van Kesteren Ch, de Vooght M M M, López-Lázaro L, Mathôt R A A, Schellens J H M, Jimeno J M, Beijnen J H
Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, The Netherlands.
Anticancer Drugs. 2003 Aug;14(7):487-502. doi: 10.1097/00001813-200308000-00001.
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.
优替德隆（曲贝替定，ET - 743）是一种源自海洋生物加勒比海被囊动物海鞘的新型抗肿瘤药物。临床前研究表明，其在低浓度下对多种肿瘤具有活性。ET - 743发挥抗肿瘤活性的机制尚未完全阐明。已证实它能与DNA小沟结合，使DNA向大沟弯曲。此外，ET - 743还会干扰DNA结合蛋白和转录因子。已启动了四项不同治疗方案的I期剂量探索研究。剂量限制性毒性为血液学毒性，包括中性粒细胞减少和血小板减少。此外，还观察到明显的肝毒性，尤其是转氨酶水平升高。I期和II期试验在多种肿瘤类型中研究了其抗肿瘤活性，包括软组织肉瘤、黑色素瘤和乳腺癌。目前正在对晚期软组织肉瘤广泛研究ET - 743。本综述描述了ET - 743的研发情况，重点介绍了其化学性质、作用方式、代谢以及临床前和临床研究。
