Microtubule active agents: beyond the taxane frontier

Abstract

Microtubules are essential to cell transport, signaling, and mitosis. An increasing range of anticancer drugs interferes with the normal formation and function of microtubules. Vinca alkaloids act as microtubule destabilizers and the taxanes act as microtubule stabilizers. Taxanes are widely used cytotoxic agents that are active in a range of solid tumor malignancies and are routinely used in a variety of settings. Significant limitations with the taxanes exist, including acquired and intrinsic tumor resistance through the expression of multidrug resistance proteins such as P-glycoprotein, risk of hypersensitivity reactions, dose-limiting hematopoietic toxicity, and cumulative neurotoxicity. Hence, there is a need to develop novel agents that act on the microtubules. Epothilones are macrolide antibiotics that bind near the taxane-binding site on microtubules and have been extensively studied in recent and ongoing clinical trials. A variety of other agents that act on the microtubules at different sites with a variety of structures are at varying stages of development.