New inhibitors of tubulin polymerisation

Abstract

Despite the relatively long tradition of the vinca alkaloids in cancer chemotherapy, the spectrum of compounds with the same mode of action has until recently been quite small. It was mainly the discovery of paclitaxel (Taxol^®, Bristol-Myers Squibb) that stimulated the search for novel substances of natural or synthetic origin that interact with tubulin and microtubules. Since the vinca structure allowed only minor alterations and the potencies of colchicine and combretastatin derivatives were rather low, most of the industrial activities concerned two new, highly-active classes of natural products, the dolastatins and the cryptophycins. Cemadotin, like other dolastatins, inhibits the growth of various tumour cells in nanomolar concentrations and is currently undergoing Phase II clinical studies. Even more active are the cryptophycins with IC₅₀ values in the picomolar range. One of the interesting features of cryptophycin 52 (LY 355703), which is now in clinical trials, is its high activity in multi-drug resistant cells. However, it is still unclear whether the high cytotoxic potency can be separated from the inherent systemic toxicity of these agents.

• cematodin
• colchicine
• combretastatins
• cryptophycin
• dolastatins
• E7010
• methoxyestradiol
• multi-drug resistance
• vinca alkaloids