Novel cytotoxic agents: Epothilones

Abstract

The epothilones are effective antitumor medications for patients with breast cancer, including patients who have been previously treated with or are resistant to anthracyclines or the taxanes. With the best currently available therapies, the median survival time for patients with metastatic breast cancer is only 2-3 years, and many patients develop resistance to taxanes or other chemotherapy drugs. The epothilones are a novel class of antitumor medications, similar to the taxanes in some respects, but that also possess several advantages. Like taxanes, epothilones are believed to produce antitumor effects by binding to and stabilizing intracellular microtubules, which are essential in DNA replication and cell division. Several in vitro and animal studies have shown that the epothilones are more potent microtubule stabilizers than the taxanes, they are effective against cancer cell lines with high levels of drug resistance, and they induce the regression of taxane-resistant human tumors. Preclinical studies also have demonstrated synergistic increases in tumor cell killing when the epothilones are combined with other antitumor medications. Epothilone B (patupilone) has been evaluated in a series of phase I and II clinical trials, which demonstrated disease stabilization or objective responses in patients with a variety of cancers, including ovarian, prostate, breast, colon, stomach, and kidney cancers. This agent is currently being evaluated in phase III clinical trials. A second epothilone, ixabepilone, was recently approved by the FDA for the treatment of metastatic breast cancer. Ixabepilone was evaluated as monotherapy for the treatment of breast cancer in phase II clinical trials of previously untreated patients and in taxane-experienced and taxane-resistant disease. A phase III clinical trial demonstrated that the combination of ixabepilone and capecitabine was superior to capecitabine alone in heavily pretreated, taxane-resistant patients. Ongoing clinical trials will continue to define the role of the epothilones in cancer therapy.