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.

[1]  J. Rapp Inhibition of neointimal smooth muscle accumulation after angioplasty by an antibody to PDGF , 1993 .

[2]  A. C. Dubbelman,et al.  Pharmacokinetics of paclitaxel and metabolites in a randomized comparative study in platinum-pretreated ovarian cancer patients. , 1993, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  M. Ferguson,et al.  Proliferation in primary and restenotic coronary atherectomy tissue. Implications for antiproliferative therapy. , 1993, Circulation research.

[4]  R. Ross The pathogenesis of atherosclerosis: a perspective for the 1990s , 1993, Nature.

[5]  B. Monsarrat,et al.  Taxol: pharmacology, metabolism and clinical implications. , 1993, Cancer surveys.

[6]  E. Lakatta,et al.  Experimental models that mimic the differentiation and dedifferentiation of vascular cells. , 1992, Circulation.

[7]  C. Runowicz,et al.  Phase II study and long-term follow-up of patients treated with taxol for advanced ovarian adenocarcinoma. , 1992, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[8]  N. Olson,et al.  Inhibition of smooth muscle cell proliferation in injured rat arteries. Interaction of heparin with basic fibroblast growth factor. , 1992, The Journal of clinical investigation.

[9]  M. Stearns,et al.  Taxol blocks processes essential for prostate tumor cell (PC-3 ML) invasion and metastases. , 1992, Cancer research.

[10]  V. Fuster,et al.  A dilemma for the 1990s. Choosing appropriate experimental animal model for the prevention of restenosis. , 1992, Circulation.

[11]  K. Miyazono,et al.  Platelet-Derived Growth Factor , 2020, Definitions.

[12]  G. Hortobagyi,et al.  Phase II trial of taxol, an active drug in the treatment of metastatic breast cancer. , 1991, Journal of the National Cancer Institute.

[13]  M. Stearns,et al.  Regulation of kinesin expression and type IV collagenase secretion in invasive human prostate PC-3 tumor sublines. , 1991, Cancer research.

[14]  N. Paweletz,et al.  Derangement of microtubule arrays in interphase and mitotic PtK2 cells treated with deuterium oxide (heavy water). , 1991, Journal of cell science.

[15]  G. V. Vande Woude,et al.  Ability of the c-mos product to associate with and phosphorylate tubulin. , 1991, Science.

[16]  R. Cook,et al.  Simian virus 40 large T antigen and p53 are microtubule-associated proteins in transformed cells. , 1991, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[17]  R. Donehower,et al.  Taxol: a novel investigational antimicrotubule agent. , 1990, Journal of the National Cancer Institute.

[18]  C. Heldin,et al.  Platelet-derived growth factor: mechanism of action and possible in vivo function. , 1990, Cell regulation.

[19]  S. Schwartz,et al.  Cell proliferation in human coronary arteries. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[20]  R. Donehower,et al.  Development of polyploidization in taxol-resistant human leukemia cells in vitro. , 1990, Cancer research.

[21]  Eric Karsenti,et al.  Regulation of microtubule dynamics by cdc2 protein kinase in cell-free extracts of Xenopus eggs , 1990, Nature.

[22]  H. Weiss,et al.  Cell constitution and characteristics of human atherosclerotic plaques selectively removed by percutaneous atherectomy. , 1989, Atherosclerosis.

[23]  R. Donehower,et al.  Demonstration of the cell cycle positions of taxol-induced "asters" and "bundles" by sequential measurements of tubulin immunofluorescence, DNA content, and autoradiographic labeling of taxol-sensitive and -resistant cells. , 1989, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[24]  D. Ettinger,et al.  Taxol: a unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms. , 1989 .

[25]  D. Ettinger,et al.  Phase I and pharmacodynamic study of taxol in refractory acute leukemias. , 1989, Cancer research.

[26]  E. Edelman,et al.  Biological and biochemical properties of fibroblast growth factors. Implications for the pathogenesis of atherosclerosis. , 1989, Arteriosclerosis.

[27]  R. Ross,et al.  Two classes of PDGF receptor recognize different isoforms of PDGF. , 1988, Science.

[28]  D. Ingber,et al.  A heparin-binding angiogenic protein--basic fibroblast growth factor--is stored within basement membrane. , 1988, The American journal of pathology.

[29]  C. Heldin,et al.  Arterial smooth muscle cells express platelet-derived growth factor (PDGF) A chain mRNA, secrete a PDGF-like mitogen, and bind exogenous PDGF in a phenotype- and growth state-dependent manner , 1988, The Journal of cell biology.

[30]  Y Iwamoto,et al.  A rapid in vitro assay for quantitating the invasive potential of tumor cells. , 1987, Cancer research.

[31]  R. Ross,et al.  The biology of platelet-derived growth factor , 1986, Cell.

[32]  T. Albrecht,et al.  Changes in the Extent of Microtubule Assembly Can Regulate Initiation of DNA Synthesis a , 1986, Annals of the New York Academy of Sciences.

[33]  G. Laurie,et al.  Basement membrane complexes with biological activity. , 1986, Biochemistry.

[34]  T. C. Takahashi,et al.  Yields of tubulin paracrystals, vinblastine-crystals, induced in unfertilized and fertilized sea urchin eggs in the presence of D2O. , 1984, Cell structure and function.

[35]  A. Otto,et al.  Microtubule‐disrupting agents can independently affect the prereplicative period and the entry into S phase stimulated by prostaglandin F2α and fibroblastic growth factor , 1983 .

[36]  R. Ma,et al.  Endothelial regeneration. III. Time course of intimal changes after small defined injury to rat aortic endothelium. , 1981 .

[37]  K. Crossin,et al.  Evidence that microtubule depolymerization early in the cell cycle is sufficient to initiate DNA synthesis , 1981, Cell.

[38]  P. Schiff,et al.  Taxol stabilizes microtubules in mouse fibroblast cells. , 1980, Proceedings of the National Academy of Sciences of the United States of America.

[39]  A. Otto,et al.  Cytoskeleton-disrupting drugs enhance effect of growth factors and hormones on initiation of DNA synthesis. , 1979, Proceedings of the National Academy of Sciences of the United States of America.

[40]  P. Schiff,et al.  Promotion of microtubule assembly in vitro by taxol , 1979, Nature.

[41]  R. Friedman,et al.  The effect of thrombocytopenia on experimental arteriosclerotic lesion formation in rabbits. Smooth muscle cell proliferation and re-endothelialization. , 1977, The Journal of clinical investigation.

[42]  Robert P. Davis,et al.  Effect of microtubular antagonists on lymphocyte mitogenesis , 1977, Nature.

[43]  M. Bissell,et al.  Synergism between anti-microtubule agents and growth stimulants in enhancement of cell cycle traverse , 1977, Nature.

[44]  R. Ross,et al.  Homocystine-induced arteriosclerosis. The role of endothelial cell injury and platelet response in its genesis. , 1976, The Journal of clinical investigation.

[45]  G M Edelman,et al.  Surface modulation in cell recognition and cell growth. , 1976, Science.

[46]  A. McPhail,et al.  Plant antitumor agents. VI. The isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia. , 1971, Journal of the American Chemical Society.

[47]  D. Northcote,et al.  Action of colchicine and heavy water on the polymerization of microtubules in wheat root meristem. , 1969, Journal of cell science.

[48]  H. Baumgartner,et al.  [Effects of vascular catheterization in normo- and hypercholesteremic rabbits]. , 1966, Pathologia et microbiologia.