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Epothilones: tubulin polymerization as a novel target for prostate cancer therapy

Nature Clinical Practice Oncology volume 6, pages 85–92 (2009)Cite this article

Abstract

Microtubules are vital and dynamic cellular organelles and many agents have been developed that target them. The cytotoxic effects of taxanes and epothilones are mediated by stabilization of microtubule dynamics. Taxanes are one of the most effective cytotoxic agents, and have a broad spectrum of antitumor activity. However, their efficacy is limited by the development of resistance to these effects. Epothilones have a similar mechanism of action to taxanes, but a decreased propensity for drug resistance. Epothilones are macrolides, and have in vitro and in vivo activity in taxane-resistant or taxane-insensitive human cancer cell lines. Several epothilones are in clinical development: ixabepilone, patupilone, BMS-310705, KOS-862, KOS-1584, and ZK-EPO. Multiple dosing schedules of ixabepilone and patupilone have been studied. The toxicity profiles of epothilones are quite diverse and depend on the compound and the administration schedule. The epothilones have demonstrated a wide range of clinical activity, including important antitumor effects, in advanced prostate cancer. Epothilones are particularly useful in patients with prostate cancer who have previously been treated with taxanes or who have taxane-refractory tumors. In the setting of castrate metastatic prostate cancer, ixabepilone and patupilone showed encouraging clinical activity in the phase II setting and further studies are needed to determine if they provide additional clinical benefit to patients with advanced disease.

Key Points

  • Microtubules are an excellent target for anticancer drugs

  • Microtubule-stabilizing agents such as taxanes and epothilones exert cytotoxic effects by stabilization of microtubule dynamics

  • Several epothilones are currently in active clinical development: ixabepilone, patupilone, BMS-310705, KOS-862, KOS-1584, and ZK-EPO

  • Epothilones have shown important antitumor activity in several tumor types, including prostate cancer

  • Ixabepilone and patupilone have shown encouraging clinical activity in patients with castrate metastatic prostate cancer

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Figure 1: Structures of epothilones.

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Authors and Affiliations

  1. Department of Internal Medicine, JJ Lee is an Assistant Professor, and WK Kelly is an Associate Professor, both in the Section of Medical Oncology, Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA.,

    James J Lee & W Kevin Kelly

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Correspondence to W Kevin Kelly.

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WK Kelly has declared he receives grant/research support from Bristol-Myers Squibb. JJ Lee declared no competing interests.

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Lee, J., Kelly, W. Epothilones: tubulin polymerization as a novel target for prostate cancer therapy. Nat Rev Clin Oncol 6, 85–92 (2009). https://doi.org/10.1038/ncponc1281

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