Archive for the ‘Trabectedin’ Category

Trabectedin, From Wikipedia, the free encyclopedia

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Posted 16 Mar 2012 — by James Street
Category ecteinascidin (ET-743), Osteosarcoma, Sarcoma, Trabectedin, Yondelis

Trabectedin (also known as ecteinascidin 743 or ET-743) is an anti-tumor drug. It is sold by Zeltia and Johnson and Johnson under the brand name Yondelis. It is approved for use in Europe, Russia and South Korea for the treatment of advanced soft tissue sarcoma. It is also undergoing clinical trials for the treatment of breast, prostate, and paediatric sarcomas. The European Commission and the U.S. Food and Drug Administration (FDA) have granted orphan drug status to trabectedin for soft tissue sarcomas and ovarian cancer.

Contents

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[edit] Discovery and development

During the 1950s and 1960s, the National Cancer Institute carried out a wide ranging program of screening plant and marine organism material. As part of that program extract from the sea squirt Ecteinascidia turbinata was found to have anticancer activity in 1969.[1] Separation and characterisation of the active molecules had to wait many years for the development of sufficiently sensitive techniques, and the structure of one of them, Ecteinascidin 743, was determined by KL Rinehart at the University of Illinois in 1984.[2] Rinehart had collected his sea squirts by scuba diving in the reefs of the West Indies.[3] Recently, the biosynthetic pathway responsible for producing the drug, as well as the bacterial symbiont of the tunicate responsible for production have been reported.[4]
The Spanish company PharmaMar licensed the compound from the University of Illinois before 1994

[citation needed]

and attempted to farm the sea squirt with limited success.

[3]

Yields from the sea squirt are extremely low – it takes 1 tonne of animals to isolate 1 gram of trabectedin – and about 5 grams were believed to be needed for a clinical trial

[5]

so Rinehart asked the Harvard chemist E. J. Corey to search for a synthetic method of preparation. His group developed such a method and published it in 1996.

[6]

This was later followed by a simpler and more tractable method which was patented by Harvard and subsequently licensed to PharmaMar.

[3]

The current supply is based on a semisynthetic process developed by PharmaMar starting from Safracin B, an antibiotic obtained by fermentation of the bacterium Pseudomonas fluorescens.

[7]

PharmaMar have entered into an agreement with Johnson and Johnson to market the compound outside Europe.[citation needed]

Trabectedin was first dosed in humans in 1996.[citation needed] In 2007, the EMEA gave authorisation for the marketing of trabectedin, under the trade name Yondelis, for the treatment of patients with advanced soft tissue sarcoma, after failure of anthracyclines and ifosfamide, or who are unsuited to receive these agents. The agency’s evaluating committee, the CHMP observed that trabectedin had not been evaluated in an adequately designed and analyzed randomized trial against current best care, and that the clinical efficacy data was mainly based on patients with liposarcoma and leiomyosarcoma. However the pivotal study did show a significant difference between two different trabectedin treatment regimens, and due to the rarity of the disease the CHMP considered that marketing authorisation could be granted under exceptional circumstances.[8] As part of the approval PharmaMar agreed to conduct a further trial to identify whether any specific chromosomal translocations could be used to predict responsiveness to trabectedin.[9] Trabectedin is also approved in South Korea[10] and Russia.

In 2008 the submission was announced of a registration dossier to the European Medicines Agency (EMEA) and the FDA for Yondelis when administered in combination with pegylated liposomal doxorubicin (Doxil, Caelyx) for the treatment of women with relapsed ovarian cancer. In 2011, Johnson&Johnson voluntarily withdrew the submission in the United States following a request by the FDA for an additional Phase III study to be done in support of the submission.[11]

Trabectedin is also in phase II trials for prostate, breast and paediatric cancers.[12]

[edit] Structure

Trabectedin is composed of 3 tetrahydroisoquinoline moieties, 8 rings including one 10-membered heteocyclic ring containing a cysteine residue, and 7 chiral centers.

[edit] Synthesis

The biosynthesis of trabectedin is believed to involve the dimerization of two tyrosine residues to form the pentacyclic core of the molecule. The total synthesis by E.J. Corey used this proposed biosynthesis to guide their synthetic strategy. The synthesis uses such reactions as the Mannich reaction, Pictet-Spengler reaction, the Curtius rearrangement, and chiral rhodium-based diphosphine-catalyzed enantioselective hydrogenation. A separate synthetic process also involved the Ugi reaction to assist in the formation of the pentacyclic core. This reaction was unprecedented for using such a one pot multi-component reaction in the synthesis of such a complex molecule.

[edit] Mechanism of action

The biological mechanism of action is believed to involve the production of superoxide near the DNA strand, resulting in DNA backbone cleavage and cell apoptosis. The actual mechanism is not yet known, but is believed to proceed from reduction of molecular oxygen into superoxide via an unusual auto-redox reaction on a hydroxyquinone moiety of the compound following. There is also some speculation the compound becomes ‘activated’ into its reactive oxazolidine form.

 

Editor’s note:  This following (inserted study in green font) could not demonstrate that N-acetylcysteine interacts with Superoxide which is hypothesized to be an important part of Trabectedin’s anti-tumor action: “no reaction of N-acetylcysteine with superoxide (O2-) could be detected within the limits of our assay procedures.”
The antioxidant action of N-acetylcysteine: its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid.
(PMID:2546864)
Department of Biochemistry, University of London King’s College Strand Campus, U.K.
Type:  Journal Article, Research Support, Non-U.S. Gov’t
DOI: 10.1016/0891-5849(89)90066-X
Aruoma OI, Halliwell B, Hoey BM, Butler J
N-acetylcysteine has been widely used as an antioxidant in vivo and in vitro. Its reaction with four oxidant species has therefore been examined. N-acetylcysteine is a powerful scavenger of hypochlorous acid (H–OCl); low concentrations are able to protect alpha 1-antiproteinase against inactivation by HOCl. N-acetylcysteine also reacts with hydroxyl radical with a rate constant of 1.36 X 10(10) M-1s-1, as determined by pulse radiolysis. It also reacts slowly with H2O2, but no reaction of N-acetylcysteine with superoxide (O2-) could be detected within the limits of our assay procedures.

 

 

[edit] References

  1. ^ Lichter et al.. Worthen LW. ed. Food-drugs from the sea. Proc: Aug 20–23, 1972.. 173. Marine Tech Soc. pp. 117–127.
  2. ^ Rinehart KL (January 2000). “Antitumor compounds from tunicates”. Med Res Rev 20 (1): 1–27. doi:10.1002/(SICI)1098-1128(200001)20:1<1::AID-MED1>3.0.CO;2-A. PMID 10608919.
  3. ^ a b c “Potent cancer drugs made — Sea squirts provide recipe”.
  4. ^ Rath CM et al (November 2011). “Meta-omic characterization of the marine invertebrate microbial consortium that produces the chemotherapeutic natural product ET-743″. ACS Chem Bio 6 (11): 1244–56. PMID 21875091.
  5. ^ “New Scientist”.
  6. ^ E. J. Corey, David Y. Gin, and Robert S. Kania (1996). “Enantioselective Total Synthesis of Ecteinascidin 743″. J. Am. Chem. Soc. 118 (38): 9202–9203. doi:10.1021/ja962480t.
  7. ^ C. Cuevas et al. (2000). “Synthesis of ecteinascidin ET-743 and phthalascidin PT-650 from cyanosafracin”. B. Org. Lett. 2: 2545–2548.
  8. ^ “CHMP evaluation”.
  9. ^ “PharmaMar website”.
  10. ^ S.Korea approves Zeltia cancer drug Yondelis, Reuters.com, May 8, 2008
  11. ^ Grogan, Kevin (3 May 2011). “J&J pulls submission for Zeltia’s Yondelis”. PharmaTimes Magazine (London, England): Online PharmaTimes. Archived from the original on 7 May 2011. Retrieved 7 May 2011.
  12. ^ “PharmaMar website”.

[show]

Phase II study of ecteinascidin 743 in heavily pretreated patients with recurrent osteosarcoma.

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Posted 15 Mar 2012 — by James Street
Category Metastases, Osteosarcoma, Osteosarcoma Outcomes, Relapse, Trabectedin, Yondelis
Cancer. 2003 Aug 15;98(4):832-40.

Source

Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.

Abstract

BACKGROUND:

Recurrent osteosarcoma is a drug-resistant disease with a dismal prognosis. The objective of this Phase II study was to evaluate the activity of ecteinascidin 743 (ET-743) as a salvage therapy in these patients.

METHODS:

Patients with recurrent osteosarcoma who had received standard chemotherapeutic agents were eligible. ET-743 was administered at a dose of 1500 microg/m(2) as a 24-hour infusion every 3 weeks. Pharmacokinetic studies were performed during the first cycle.

RESULTS:

Twenty-five patients were enrolled, 23 of whom were assessable for response (median age of 18 years; range, 12-67 years). The median number of previous chemotherapeutic agents was five (range, three to eight previous agents). Sixty-one cycles were administered (median number of cycles per patient was 2; range, 1-9 cycles per patient). Three patients (12%) achieved minor responses (49% 36% and 25%, respectively). Fifteen patients (60%) developed a transient elevation of hepatic transaminases (Grade 3 or 4 [according to the National Cancer Institute Common Toxicity Criteria]), which was not cumulative. Grade 3 or 4 neutropenia and thrombocytopenia were observed in 12 patients (48%) and 6 patients (24%), respectively. The mean area under the curve (AUC) in 4 patients experiencing Grade 4 toxicity (76.4 +/- 29.3 ng x hr/mL) was significantly greater (P = 0.034) than that in those for whom the most severe toxicity was Grade 3 (39.5 +/- 17.2 ng x hr/mL [n = 12]) or Grade 1-2 (52.6 +/- 15.6 ng x hr/mL [n = 5]). There were no other significant correlations found between pharmacokinetic variables and patient characteristics, toxicity, or therapeutic response.

CONCLUSIONS:

ET-743 was found to be well tolerated in heavily pretreated osteosarcoma patients but had limited antitumor activity as a single agent. The combination of ET-743 with cisplatin or doxorubicin should be considered.

Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11563

Lessons from the Past and Charting the Future of Marine Natural Products Drug Discovery and Chemical Biology

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Posted 15 Mar 2012 — by James Street
Category Cancer Journals, Educational, Trabectedin, Understanding Cancer, Yondelis
Chemistry & Biology

Volume 19, Issue 1, 27 January 2012, Pages 85–98

Cover image
Review

  • William H. Gerwick1, Corresponding author contact information, E-mail the corresponding author,
  • Bradley S. Moore1, Corresponding author contact information, E-mail the corresponding author
  • 1 Scripps Institution of Oceanography and Skaggs School of Pharmacy and Pharmaceutical Science, University of California San Diego, La Jolla, CA 92037, USA
  • Available online 26 January 2012.

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Marine life forms are an important source of structurally diverse and biologically active secondary metabolites, several of which have inspired the development of new classes of therapeutic agents. These success stories have had to overcome difficulties inherent to natural products-derived drugs, such as adequate sourcing of the agent and issues related to structural complexity. Nevertheless, several marine-derived agents are now approved, most as “first-in-class” drugs, with five of seven appearing in the past few years. Additionally, there is a rich pipeline of clinical and preclinical marine compounds to suggest their continued application in human medicine. Understanding of how these agents are biosynthetically assembled has accelerated in recent years, especially through interdisciplinary approaches, and innovative manipulations and re-engineering of some of these gene clusters are yielding novel agents of enhanced pharmaceutical properties compared with the natural product.

Figures and tables from this article:

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Figure 1. Examples of Marine Natural Products with Characterized Biosynthetic Pathways(A) Laboratory cultured and (B) environmental uncultured marine microbes whose biosynthetic pathways have been established by a variety of omic approaches (includes ecteinascidin-743 shown in Figure 4).

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Full-size image (26K)
Figure 2. Pie Charts Illustrating the Collected Sources and Predicted Biosynthetic Sources of Marine Derived or Inspired Drugs and Clinical Trial Agents(A) Pie chart illustrating the original collected sources of marine natural product derived or inspired agents currently as approved drugs or in clinical trials (20 total).(B) Pie chart of the marine-derived drugs and clinical trial agents divided by their subsequently shown or predicted source organisms (20 total). Cyanobacteria are differentiated from other bacteria in this chart because of their distinctive and characteristic physiological and metabolic capabilities.

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Figure 3. Pie Chart Illustrating the Collected Sources of Marine Natural Products Used as Research BiochemicalsProducts that are available commercially for their useful pharmacological properties in biomedical research (121 total).

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Figure 4. Chemical Structures of the Approved Drugs Deriving from or Inspired by a Marine Natural Product and Other Marine Metabolites Discussed in the TextOne-letter amino acid codes are used for depicting the structure of ziconotide.

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Full-size image (30K)
Figure 5. Assembly Line Biosynthesis of Salinosporamide and Library Development of Structure Analogs via Mutasynthesis and Other Genetic Engineering ApproachesDomain abbreviations for the SalA and SalB multifunctional proteins are as follows: ACP, acyl carrier protein; KS, ketosynthase; AT, acyltransferase; C, condensation; A, adenylation; PCP, peptidyl carrier protein.

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Full-size image (80K)
Figure 6. Parallel Strategy Employed by Grindberg et al. (2011) to Rapidly Access the Biosynthetic Gene Cluster for Apratoxin A, a Promising Anticancer Lead Compound from the Marine Cyanobacterium Moorea bouilloniiOn the top arm, single cells are obtained by microdissection from nonaxenic cultures of cyanobacteria, and DNA is extracted and amplified by Multiple Displacement Amplification (MDA) for partial genome sequencing. The sequences of recognizable gene motifs associated with natural product pathways are then used to construct PCR probes to screen a fosmid library that is produced in the normal fashion (lower arm). Fosmids probing positively by this process can be further characterized for desired gene motifs, and then sequenced. The melding of these approaches can accelerate the process of biosynthetic gene cluster discovery and description, such as is illustrated here for apratoxin A, especially in cases of nonaxenic cultures or environmental samples.

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Table 1. Six Marine Natural Products and Fourteen Marine Natural Products Inspired Compounds that Are FDA-Approved Agents or in Clinical Trial with Details of Their Collected Source, Predicted Biosynthetic Source, Molecular Target, and Disease Treated

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Additional perspectives on approved FDA drugs and clinical trial agents that were derived or inspired by marine natural products can be found in Mayer et al. (2010) and Newman and Cragg (2010).

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Development of Yondelis® (trabectedin, ET-743). A semisynthetic process solves the supply problem

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Posted 15 Mar 2012 — by James Street
Category Trabectedin, Yondelis

Carmen Cuevas and Andrés Francesch

Nat. Prod. Rep., 2009, 26, 322-337
DOI: 10.1039/B808331M
Received 30 Sep 2008, First published on the web 07 Jan 2009

ET-743 (Yondelis): A Novel Agent with Activity in Soft Tissue Sarcomas

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Posted 15 Mar 2012 — by James Street
Category Combination Treatments, Drug Interactions, Drug Resistance, Osteosarcoma, Sarcoma, Trabectedin, Yondelis
  1. Jérôme Fayettea,b,
  2. Isabelle Ray Coquarda,
  3. Laurent Albertia,
  4. Dominique Ranchèrea,
  5. Helen Boylea and
  6. Jean-Yves Blaya,b

+ Author Affiliations


  1. aHôpital Edouard Herriot, Medical Oncology Department, Lyon, France;

  2. bINSERM U590, Centre Léon Bérard, Lyon, France
  1. Jean-Yves Blay, M.D., Ph.D., Hôpital Edouard Herriot, Service d’oncologie médicale, Pavillon E, 5 place d’Arsonval, 69003 LYON, France. Telephone: 33-4-72-11-73-98; Fax: 33-4-72-11-73-28; e-mail: blay@lyon.fnclcc.fr
  • Received September 19, 2005.
  • Accepted September 26, 2005.

Learning Objectives

After completing this course, the reader will be able to:

  1. Describe the original mechanism of action of ET-743.

  2. Explain the management of patients treated with ET-743, including what biological exams are needed because of toxicity and what is the optimal schedule of administration.

  3. Choose the best histological subtype of sarcoma for treatment with ET-743 and describe the clinical aim of treatment.

  4. Discuss putative combinations of ET-743 with other therapies.

Access and take the CME test online and receive 1 AMA PRA category 1 credit at CME.TheOncologist.com

Abstract

Ecteinascidin-743 (ET-743) is a natural product derived from the marine tunicate Ectenascidia turbinate. ET-743 binds in the minor groove of DNA, blocks transcription factors activity, and traps protein from the nucleotide excision repair system, thus blocking cells in G2-M phase. ET-743 demonstrated cytotoxic activity at very low concentrations against sarcoma cell lines in pre-clinical studies. In several phase II clinical studies in patients with advanced sarcoma failing conventional doxorubicin- and ifosfamide-based chemotherapy, ET-743 delivered by continuous intravenous 24-hour infusion at a dose of 1,500 μg/m2 every 21 days yielded 8% overall response and 30%–40% stabilization rates for a clinical benefit rate close to 40%. Interestingly, long-term stabilizations over more than 3 years have been described. In vivo, ET-743 has a specific toxicity profile, the major toxicity of this product being hepatic, through biliary duct destruction, and hematologic. ET-743 has also been evaluated in first-line treatment for these patients. Finally, due to its original mode of action and the lack of cross-resistance with other chemotherapy agents, ET-743 was tested in a preclinical model in combination with other drugs. Synergy was reported in vitro with doxorubicin and cisplatin; phase I combination studies are in progress.

Introduction

Despite an optimal loco-regional treatment, 35%–50% of patients with sarcoma will develop metastasis. Systemic chemotherapy is then the standard treatment; the active drugs are doxorubicin and ifosfamide and, to a lesser extent, dacarbazine [1, 2]. Initial response rates to doxorubicin-containing regimens are close to 10%–30%, with few long-term survivors. In second line, after failure of doxorubicin and ifosfamide, no drug had demonstrated significant antitumor activity so far. Ecteinascidin-743 (ET-743) is a tetrahydro-isoquinoline alkaloid isolated from Ectenascidia turbinata, a tunicate that grows on mangrove roots throughout the Caribbean Sea. At nanomolar concentrations, ET-743 is active against a variety of solid tumor cell lines, including sarcoma cell lines. In this review, we will describe the mechanism of action of ET-743, its toxicity, its clinical results in sarcomas, and its future development, including new associations.

Mechanism of Action

ET-743 binds in the minor groove of DNA and alkylates N2 of guanines located either in the 5′-PuGC-3′ or 5′ PyrGG-3′ sequence [3], which bends DNA toward the major groove [4]. Other alkylations are formed, but they are reversible and less stable [4]. Two of the three subunits of the drug bind to DNA while the third does not have contact with DNA and protrudes out from the minor groove, interfering with several DNA-binding factors. ET-743 strongly inhibits the binding of NF-Y [5], a factor that activates the CCAAT element present in 25% of eukaryotic promoters, including many promoters that regulate genes controlling the cell cycle. In vivo studies showed that the HSP70 promoter containing two CCAAT boxes activated by NF-Y is rapidly inhibited by ET-743 whereas other promoters lacking CCAAT boxes were not affected [6]. Importantly, the MDR1 (multidrug resistance) gene encoding for the P glycoprotein (P-gp) is also under dependence of a promoter containing CCAAT boxes [7]. This may explain why ET-743 is efficient against cells over-expressing MDR1 and why it does not select for the emergence of a P-gp phenotype in ET-743–resistant cell lines or exhibit cross-resistance with other cytotoxic agents [8]. Actually, ET-743 is a general inhibitor of cancer-activated transcription but not of “uninduced” (i.e., basal) transcription: Induction of the Sp1-regulated p21 gene by Trichostatin A (TSA), a promoter activator, was blocked by ET-743 at concentrations that had minimal effect on uninduced constitutive expression, and microarray analysis of cells treated with TSA and/or ET-743 indicated that activation of TSA-responsive promoters was blocked by ET-743 with little effect on nonresponsive promoters [9]. In addition, ET-743 at higher concentrations can alter the interaction between several DNA-binding proteins and DNA. (Two subunits of NF-Y exhibit homology with histones 2A and 2B.) ET-743 may target topoisomerase I, resulting in DNA breaks [10], although this may not be relevant in vivo because this effect is observed at high concentration and the drug remains active in cells deficient for topoisomerase I [11, 12].

ET-743 activity may also involve the DNA repair machinery. Defects in the mismatch repair pathway, usually associated with increased resistance to methylating agents and cisplatin, do not affect the cytotoxic activity of ET-743 [11]. DNA-dependent protein kinase may repair ET-743–induced damages because it is active in cells deficient in this enzyme [11]. Whereas all known DNA-interacting cytotoxic drugs are either more or equally active in nucleotide excision repair (NER)–deficient cells, ET-743 exerts decreased cytotoxic activity in NER-deficient cell lines [11, 13, 14]. Indeed, ET-743 interacts with the transcription-coupled NER machinery to induce lethal DNA strand breaks. The preferred binding sequences for ET-743 are less efficiently excised and trap DNA-NER proteins, forming cytotoxic complexes similar to a poisoned topoisomerase I- or topoisomerase II-DNA complex. In the absence of an intact NER nuclease complex, this toxic lesion does not occur, and the ET-743–DNA adducts, though not repaired by the NER pathway, are less toxic to cells [15]. Moreover, translesion synthesis and homologous recombinations lead to ET-743 resistance of NER-deficient cells [16]. p53 may activate apoptosis after ET-743–induced DNA damage because an increase of p53 is observed in cell lines expressing wild-type p53. However, p53 status does not appear to correlate to sensitivity to ET-743 [17]. Finally, the telomerase activity decreases the efficiency of ET-743, [18].

ET-743 blocks cells in G2-M phase. Indeed, cell lines exposed to ET-743 for 1 hour progress through S phase more slowly than control cells and then accumulate in the G2-M phase. The sensitivity to ET-743 of G1 synchronized cells was much higher than that of cells synchronized in S phase and even higher than that of cells synchronized in G2-M [13, 17]. Expression microarray experiments were used to identify genes involved in sensitivity or resistance to ET-743. A first study determined a set of 70 genes whose expression was modulated in drug-resistant cells [19]. Another study with a cDNA microarray containing 6,700 cancer-related genes showed upregulation of 86 genes and downregulation of 244 genes in response to ET-743 [20]. Immunochemistry revealed marked differences in the cytoskeleton architecture between ET-743–sensitive and –resistant cells, and collagen I seems to be an important protein [21].

ET-743, then, exerts its cytotoxic role through an original mode of action involving DNA repair machinery. Its potent cytotoxic activity on sarcoma cell lines prompted investigation of its activity in the clinic.

Toxicity in Clinical Trials

The most prominent toxicities observed in the different phase II studies were grade 3 or 4 transaminase increase (26%–59%, [22–26]) and neutropenia (33%–52%, [22–26]). Regarding liver toxicity, studies in rats showed a predominant biliary toxicity: Twenty-four hours after ET-743, liver degeneration and patchy focal necrosis of bile duct epithelial cells were observed and associated with mild inflammation followed by fibrosis.

Sporadic and focal zones of hepatic necrosis and hemorrhage were observed although the majority of hepatocytes appeared normal. Pathological alterations persisted up to 3 months [27]. In humans, patients with any baseline liver-function test exceeding the upper limit of the normal ranges have a significantly greater incidence of severe hepatic toxicity [28]. Levels of plasma liver enzymes (e.g., transaminases, bilirubin, alkalin phosphatases, and 5′-nucleotidase) should be checked before each course. Dexamethasone may decrease this toxicity [28]. Pretreatment, but not concomitant treatment, of rats with high dose of dexamethasone 24 hours before ET-743 improved or prevented ET-743–induced liver damages [29], probably through the induction of the cytochrome p450. Beta-naphthoflavone [30] and indole-3-carbinol [31] may protect liver as well. Granulocytic (colony-forming units granulocyte-macrophage [CFU-GM]) and megakaryocytic progenitors are sensitive to the drug [32], but the dose of ET-743 that inhibits 90% of CFU-GM only inhibited 45% survival of stem cells, resulting in the lack of long-term myelosuppression [33]. A specific toxicity for monocytes/macrophages may account for the anti-inflammatory properties of ET-743 [34].

ET-743 as Monotheraphy in Patients with Sarcoma

Different preclinical and phase I studies determined the schedule of administration: The recommended schedule for ET-743 is delivered by continuous intravenous 24-hour infusion at the dose of 1,500 μg/m2 every 3 weeks, until progression or toxicity. Table 1⇓ gives a synthetic overview of the management of ET-743 in sarcoma.

Table 1.

Summary for ecteinascidin-743 (ET-743) use

A first multicentric phase II study enrolled 54 heavily pretreated patients. Before ET-743, 48% had received one or two drugs and 52% three or more; 41% had leiomyosarcoma (eight of 22 of uterine origin). Two partial responses (PRs) were observed, for an overall response (OR) rate of 4% (95% confidence interval [CI], 0.5%–12.8%). Four minor responses and nine disease stabilizations (SDs) lasting more than 6 months were observed. Twenty-four percent of patients were free from progression at 6 months. The median survival was 12.8 months, with 30% of patients alive at 2 years. Two treatment-related deaths occurred [35].

The second study included 36 patients and reported one complete response (CR) and two PRs for a response rate of 8% (95% CI, 2%–23%), with a clinical benefit of 14%. Prolonged responses were observed (up to 20 months), and the 1-year overall survival was 53% (95% CI, 39%–73%), an unusual observation in this population of patients [22].

These results were confirmed by a large phase II study of the Soft Tissue and Bone Sarcoma Group of the European Organization for Research and Treatment of Cancer in 104 pretreated patients. Eight PRs were observed for an OR rate of 8%, and 45 SDs (longer than 6 months in 26% patients) were observed. A clinical benefit was observed for 56% of leiomyosarcoma and 61% of synovialosarcoma patients. The progression-free survival at 6 months was 29% [24]. The median duration of survival of 9.2 months was again unusually high in this cohort of heavily pretreated patients, especially considering the low response rate. The rates of objective regression and stable disease are similar in doxorubicin/ifosfamide chemosensitive and chemoresistant sarcomas. However, in this study, patients exhibiting a prolonged stable disease had an outcome similar to responding patients, supporting the relevance of the progression arrest rate (i.e., objective response + stable disease) as a prognostic parameter instead of objective response [36].

In a single institution experience, 89 patients (82 assessable) with advanced refractory sarcoma (leiomyosarcoma 36%, liposarcoma 18%, and osteosarcoma 16%) were treated with ET-743. The objective response rate was 7% (one CR, five PRs), and the clinical benefit rate at 3 and 6 months was 38% and 23%, respectively [26].

To decrease toxicity, a randomized phase II study of ET-743 given by two different dosing schedules (3-hour infusion weekly × 3 every 4 weeks versus 24-hour infusion every 3 weeks) in patients with leiomyosarcoma or liposarcoma (due to the observed better activity of ET-743 in these subtypes with respect to the other) refractory to conventional doxorubicin and ifosfamide chemotherapy was carried out. Objective responses and stable disease were observed in a subset of refractory patients with both treatment schedules, but response rate and progression-free survival were superior with 24-hour CIV (continuous infusion of vancomycin) treatment [37]. This trial has been extended, and final results are expected at the end of 2005. A comparative phase III trial of ET-743 and ifosfamide is under discussion in patients with an anthracycline-refractory uterine leiomyosarcoma.

After promising results in pretreated patients, ET-743 was tested in the first line of treatment of unresectable advanced sarcoma. Thirty-six patients (35 assessable) were treated with the standard schedule: One CR and five PRs were achieved for an OR rate of 17.1% (95% CI, 6.6%–33.6%). In addition, one patient had a minor response. The estimated 1-year progression-free and overall survival rates were 21% (95% CI, 11%–41%) and 72% (95% CI, 59%–88%), respectively [25]. ET-743 was ineffective in gastrointestinal stromal tumor [23] and in osteosarcoma [38], but responses were reported in Ewing sarcoma [39].

ET-743 in Combination with Other Drugs

Because of its original mechanism of action, ET-743 may act synergistically in combination with other cytotoxic agents. Several preclinical or phase I studies explored this possibility. Preclinical studies showed that ET-743 and cisplatin are synergic, without additive toxicity [40]. Interestingly, ET-743 could be used at lower, relatively nontoxic doses to potentiate cytotoxicity of cisplatin. A phase I study was performed to determine ET-743 and cisplatin doses in combination regimens [41]. The combination with doxorubicin may be effective for tumors displaying low sensitivity to each drug given alone [42]. For tumor cells sensitive to both agents, additive effects are observed, whereas another study showed synergy [43]. The most favorable synergy in vitro was observed using a sequence with ET-743 first, followed by doxorubicin. Based on these findings, phase I studies on the combination of both drugs were initiated. Other combinations were tested with paclitaxel (showing a limited schedule dependent synergy) and with plasminogen-related protein B (an antiangiogenic factor) in preclinical models of chondrosarcoma [44]. No synergy was observed, however, between ET-743 and radiotherapy [45].

Conclusion

ET-743 has an original mode of action, involving enzymes of the DNA repair machinery. ET-743 has a demonstrated activity as first or second treatment of advanced sarcomas, after doxorubicin, ifosfamide, and dacarbazine. Some patients achieved very prolonged long-term survival. The utility of combination regimens, as well as the activity of this agent in other tumor types, in particular ovarian carcinoma, is currently under investigation.

Disclosure of Potential Conflicts of Interest

The authors indicate no potential conflicts of interest.

References

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    Zewail-Foote M, Li VS, Kohn H et al. The inefficiency of incisions of ecteinascidin 743-DNA adducts by the UvrABC nuclease and the unique structural feature of the DNA adducts can be used to explain the repair-dependent toxicities of this antitumor agent. Chem Biol 2001;8: 1033–1049.
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Anti-inflammatory Properties of the Novel Antitumor Agent Yondelis (Trabectedin): Inhibition of Macrophage Differentiation and Cytokine Production

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Posted 15 Mar 2012 — by James Street
Category Osteosarcoma, Sarcoma, Trabectedin, Yondelis
  1. Paola Allavena1,
  2. Mauro Signorelli1,3,
  3. Marcello Chieppa1,
  4. Eugenio Erba2,
  5. Giancarlo Bianchi1,
  6. Federica Marchesi1,
  7. Chiara Omero Olimpio1,
  8. Claudia Bonardi3,
  9. Annalisa Garbi3,
  10. Andrea Lissoni3,
  11. Filippo de Braud4,
  12. José Jimeno6, and
  13. Maurizio D’Incalci2,5

+ Author Affiliations


  1. Departments of 1Immunology and Cell Biology and 2Oncology, “Mario Negri” Institute; 3Department of Obstetrics and Gynecology, University of Milano Bicocca, Hospital S. Gerardo; 4START Project, European Institute of Oncology; 5Southern Europe New Drugs Organization, Milan, Italy; and 6Pharmamar, Madrid, Spain
  1. Requests for reprints:
    Paola Allavena, Istituto Ricerche Farmacolgiche Mario Negri, Via Eritrea 62, 20152 Milano, Italy. Phone: 39-02-390141; Fax: 39-02-39014596; E-mail: allavena@marionegri.it.

Abstract

Yondelis (Trabectedin) is a novel antitumor agent of marine origin extracted from the tunicate Ecteinascidia turbinata. This original compound is active against several human tumors including sarcoma and ovarian and breast adenocarcinoma, as evidenced in phase II clinical trials in advanced multitreated patients. Yondelis is a DNA minor groove binder that blocks cell cycle and interferes with inducible gene transcription in a selective manner. In this study, we investigated the immunomodulatory properties of Yondelis on leukocytes. Human blood monocytes were highly susceptible in vitro to its cytotoxic effect and underwent apoptosis at pharmacologically relevant concentrations (5 nmol/L), whereas lymphocytes were up to 5-fold less sensitive. Macrophages differentiated in vitro with macrophage colony-stimulating factor and tumor-associated macrophages (TAM), isolated from patients with ovarian cancer, were also susceptible. At subcytotoxic concentrations, Yondelis inhibited the in vitro differentiation of monocytes to macrophages. In tumor-treated patients, drug infusion caused a selective decrease of monocyte counts and of ex vivo macrophage differentiation. The in vitro production of two proinflammatory mediators, CCL2 and IL-6, was markedly reduced by Yondelis in monocytes, macrophages, TAM, and freshly isolated ovarian tumor cells. The chemokine CCL2 is the major determinant of monocyte recruitment at tumor sites, whereas IL-6 is a growth factor for ovarian tumors. In view of the protumor activity of TAM and of the strong association between chronic inflammation and cancer progression, the inhibitory effect of Yondelis on macrophage viability, differentiation, and cytokine production is likely to contribute to the antitumor activity of this agent in inflammation-associated human tumors.

Cross-Talk between Nucleotide Excision and Homologous Recombination DNA Repair Pathways in the Mechanism of Action of Antitumor Trabectedin

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Posted 13 Mar 2012 — by James Street
Category Sarcoma, Trabectedin
  1. Ana B. Herrero1,
  2. Cristina Martín-Castellanos1,
  3. Esther Marco2,
  4. Federico Gago2, and
  5. Sergio Moreno1

+ Author Affiliations


  1. 1Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Cientificas/Universidad de Salamanca, Campus Miguel de Unamuno, Salamanca and 2Departamento de Farmacología, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain
  1. Requests for reprints:
    Sergio Moreno, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Cientificas/Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain. Phone: 34-92329-4810; Fax: 34-92329-4795; E-mail: smo@usal.es.

Abstract

Trabectedin (Yondelis) is a potent antitumor drug that has the unique characteristic of killing cells by poisoning the DNA nucleotide excision repair (NER) machinery. The basis for the NER-dependent toxicity has not yet been elucidated but it has been proposed as the major determinant for the drug’s cytotoxicity. To study the in vivo mode of action of trabectedin and to explore the role of NER in its cytotoxicity, we used the fission yeast Schizosaccharomyces pombe as a model system. Treatment of S. pombe wild-type cells with trabectedin led to cell cycle delay and activation of the DNA damage checkpoint, indicating that the drug causes DNA damage in vivo. DNA damage induced by the drug is mostly caused by the NER protein, Rad13 (the fission yeast orthologue to human XPG), and is mainly repaired by homologous recombination. By constructing different rad13 mutants, we show that the DNA damage induced by trabectedin depends on a 46–amino acid region of Rad13 that is homologous to a DNA-binding region of human nuclease FEN-1. More specifically, an arginine residue in Rad13 (Arg961), conserved in FEN1 (Arg314), was found to be crucial for the drug’s cytotoxicity. These results lead us to propose a model for the action of trabectedin in eukaryotic cells in which the formation of a Rad13/DNA-trabectedin ternary complex, stabilized by Arg961, results in cell death. (Cancer Res 2006; 66(16): 8155-62)

A Review of Trabectedin (ET-743): A Unique Mechanism of Action

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Posted 13 Mar 2012 — by James Street
Category Trabectedin
  1. Maurizio D’Incalci1 and
  2. Carlos M. Galmarini2

+ Author Affiliations


  1. Authors’ Affiliations:1Department of Oncology, Istiuto di Ricerche Farmacologiche “Mario Negri,” Milan, Italy and 2Cell Biology Department, PharmaMar SAU Colmenar Viejo, Madrid, Spain
  1. Corresponding Author:
    Maurizio D’Incalci, Istituto Mario Negri, Via La Masa, 19, 20156 Milan, Italy. Phone: 39-02-39-01-44-73; Fax: 39-02-39-01-47-34. E-mail: maurizio.dincalci@marionegri.it

Abstract

Trabectedin (ET-743) is a marine alkaloid isolated from the Caribbean tunicate Ecteinascidia turbinata, with a chemical structure characterized by three fused tetrahydroisoquinoline rings. Two of these rings (subunits A and B) provide the framework for covalent interaction with the minor groove of the DNA double helix, whereas the third ring (subunit C) protrudes from the DNA duplex, apparently allowing interactions with adjacent nuclear proteins. The compound’s chemical interactions trigger a cascade of events that interfere with several transcription factors, DNA binding proteins, and DNA repair pathways, likely to be different from other DNA-interacting agents. Trabectedin also causes modulation of the production of cytokines and chemokines by tumor and normal cells, suggesting that the antitumor activity could also be ascribed to changes in the tumor microenvironment. The promising data on the combination of trabectedin with other anticancer agents, observed in preclinical systems, have prompted several clinical studies that are currently ongoing. One of these combinations (trabectedin-pegylated liposomal doxorubicin) was recently authorized by the European Commission for the treatment of patients with relapsed platinum-sensitive ovarian cancer. Mol Cancer Ther; 9(8); 2157–63. ©2010 AACR.

  • Received March 16, 2010.
  • Revision received May 28, 2010.
  • Accepted May 28, 2010.

Steroid premedication markedly reduces liver and bone marrow toxicity of trabectedin in advanced sarcoma

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Posted 13 Mar 2012 — by James Street
Category Sarcoma, Trabectedin

Received 25 July 2005; received in revised form 9 February 2006; accepted 22 February 2006.

Trabectedin (ET-743): evaluation of its use in advanced soft-tissue sarcoma

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Posted 13 Mar 2012 — by James Street
Category Sarcoma, Trabectedin
Summary
August 2007, Vol. 3, No. 4, Pages 381-392 , DOI 10.2217/14796694.3.4.381
(doi:10.2217/14796694.3.4.381)

 

Drug Evaluation

Patrick Schöffski†, Pascal Wolter, Paul Clement, Raf Sciot, Ivo De Wever, Agnieszka Wozniak, Cristiana Stefan & Herlinde Dumez

† Author for correspondence


Trabectedin (ET-743; Yondelis®) is a novel DNA-binding agent, originally derived from the marine tunicate, Ecteinascidia turbinata, and now produced synthetically. The efficacy of trabectedin in patients with advanced soft-tissue sarcoma has been demonstrated in three Phase II studies involving 189 previously treated patients. A pooled analysis of data from these studies showed that trabectedin induced tumor control (objective responses plus disease stabilization) in approximately 50% of patients; median overall survival was 10.3 months and progression-free survival at 6 months was 19.8%, with 29.3% of patients alive at 2 years. Responses were achieved in patients who were resistant to both doxorubicin and ifosfamide. Trabectedin is generally well tolerated, with adverse events being noncumulative, reversible and manageable. Unlike other commonly used cytotoxic agents, trabectedin is not associated with cardiotoxicity or neurotoxicity and alopecia is rare. Trabectedin is an interesting new anticancer agent that offers much promise for the treatment of advanced soft-tissue sarcoma.

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