Microtubules as Targets for Drug and Toxic Chemical Action: The Mechanisms of Action of Colchicine and Vinblastine

Abstract

Colchicine (Fig. 1), the earliest chemical substance discovered that acts on microtubules, was initially described as a spindle poison in the 1930s because it produced strikingly disorganized mitotic spindles and chromosome patterns in treated cells (reviewed by Dustin, 1978). It was many years before it was established that the mechanism of action of colchicine involved disruption of microtubules (see Borisy and Taylor, 1967a,b; Wilson and Friedkin, 1967). Other microtubule-disruptive substances originally identified as spindle poisons include griseofulvin (see Deysson, 1964), podophyllotoxin, a plant alkaloid that binds to tubulin in the vicinity of the colchicine binding site (see Wilson, 1975), and a clinically important group of alkaloids commonly known as the “vinca alkaloids.” These drugs were discovered in 1957 in extracts of the plant Catharanthus rosea, originally called Vinca rosea (Cutts et al., 1957; Noble et al., 1958). Three vinca alkaloids, vinblastine, vincristine (Fig. 1), and vindesine, are currently used for the treatment of several forms of cancer (Gerzon, 1980).