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Vol. 53, Issue 5, 908-915, May 1998

A Comparison of Thermodynamic Parameters for Vinorelbine- and Vinflunine-Induced Tubulin Self-Association by Sedimentation Velocity

Sharon Lobert, Jeffrey W. Ingram, Bridget T. Hill, and John J. Correia

School of Nursing (S.L.) and Department of Biochemistry, University of Mississippi Medical Center, Jackson, Mississippi 39216 (S.L., J.W.I., J.J.C.), and the Division de Cancerologie Experimentale, Centre de Recherche Pierre Fabre, 81106 Castres Cedex 06, France (B.T.H.)

We present a comparison of the energetics of spiral formation for two vinca alkaloids: a novel difluorinated vinorelbine derivative 20',20'-difluoro-3',4'-dihydrovinorelbine (F12158, or vinflunine) and the parent compound, vinorelbine. Vinca alkaloids are antineoplastic agents that halt cell division at metaphase by inhibiting microtubule assembly and inducing tubulin self-association into spiral aggregates. The overall affinities for tubulin of vincristine, vinblastine, and vinorelbine seem to correlate with their clinical doses, where vincristine with the highest overall affinity is used at the lowest doses. Doses of chemotherapeutic agents, however, also are determined by toxicities. In the physicochemical study described here, we used sedimentation velocity to compare vinorelbine- and vinflunine-induced self-association of porcine brain tubulin in the presence of 50 µM GDP or 50 µM GTP. Vinflunine demonstrates 3-16-fold lower overall affinity for tubulin and induces smaller polymers compared with vinorelbine. Sedimentation velocity provides the only direct evidence to date that vinflunine is a tubulin-binding drug. Stopped-flow light scattering demonstrates the shortest relaxation times for polymer redistribution for vinflunine consistent with induction of the shortest spirals. Data collected at 5°, 15°, 25°, and 37° show increasing &smacr;20,w values with increasing temperature and are consistent with an entropically driven process. These data are entirely consistent with our hypothesis that vinflunine is likely to result in reduced clinical neurotoxicity relative to vinorelbine, vinblastine, and vincristine.

Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics


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