Novel tubulin-targeting agents: anticancer activity and pharmacologic profile of epothilones and related analogues

Abstract

Background: Epothilones are 16-member ring macrolides with antimicrotubule activity that share a similar mechanism of action to the taxanes but have demonstrated potent antiproliferative activity in several different multidrug-resistant and paclitaxel-resistant tumor cell lines in vitro and in vivo . Design: This review summarizes data from preclinical and phase I clinical studies of epothilone B (patupilone; EPO960) and epothilone D (KOS-862) and their second-generation (ixabepilone, BMS-310705, KOS-1584) and third-generation (ZK-EPO, ABJ-879) derivatives. Data were identified by searches of PubMed and the Proceedings of the American Society of Clinical Oncology annual meetings from 2000 to 2006. Results: Epothilones demonstrate a linear dose-dependent pharmacokinetic profile, are well tolerated, and exhibit antitumor activity in a variety of tumor types in phase I studies of patients with cancer. Although similar in chemical structure, the epothilones demonstrate a striking difference in toxicity profile in phase I studies. Diarrhea is the dose-limiting toxicity (DLT) associated with patupilone, whereas neurotoxicity and neutropenia are the DLTs most commonly encountered with other epothilones. Consistent with preclinical data, partial responses were observed with patupilone and ixabepilone in patients with breast cancer previously treated with taxanes. Conclusion: The epothilones demonstrate promising antitumor activity in a broad spectrum of taxane-sensitive and -refractory tumors at doses and schedules associated with tolerable side-effects.