TAXOL INHIBITS NEOINTIMAL SMOOTH-MUSCLE CELL ACCUMULATION AFTER ANGIOPLASTY IN THE RAT

Despite significant improvements in the primary success rate of the me dical and surgical treatments for atherosclerotic disease, including a ngioplasty, bypass grafting, and endarterectomy, secondary failure due to late restenosis continues to occur in 30-50% of individuals. Reste nosis and the later stages in atherosclerotic lesions are due to a com plex series of fibroproliferative responses to vascular injury involvi ng potent growth-regulatory molecules (such as platelet-derived growth factor and basic fibroblast growth factor) and resulting in vascular smooth muscle cell (VSMC) proliferation, migration, and neointimal acc umulation, We show here, based on experiments with both taxol and deut erium oxide, that microtubules are necessary for VSMCs to undergo the multiple transformations contributing to the development of the neoint imal fibroproliferative lesion. Taxol was found to interfere both with platelet-derived growth factor-stimulated VSMC migration and with VSM C migration and with VSMC proliferation, at nanomolar levels in vitro. In vivo, taxol prevented medial VSMC proliferation and the neointimal VSMC accumulation in the rat carotid artery after balloon dilatation and endothelial denudation injury, This effect occurred at plasma leve ls approximately two orders of magnitude lower than that used clinical ly to treat human malignancy (peak levels achieved in this model were similar to 50-60 nM), Taxol may therefore be of therapeutic value in p reventing human restenosis with minimal toxicity.