Cytoskeletons and antimitotic agents developed in Japan

Resistance to antimitotic agents is caused by decreased accumulation, altered tubulin, altered microtubule-associated proteins and increased metabolism. Vinca alkaloids, paclitaxel and docetaxel are actively effluxed by P-glycoprotein and/or the MRP1. Decreased intracellular accumulation is one of the major determinants of resistance to antimitotic agents. Increased tubulin levels and a decreased polymerization ratio were observed in resistant cells. Increased acetylation of tubulin and altered intracellular distribution of tubulin were also observed in resistant cells; however, the relationship between the function of tubulin and resistance remains unclear. The expression of each beta-tubulin isotype (beta 1-beta 6) is altered in resistant cells, but the functional differences among the isotypes have not been clarified. Recent evidence has demonstrated the alteration of binding properties of antimitotic agents in resistant cells. Therefore, the altered expressions of tubulin isotypes and related molecules might influence the antimitotic action and adverse events by antimitotic agents. Taxanes are metabolized and inactivated by p450 isozymes, and this is related to drug-resistant to taxanes.