The Epothilones: How Pharmacology Relates to Clinical Utility

Abstract

Objective: To review the pharmacologic properties of a novel class of chemotherapeutic agents, the epothilones, and to summarize findings from recent clinical trials investigating the various epothilones in cancer therapy. Data Sources: Literature searches were conducted using MEDLINE, PubMed, and the abstract search engines for the American Society of Clinical Oncology and American Association for Cancer Research annual meetings (all searches through November 2008). Primary search terms included epothilone, BMS-247550, ixabepilone, EPO906, patupilone, sagopilone, and ZK-EPO. Study Selection and Data Extraction: Publications were given priority for inclusion if they discussed structural or pharmacologic properties of the epothilones as a class or if they included preclinical or clinical data for epothilones currently in clinical development. Data Synthesis: The epothilones are a novel class of microtubule-stabilizing agents (MSAs). Epothilones are structurally and pharmacologically distinct from taxanes, but the exact ways in which the pharmacophores of the 2 classes differ has not been firmly established. A number of natural, semisynthetic, and fully synthetic epothilones are in various stages of clinical development. These agents differ from each other and from existing MSAs; these differences influence potency, stability, and solubility. Ixabepilone is currently approved to treat multidrug-resistant metastatic breast cancer and has demonstrated efficacy in earlier stages of breast cancer and in several other tumor types. Patupilone and sagopilone are currently under clinical investigation and have each shown promise in a number of treatment settings and tumor types. All 3 agents appear to be associated with manageable toxicities, but no class-wide toxicity profile exists for the epothilones and dose-limiting toxicities differ among the agents. Conclusions: The epothilones have demonstrated significant potential for addressing the growing therapeutic challenge of taxane resistance, and the ever-increasing pool of information regarding structure–activity relationships of these MSAs will help to optimize microtubule-targeted chemotherapy.