Epothilones: A Novel Class of Non-taxane Microtubule-stabilizing Agents

Abstract

The epothilones are a novel class of non-taxane microtubule-stabilizing agents obtained from the fermentation of the cellulose degrading myxobacteria, Sorangium cellulosum. Preclinical studies have shown that the epothilones are more potent than the taxanes and active in some taxane-resistant models. Similar to paclitaxel and other taxanes, the epothilones block cells in mitosis, resulting in cell death. The chief components of the fermentation process are epothilones A and B, with epothilones C and D found in smaller amounts. Trace amounts of other epothilones have also been detected. Pre-clinical studies have shown that epothilone B is the most active form, exhibiting significantly higher antitumor activity than paclitaxel and docetaxel. Several phase I and phase II clinical trials are ongoing with epothilone B and BMS 247550, an epothilone B analog. Preliminary reports indicate these agents are active against human cancers in heavily pre-treated patients. The epothilones appear to be well tolerated, with a side effect profile that is similar to that reported with the taxanes. This article will review some basic aspects of epothilone chemistry and biology, and pre-clinical and preliminary clinical experience with epothilone B and its analog, BMS 247550.

Is Cell Death a Critical End Point for Anticancer Therapies or Is Cytostasis Sufficient?

“…For example, the National Cancer Institute drug screen identifies both cytotoxic as well as cytostatic drug concentrations for our traditional anticancer drugs and thousands of other compounds, if one defines cytostasis as a concentration that prevents cell growth altogether, the total growth inhibition concentration (11). Furthermore, it could be argued that all microtubule-targeting agents from vincristine to paclitaxel and, more recently, the epothilones are inherently cytostatic (12,13). None of these agents are intrinsically able to cause cytotoxicity.…”

CYT997: a novel orally active tubulin polymerization inhibitor with potent cytotoxic and vascular disrupting activity in vitro and in vivo

“…In recent years, there has been considerable research toward the identification of new tubulin-binding compounds that address the shortcomings of the classic agents (8,9). Thus, various analogues of the taxanes and Vinca alkaloid classes have been reported (10,11), as have a range of other natural product-derived compounds, such as the epothilones (12). Several small molecule tubulin-binding drugs, chemically distinct from the Vinca and taxanes class, have also been described.…”

Preclinical efficacy spectrum and pharmacokinetics of ixabepilone

“…Four main natural epothilones are produced by S. cellulosum: A and B and, to a lesser extent, C and D [7]. These 16-membered macrolide antibiotics are highly effective at inducing cell arrest at the G 2 /M phase, resulting in apoptosis [8,9].…”