title: ET-743: a novel agent with activity in soft tissue sarcomas.
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 microg/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.
authors.affiliation: Hôpital Edouard Herriot, Medical Oncology Department, Lyon, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Fayette
authors.forename: Isabelle Ray
authors.initials: IR
authors.lastname: Coquard
authors.forename: Laurent
authors.initials: L
authors.lastname: Alberti
authors.forename: Dominique
authors.initials: D
authors.lastname: Ranchère
authors.forename: Helen
authors.initials: H
authors.lastname: Boyle
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Blay
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D004149:Dioxoles / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007546:Isoquinolines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D012509:Sarcoma / Q000188:drug therapy*; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin
chemical_list: D004149:Dioxoles; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin