Novel actions of the antitumor drugs vinflunine and vinorelbine on microtubules

Vinflunine is a novel Vinca alkaloid presently in Phase I clinical trials. In preclinical studies, it exhibited superior antitumor activity to that of other Vinca alkaloids, including vinorelbine from which it was synthetical ly derived. Vinca alkaloids appear to inhibit cell proliferation by affecti ng the dynamics of spindle microtubules, Here we have analyzed the effects of vinflunine and vinorelbine on microtubule dynamic instability and treadm illing and found that these newer drugs exert effects on microtubule dynami cs that differ significantly from those of the classic Vinca alkaloid, vinb lastine, The major effects of vinflunine and vinorelbine on dynamic instabi lity were a slowing of the microtubule growth rate, an increase in growth d uration, and a reduction in shortening duration. In marked contrast to the action of vinblastine, they neither reduced the rate of shortening nor incr eased the percentage of time the microtubules spent in an attenuated state, neither growing nor shortening detectably. In addition, vinflunine and vin orelbine suppressed treadmilling, but less strongly than vinblastine, The d iverse actions of these drugs on microtubules are likely to produce differe nt effects on mitotic spindle function, leading to different effects on cel l cycle progression and cell killing. Nontumor cells with normal checkpoint proteins may tolerate the relatively less powerful inhibitory effects of v influnine and vinorelbine on microtubule dynamics better than the more powe rful effects of vinblastine, Thus the unique constellation of effects of vi nflunine and vinorelbine on dynamic instability and treadmilling may contri bute to their superior antitumor efficacies.