Anticancer therapy with novel tubulin-interacting drugs.

Abstract

Antimitotic agents that target tubulin, including the taxanes and vinca alkaloids, are important components of current anticancer therapy. Whilst these antimitotic drugs are highly effective in the treatment of a number of cancers, both acquired and intrinsic resistance to these agents is a major clinical problem. Furthermore, the systemic toxicity, and in some cases lack of oral availability, make these agents less than ideal. Recently much effort has been directed on the isolation and synthesis of new antimitotic drugs that target the tubulin/microtubule system and display efficacy against drug-refractory carcinomas. Newly described compounds include structurally diverse natural products, such as dolastatin, epothilones and discodermolide, derivatives and structural analogues of traditional antimitotics, and novel synthetic molecules. Additionally, new developments in drug targeting are improving efficacy and therapeutic indices of traditional agents. A number of promising 'new generation' antimitotics are now undergoing clinical testing. These new agents are reviewed here in terms of their mechanism(s) of action on microtubules, effectiveness against drug-resistant tumour cells and clinical potential.