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.