Taxol inhibits neointimal smooth muscle cell accumulation after angioplasty in the rat.
Despite significant improvements in the primary success rate of the medical and surgical treatments for atherosclerotic disease, including angioplasty, bypass grafting, and endarterectomy, secondary failure due to late restenosis continues to occur in 30-50% of individuals. Restenosis and the later stages in atherosclerotic lesions are due to a complex series of fibroproliferative responses to vascular injury involving 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 accumulation. We show here, based on experiments with both taxol and deuterium oxide, that microtubules are necessary for VSMCs to undergo the multiple transformations contributing to the development of the neointimal fibroproliferative lesion. Taxol was found to interfere both with platelet-derived growth factor-stimulated VSMC migration and with VSMC 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 levels approximately two orders of magnitude lower than that used clinically to treat human malignancy (peak levels achieved in this model were approximately 50-60 nM). Taxol may therefore be of therapeutic value in preventing human restenosis with minimal toxicity.
Sollott
S J
SJ
Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
Cheng
L
L
Pauly
R R
RR
Jenkins
G M
GM
Monticone
R E
RE
Kuzuya
M
M
Froehlich
J P
JP
Crow
M T
MT
Lakatta
E G
EG
Rowinsky
E K
EK
D000800:Angioplasty, Balloon / Q000009:adverse effects*; D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects* / Q000254:growth & development / Q000473:pathology / Q000601:surgery; D002450:Cell Communication / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D017666:Deuterium Oxide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007150:Immunohistochemistry; D008870:Microtubules / Q000187:drug effects; D024510:Muscle Development; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000254:growth & development / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017539:Tunica Intima / Q000187:drug effects* / Q000254:growth & development / Q000473:pathology
D010982:Platelet-Derived Growth Factor; D017666:Deuterium Oxide; D017239:Paclitaxel