Ixabepilone: targeting beta III-tubulin expression in taxane-resistant malignancies

Microtubule-targeting agents, such as taxanes and epothilones, block mitosis and cell proliferation by targeting the dynamics of the cytoskeleton. The taxanes are widely used for treatment of various malignancies, but primary and acquired resistance to chemotherapy remains a significant clinical concern. Class I, II, III, IV, and V beta-tubulin isotypes are expressed in human tumors. Overexpression of the beta III-tubulin isotype is one mechanism that can render tumor cells resistant to taxanes. The relative expression of beta III-tubulin correlates with clinical outcomes in several tumor types, including breast cancer, non-small cell lung cancer, and ovarian cancer. A novel analogue of epothilone B, ixabepilone, has recently been approved in combination with capecitabine for the treatment of patients with anthracycline- and taxane-resistant locally advanced or metastatic breast cancer and as monotherapy in patients whose tumors are resistant or refractory to an anthracycline, a taxane, and capecitabine. The significant antitumor activity of ixabeplione in taxane-resistant tumors may be related to Its preferential suppression of the dynamic instability of alpha/beta III-microtubules in cells expressing high levels of beta III-tubulin. [Mol Cancer Ther 2009;8(1):17 - 25]