Epothilones are a new class of antimicrotubule agents currently in clinical trials. Their chemical structures are distinct from
taxanes and are more amenable to synthetic modification. Six
epothilones have been studied in preclinical and clinical trials:
patupilone (
epothilone B),
ixabepilone (
BMS247550),
BMS 310705,
sagopilone (
ZK-EPO),
KOS-862 (
epothilone D), and
KOS-1584. In vitro data have shown increased potency in
taxane-sensitive and
taxane-resistant
cancer cell lines. This enhanced cytotoxic effect has been attributed to
epothilone being a poor substrate for
p-glycoprotein drug resistance
protein and having high affinity to the various
beta tubulin isoforms. Phase I clinical data have shown different dose-limiting toxicities for each of the
epothilones. These effects are
drug specific, dose specific, and schedule of administration specific. While
diarrhea and myelosuppression are the dose-limiting toxicities for
patupilone and
BMS 310705, respectively, neurologic toxicity, as seen with
taxanes, is the dose-limiting toxicity of
ixabepilone,
sagopilone, and
KOS-862. In an effort to decrease neurologic toxicity, investigators have modified dosing schedules with limited success.
Ixabepilone has the most mature clinical results with published phase II and III data, and regulatory approval for clinical use in the treatment of
breast cancer.
Ixabepilone has also been combined with other
anticancer agents and has regulatory approval in combination with
capecitabine for heavily treated
breast cancer.