title: Yondelis (trabectedin, ET-743): the development of an anticancer agent of marine origin.
abstract: Yondelis (trabectedin, ET-743) is a novel antitumor agent derived from a marine source, the Caribbean tunicate Ecteinascidia turbinata. Preclinical studies demonstrated activity at low concentrations against a variety of tumors. The mechanism by which ET-743 exerts its antitumor activity has not been completely elucidated yet. Binding to the minor groove of DNA which causes a bend towards the major groove has been demonstrated. Furthermore, ET-743 interferes with DNA binding proteins and transcription factors. Clinical studies have been initiated as phase I dose-finding studies at four different treatment regimens. Dose-limiting toxicities were hematological, including neutropenia and thrombocytopenia. Furthermore, significant liver toxicity was observed, especially as a rise in transaminase levels. Antitumor activity in phase I and phase II trials was studied in multiple tumor types, including soft tissue sarcomas, melanomas and breast cancer. ET-743 is currently being extensively investigated in advanced soft tissue sarcomas. The present review describes the development of ET-743, highlighting chemical properties, mode of action, metabolism and preclinical and clinical studies.
authors.affiliation: Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, The Netherlands.
authors.forename: Ch
authors.initials: Ch
authors.lastname: van Kesteren
authors.forename: M M M
authors.initials: MM
authors.lastname: de Vooght
authors.forename: L
authors.initials: L
authors.lastname: López-Lázaro
authors.forename: R A A
authors.initials: RA
authors.lastname: Mathôt
authors.forename: J H M
authors.initials: JH
authors.lastname: Schellens
authors.forename: J M
authors.initials: JM
authors.lastname: Jimeno
authors.forename: J H
authors.initials: JH
authors.lastname: Beijnen
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D002986:Clinical Trials as Topic; D004149:Dioxoles / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007546:Isoquinolines / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy*; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004149:Dioxoles; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin