Microtubule-binding agents: a dynamic field of cancer therapeutics

Abstract

Microtubule-binding agents are one of the oldest and most diverse family of anticancer agents. This family has recently been enriched with the approval of ixabepilone, vinflunine and cabazitaxel. Most approved and investigational agents are either natural or semi-synthetic compounds. These agents act primarily by reducing microtubule dynamics, inducing mitotic arrest and tumour cell death. They are therefore complementary to agents that target DNA or to targeted therapies such as tyrosine kinase inhibitors or monoclonal antibodies. Novel agents are being developed as vascular-disrupting agents. Although cardiac toxicity of such agents remains a possible issue, some of them have proceeded to Phase III clinical trials. Although hundreds of agents have been shown to influence microtubule dynamics in vitro, a large number of novel agents are currently being evaluated in clinical trials. These agents bind either to the vinca site, the taxane site or the colchicine site, although some novel agents seem to bind to other sites. Resistance mechanisms to microtubule-binding agents are complex and include ATP binding cassette efflux pumps, microtubular alterations and modifications in apoptotic signalling. Identification of these mechanisms has prompted the identification of novel agents indifferent to these resistance mechanisms. Although neurological toxicity remains a key issue associated with microtubule-binding agents, myeloid toxicity is usually manageable. The development of novel agents with reduced neurological toxicity or of assays that predict toxicity in individual patients are priorities for the optimization of this family of compounds. The long-term mutagenic effect of this family of agents has not yet been evaluated. Given the prolonged life expectancy of many patients treated with these compounds, this effect should be determined.