LOW POTENCY OF TAXOL AT MICROTUBULE MINUS ENDS - IMPLICATIONS FOR ITSANTIMITOTIC AND THERAPEUTIC MECHANISM

In many cells, low concentrations of Taxol potently block mitosis at t he transition from metaphase to anaphase. with no change in microtubul e polymer mass and no microtubule bundling, Mitotic block ultimately r esults in apoptotic cell death and appears to be the most potent antit umor mechanism of Taxl (M. A. Jordan et al., Cancer Res. 56: 816-825, 1996). Mitotic inhibition results, at least in part, from stabilizatio n of growing and shortening dynamics, specifically at the plus ends of microtubules, by the binding of very few Taxol molecules to the micro tubule surface (M. A. Jordan et al., Proc, Natl. Acad. Sci. USA, 90: 9 552-9556, 1993; W. B. Derry et al., Biochemistry, 34: 2203-2211, 1995) , A number of actions of Taxol on mitotic spindle function may be due to its effects on microtubule dynamics at the minus ends of microtubul es, effects that previously have not been described. Here, we determin ed the effects of Taxol on minus ends of purified microtubules at stea dy state, In contrast to the strong stabilizing effects on plus ends, substoichiometric ratios of Taxol bound to tubulin in microtubules did not affect growing, shortening, or dynamicity at minus ends. Thus, in blocked mitotic cells, Taxol can potently suppress dynamics at plus e nds of spindle microtubules, whereas its impotence at minus ends permi ts continued microtubule depolymerization at the spindle poles. Differ ential effects of Taxol at opposite microtubule ends may explain Taxol 's actions on spindle structure and function and its unique potent ant itumor action.