;59:597-601.
    4. Mehta K, et al. Antiproliferative effect of curcumin (diferuloylmethane) against human breast tumor cell lines. Anticancer Drugs 1997;8:470-81.
    5. Rao CV, et al. Chemoprevention of colon carcinogenesis by dietary curcumin, a naturally occurring plant phenolic compound. Cancer Res 1995;55:259-66.
    6. Siwak D, et al Curcumin-induced antiproliferative and proapoptotic effects in melanoma cells are associated with suppression of 1kB kinase and nuclear factor kB activity and are independent of the B-Raf/Mitogen activated/extracellular signal-regulated protein kinase pathway and the Akt pathway. Cancer 2005;104(4):879-90.
    7. Uddin S, et al. Curcumin suppresses growth and induces apoptosis in primary effusion lymphoma. Oncogene 2005:1-9.
    8. Venkatesan N. Curcumin prevents adriamycin nephrotoxicity in rats. Br J Pharmacol 2000;129:231-4.
    9. Bundy R, et al. Turmeric extract may improve irritable bowel syndrome symptomology in otherwise healthy adults: a pilot study. J Altern Complement Med. 2004 Dec;10(6):1015-8.
    10. Hanai H, Iida T, Takeuchi K, et al. Curcumin maintenance therapy for ulcerative colitis: randomized, multicenter, double-blind, placebo-controlled trial. Clin Gastroenterol Hepatol. 2006 Dec;4(12):1502-6.
    11. Ng TP, Chiam PC, Lee T, et al. Curry consumption and cognitive function in the elderly. Am J Epidemiol 2006; 164(9):898-906.
    12. Baum L, Lam CW, Cheung SK, et al. Six-month randomized, placebo-controlled, double-blind, pilot clinical trial of curcumin in patients with Alzheimer disease. J Clin Psychopharmacol. 2008 Feb;28(1):110-3.
    13. Tang M, Larson-Meyer DE, Liebman M. Effect of cinnamon and turmeric on urinary oxalate excretion, plasma lipids, and plasma glucose in healthy subjects.Am J Clin Nutr 2008 May;87(5):1262-7.
    14. Watson JL, Hill R, Lee PW, et al. Curcumin induces apoptosis in HCT-116 human colon cancer cells in a p21-independent manner. Exp Mol Pathol 2008 Jun;84(3):230-3.
    15. Liao YF, Hung HC, Hour TC, et al. Curcumin induces apoptosis through an ornithine decarboxylase-dependent pathway in human promyelocytic leukemia HL-60 cells. Life Sci 2008 Feb 13;82(7-8):367-75.
    16. Somasundaram S, et al. Dietary curcumin inhibits chemotherapy-induced apoptosis in models of human breast cancer. Cancer Res 2002;62:3868-75.
    17. Kunnynajjara AB, Guha S, Krishnan S, et al. Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation, angiogenesis, and inhibition of nuclear factor-kappaB-regulated gene products. Cancer Res. 2007 Apr 15;67(8):3853-61.
    18. Juan H, Terhaag B, Cong Z, et al. Unexpected effect of concomitantly administered curcumin on the pharmacokinetics of talinolol in healthy Chinese volunteers. Eur J clin Pharmacol 2007 Jul;63(7):663-8.
    19. Leung AY, et al. Encyclopedia of Common Natural Ingredients Used in Food, Drugs and Cosmetics, 2nd ed. New York: Wiley; 1996.
    20. Asai A, Miyazawa T. Occurrence of orally administered curcuminoid as glucuronide and glucuronide/sulfate conjugates in rat plasma. Life Sci 2000;67:2785-93.
    21. Kunnynajjara AB, Diagaradjane P, Guha S, et al. Curcumin sensitizes human colorectal cancer xenografts in nude mice to gamma-radiation by targeting nuclear factor-kappaB-regulated gene products. Clin Cancer Res. 2008 Apr 1;14(7):2128-36.
    22. Blumenthal, et al. Herbal Medicine, Expanded Commission E Monographs. Austin: American Botanical Council; 2000.
    23. Appiah-Opong R, Commandeur JN, van Vugt-Lussenburg B, Vermeulen NP. Inhibition of human recombinant cytochrome P450s by curcumin and curcumin decomposition products. Toxicology. 2007 Jun 3;235(1-2):83-91.
    24. McGuffin M, et al. American Herbal Products Association’s Botanical Safety Handbook. Florida: CRC Press; 1997.
    25. Brinker F. Herbal Contraindications and Drug Interactions, 2nd ed. Sandy (OR): Eclectic Medical Publications; 1998.
    26. Baum L, Cheung SK, Mok VC, et al. Curcumin effects on blood lipid profile in a 6-month human study. Pharmacol Res 2007 Dec;56(6):509-14.
    27. James J. Curcumin: clinical trial finds no antiviral effect. AIDS Treat News 1996;242:1.
    28. Li JK, et al. Mechanisms of cancer chemoprevention by curcumin. Proc Natl Sci Counc Repub China B 2001;25:59-66.
    29. Dhillon N, Aggarwal BB, Newman RA, et al. Phase II trial of curcumin in patients with advanced pancreatic cancer. Clin Cancer Res. 2008 Jul 15;14(14):4491-9.
    30. Bartik L, Whitfield GK, Kaczmarska M, et al. Curcumin: a novel nutritionally derived ligand of the vitamin D receptor with implications for colon cancer chemoprevention. J Nutr Biochem. 2010 Feb 11. [Epub ahead of print]
    31. Pavithra BH, Prakash N, Jayakumar K. Modification of pharmacokinetics of norfloxacin following oral administration of curcumin in rabbits. J Vet Sci. 2009 Dec;10(4):293-7.
    32. Zhang W, Lim LY. Effects of spice constituents on P-glycoprotein-mediated transport and CYP3A4-mediated metabolism in vitro. Drug Metab Dispos. 2008;36:1283-1290.
    33. Zhang W, Tan TM, Lim LY. Impact of curcumin-induced changes in P-glycoprotein and CYP3A expression on the pharmacokinetics of peroral celiprolol and midazolam in rats. Drug Metab Dispos. 2007;35:110-115.
    34. Kuptniratsaikul V, Thanakhumtorn S, Chinswangwatanakul P, et al. Efficacy and safety of Curcuma domestica extracts in patients with knee osteoarthritis. J Altern Complement Med. 2009 Aug;15(8):891-7.
    35. Chang KW, Hung PS, Lin IY, et al. Curcumin upregulates insulin-like growth factor binding protein-5 (IGFBP-5) and C/EBPalpha during oral cancer suppression. Int J Cancer. 2010 Feb 2.
    36. Bayet-Robert M, Kwiatkowski F, Leheurteur M, et al. Phase I dose escalation trial of docetaxel plus curcumin in patients with advanced and metastatic breast cancer. Cancer Biol Ther. 2010 Jan;9(1):8-14.
    37. Lee JI, Cho BK, Ock SM, Park HJ. Pigmented contact cheilitis: from green tea? Contact Dermatitis. 2010 Jan;62(1):60-1.
    38. Chen Y, Liu WH, Chen BL, et al. Plant polyphenol curcumin significantly affects CYP1A2 and CYP2A6 activity in healthy, male Chinese volunteers. Ann Pharmacother. 2010 Jun;44(6):1038-45.
    39. Hata M, Sasaki E, Ota M, et al. Allergic contact dermatitis from curcumin (turmeric). Contact Dermatitis. 1997 Feb;36(2):107-8.
    40. Lamb SR, Wilkinson SM. Contact allergy to tetrahydrocurcumin. Contact Dermatitis. 2003 Apr;48(4):227.
    41. Liddle M, Hull C, Liu C, Powell D. Contact urticaria from curcumin. Dermatitis. 2006 Dec;17(4):196-7.
    42. Cemil B, Topuz K, Demircan MN, et al. Curcumin improves early functional results after experimental spinal cord injury. Acta Neurochir (Wien). 2010 Jun 10. [Epub ahead of print]
    43. Bachmeier BE, Mirisola V, Romeo F,  et al. Reference profile correlation reveals estrogen-like trancriptional activity of Curcumin. Cell Physiol Biochem. 2010;26(3):471-82.

    Quercetin Aglycone Is Bioavailable in Murine Pancreas and Pancreatic Xenografts

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    Posted 09 Jun 2011 — by James Street
    Category Gemcitabine, Pancreatic, quercetin
    Lifeng Zhang†, Eliane Angst‡, Jenny L. Park‡, Aune Moro‡, David W. Dawson§, Howard A. Reber‡, Guido Eibl‡, O. Joe Hines‡, Vay-Liang W. Go† and Qing-Yi Lu*†
    † Departments of Medicine
    ‡ Surgery
    § Pathology and Laboratory Medicine
    David Geffen School of Medicine, University of California, Los Angeles, California 90095
    J. Agric. Food Chem., 2010, 58 (12), pp 7252–7257
    DOI: 10.1021/jf101192k
    Publication Date (Web): May 25, 2010
    Copyright © 2010 American Chemical Society
    *Address correspondence to this author at the Center for Human Nutrition, Department of Medicine, University of California, Los Angeles, 900 Veteran Ave., 14-165, Los Angeles, CA 90095 [e-mail qlu@mednet.ucla.edu; fax (310) 206-5264].

    Quercetin is a potential chemopreventive and chemotherapeutic agent for pancreatic and other cancers. This study examined the distribution of quercetin in plasma, lung, liver, pancreas, and pancreatic cancer xenografts in a murine in vivo model and the uptake of quercetin in pancreatic cancer MiaPaCa-2 cells in a cellular in vitro model. Mice were randomly allocated to control or 0.2 and 1% quercetin diet groups utilizing the AIN93G-based diet (n = 12 per group) for 6 weeks. In addition, 6 mice from each group were injected weekly with the chemotherapeutic drug gemcitabine (120 mg/kg mouse, ip). MiaPaCa cells were collected from culture medium after cells were exposed to 30 μM quercetin for 0.5, 1, 2, 4, 8, and 24 h. Levels of quercetin and 3-O′-methylquercetin in mouse tissues and MiaPaCa-2 cells were measured by high-pressure liquid chromatography following enzymatic hydrolysis and then extraction. The study showed that quercetin is accumulated in pancreatic cancer cells and is absorbed in the circulating system, tumors, and tissues of pancreas, liver, and lung in vivo. A higher proportion of total quercetin found in tumors and pancreas is aglycones. Gemcitabine cotreatment with quercetin reduced absorption of quercetin in the mouse circulatory system and liver. Results from the study provide important information on the interpretation of the chemotherapeutic efficacy of quercetin.

    Keywords (keywords):

    Quercetin; bioavailability; pancreas; pancreatic cancer; in vivo; HPLC

    A phase I clinical, plasma, and cellular pharmacology study of gemcitabine

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    Posted 08 Jun 2011 — by James Street
    Category Gemcitabine

    Journal of Clinical Oncology, Vol 9, 491-498, Copyright © 1991 by American Society of Clinical Oncology

     

    ARTICLES

    JL Abbruzzese, R Grunewald, EA Weeks, D Gravel, T Adams, B Nowak, S Mineishi, P Tarassoff, W Satterlee and MN Raber
    Department of Medical Oncology, University of Texas MD Anderson Cancer Center, Houston 77030.

    A novel deoxycytidine analog, gemcitabine (2′,2′-difluorodeoxycytidine [dFdC]), has been studied in a phase I clinical and pharmacology trial. Doses ranging from 10 to 1,000 mg/m2 were administered over 30 minutes weekly times 3 weeks every 4 weeks. The maximum-tolerated dose (MTD) was 790 mg/m2. The dose-limiting toxicity was myelosuppression, with thrombocytopenia and anemia quantitatively more important than granulocytopenia. Nonhematologic toxicity was minimal. Two responses in patients with adenocarcinomas of the colon and lung were documented. The maximum dFdC plasma concentration, reached after 15 minutes of infusion, was proportional to the total dose administered. Elimination, due mainly to deamination, was rapid (terminal half-life [t1/2], 8.0 minutes) and dose independent. (NOTE: Terminal plasma half-life is the time required to divide the plasma concentration by two after reaching pseudo-equilibrium, and not the time required to eliminate half the administered dose. When the process of absorption is not a limiting factor, half-life is a hybrid parameter controlled by plasma clearance and extent of distribution. In contrast, when the process of absorption is a limiting factor, the terminal half-life reflects rate and extent of absorption and not the elimination process (flip-flop pharmacokinetics). The terminal half-life is especially relevant to multiple dosing regimens, because it controls the degree of drug accumulation, concentration fluctuations and the time taken to reach equilibrium.) Gemcitabine as a half life of:

    Short infusions 32-94 minutes
    for long infusions 245-638 minutes

    The deamination product 2′,2′- difluorodeoxyuridine (dFdU) was eliminated with biphasic kinetics characterized by a long terminal phase (t1/2, 14 hours); it was the sole metabolite detected in urine. The concentration of dFdC 5′- triphosphate in circulating mononuclear cells increased in proportion to the dFdC dose at infusions between 35 and 250 mg/m2. No further increment in dFdC 5′-triphosphate (dFdCTP) was observed at higher doses, which resulted in plasma dFdC concentrations greater than 20 mumol/L (350 to 1,000 mg/m2), suggesting saturation of dFdC 5′- phosphate accumulation. The recommended dose for phase II clinical trials in solid tumors is 790 mg/m2/wk.

    Expression of human HSP70 during the synthetic phase of the cell cycle

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    Posted 08 Jun 2011 — by James Street
    Category Gemcitabine, HSP70 gene, quercetin

    Abstract

    Expression of the major heat shock and stress-induced protein, HSP70, is under complex regulatory control in human cells. In addition to being induced by physiological stress such as heat shock or transition metals (SUCH AS A TINTANIUM IMPLANT,) the HSP70 gene is induced by serum stimulation and immortalizing products of the adenovirus E1A 13S and polyoma large tumor antigen genes. Here we show that expression of the human HSP70 gene is tightly regulated during the cell cycle. Using selective mitotic detachment, a noninductive method to obtain synchronous populations of HeLa cells, we show that levels of HSP70 mRNA rapidly increase 10- to 15-fold upon entry into S phase and decline by late S and G2. A transient increase in HSP70 synthesis is detected during early S phase. The subcellular localization of HSP70 varies throughout the cell cycle; the protein is diffusely distributed in the nucleus and cytoplasm in G1, localized in the nucleus in S, and again diffusely distributed in G2 cells. We suggest that the temporal pattern of HSP70 expression during S phase, the nuclear localization, and activation by trans-acting immortalizing proteins indicate a role for HSP70 in the nucleus of replicating cells.

    Drug resistance against gemcitabine and topotecan mediated by constitutive hsp7O overexpression in vitro: implication of quercetin as sensitiser in chemotherapy

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    Posted 08 Jun 2011 — by James Street
    Category Drug Interactions, Gemcitabine, Inflamation, metastases, quercetin
    Br J Cancer. 1996 July; 74(2): 172–177.
    PMCID: PMC2074570
    Drug resistance against gemcitabine and topotecan mediated by constitutive hsp70 overexpression in vitro: implication of quercetin as sensitiser in chemotherapy.
    G. Sliutz, J. Karlseder, C. Tempfer, L. Orel, G. Holzer, and M. M. Simon
    Department of Gynaecology and Obstetrics, University of Vienna, Medical School, Austria.
    Small right arrow pointing to: This article has been cited by other articles in PMC.
    Abstract
    Heat shock proteins have been reported to confer resistance to certain antineoplastic drugs. We investigated the impact of hsp70 overexpression on the efficacy of two new anti-cancer drugs, topotecan and gemcitabine. We used the fibrosarcoma WEHI-S cells stably transfected to overexpress the hsp70 cDNA from the constitutive SV40 promoter and appropriate control cells. After topotecan and gemcitabine treatment hsp70-overexpressing cells showed a marked elevation in cell survival, suggesting that hsp70 overexpression was sufficient to confer resistance to the drugs. In addition, hsp70-overexpressing cells were capable of starting cell proliferation after treatment with drug dosages that were lethal to control cells. Our results demonstrate that hsp70 overexpression represents a possible cause of drug resistance. In order to transfer these data to tumour cells constitutively expressing stress hsp70 due to the constitutive activity of the original hsp70 promoter we sought to supress the heat shock response pathway by the natural flavonoid quercetin, known to inactivate the heat shock transcription factor (HSF). Using a suitable cell line, we demonstrated the sensitising activity of quercetin. We found that antineoplastic drug concentrations exerting cytotoxic activity were markedly lower when cells were pretreated with quercetin. Concomitantly, hsp70 expression was strongly down-regulated under quercetin treatment. Our data indicate that quercetin may be useful as a sensitiser in chemotherapeutically treated patients suffering from hsp70-overexpressing tumours.
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