Unique Features of the Mode of Action of ET-743

D’Incalci, Maurizio; Erba, Eugenio; Damia, Giovanna; Galliera, Emanuela; Carrassa, Laura; Marchini, Sergio; Mantovani, Roberto; Tognon, Gianluca; Fruscio, Robert; Jimeno, J.; Faircloth, Glynn

doi:10.1634/theoncologist.7-3-210

Cited by 43 publications

(30 citation statements)

References 22 publications

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“…In addition to the activity reported for trabectedin as a single agent, mechanistic (D'Incalci et al, 2002;Kanzaki et al, 2002) and preclinical (Takahashi et al, 2002;Meco et al, 2003) studies have noted evidence of in vitro and in vivo synergism of trabectedin in combination with anthracyclines, taxanes and platin salts in experimental models of several solid tumours, including breast cancer. Phase I combination studies have also reported feasibility and activity in resistant solid tumours when trabectedin is combined with anthracyclines (Gianni et al, 2003;Cohen et al, 2005), paclitaxel (Chu et al, 2004), platinum compounds (Sessa et al, 2004) or capecitabine (Holden et al, 2003).…”

Section: Discussionmentioning

confidence: 97%

A phase II study of Yondelis® (trabectedin, ET-743) as a 24-h continuous intravenous infusion in pretreated advanced breast cancer

et al. 2006

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Yondeliss (trabectedin, ET-743) is a novel marine-derived anticancer compound found in the ascidian Ecteinascidia turbinata. It is currently under phase II/III development in breast cancer, hormone refractory prostate cancer, sarcomas and ovarian cancer. Activity in breast cancer experimental models has been reported, and preliminary evidence of activity in this setting during the phase I programme has also been observed. The present study assessed the activity and feasibility of trabectedin in women with advanced breast cancer previously treated with conventional therapies. Patients with advanced disease previously treated with at least one but not more than two regimens that included taxanes or anthracyclines as palliative therapy were eligible. Trabectedin 1.5 mg m À2 was administered as a 24-h continuous infusion every 3 weeks. Patients were kept on therapy until disease progression, unacceptable toxicity or patient refusal. Twenty-seven patients were included between April 1999 and September 2000. Their median age was 54 years (range: 36 -67) and 63% of them had two metastatic sites. Twenty-two patients were performance status 1. All patients had previously received anthracyclines, and 23 out of 27 patients had received taxanes. Of 21 patients with measurable disease, three confirmed partial responses, one unconfirmed partial response and two minor responses (49 and 32% tumour shrinkage) were observed; six patients had stable disease. Median survival was 10 months (95% confidence interval: 4.88 -15.18). Transient and noncumulative transaminitis was observed in most of the patients. The pharmacokinetic profile of trabectedin in this patient's population is in line with the overall data available with this schedule. The policy of dose adjustments based on the intercycle peaks of bilirubin and alkaline phosphatase appears to have a positive impact in the therapeutic index of trabectedin. Trabectedin can induce response and tumour control in previously treated advanced breast cancer, with manageable toxicity, thus warranting further development as a single agent or in combination regimens.

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Section: Discussionmentioning

confidence: 97%

A phase II study of Yondelis® (trabectedin, ET-743) as a 24-h continuous intravenous infusion in pretreated advanced breast cancer

et al. 2006

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“…This rather unique mechanism can account for the unusual behavior of these mutant cells because defects in NER proteins, which are involved in the repair of DNA damage caused by many DNA-binding anticancer drugs (e.g., the nitrogen mustard mechlorethamine, cisplatin, or MMC; refs. 5, 6), typically lead to increased drug sensitivity (5,40,41) and not the reverse, as is the case for trabectedin.…”

Section: Discussionmentioning

confidence: 99%

Relevance of the Fanconi anemia pathway in the response of human cells to trabectedin

Casado

Rı́o

Marco³

et al. 2008

Molecular Cancer Therapeutics

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Trabectedin (Yondelis; ET-743) is a potent anticancer drug that binds to DNA by forming a covalent bond with a guanine in one strand and one or more hydrogen bonds with the opposite strand. Using a fluorescence-based melting assay, we show that one single trabectedin-DNA adduct increases the thermal stability of the double helix by >20°C. As deduced from the analysis of phosphorylated H2AX and Rad51 foci, we observed that clinically relevant doses of trabectedin induce the formation of DNA double-strand breaks in human cells and activate homologous recombination repair in a manner similar to that evoked by the DNA interstrand cross-linking agent mitomycin C (MMC). Because one important characteristic of this drug is its marked cytotoxicity on cells lacking a functional Fanconi anemia (FA) pathway, we compared the response of different subtypes of FA cells to MMC and trabectedin. Our data clearly show that human cells with mutations in FANCA, FANCC, FANCF, FANCG, or FANCD1 genes are highly sensitive to both MMC and trabectedin. However, in marked contrast to MMC, trabectedin does not induce any significant accumulation of FA cells in G 2 -M. The critical relevance of FA proteins in the response of human cells to trabectedin reported herein, together with observations showing the role of the FA pathway in cancer suppression, strongly suggest that screening for mutations in FA genes may facilitate the identification of tumors displaying enhanced sensitivity to this novel anticancer drug.

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“…Trabectedin (Yondelis) is a novel antitumor agent originally isolated from the Caribbean marine tunicate, Ecteinascidia turbinata, which was selected for clinical investigation due to its potent cytotoxic activity against a variety of tumor cell lines in vitro and human tumor xenografts in vivo (1). Currently, trabectedin is undergoing phase II/III clinical trials both in Europe and the U.S., with promising results for the treatment of soft tissue sarcomas, and breast and ovarian cancers (2)(3)(4).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2006

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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/DNAtrabectedin ternary complex, stabilized by Arg961, results in cell death. (Cancer Res 2006; 66(16): 8155-62)

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Unique Features of the Mode of Action of ET-743

Abstract: ABSTRACT

Cited by 43 publications

References 22 publications

A phase II study of Yondelis® (trabectedin, ET-743) as a 24-h continuous intravenous infusion in pretreated advanced breast cancer

A phase II study of Yondelis® (trabectedin, ET-743) as a 24-h continuous intravenous infusion in pretreated advanced breast cancer

Relevance of the Fanconi anemia pathway in the response of human cells to trabectedin

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

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