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(Circulation. 2005;111:2662-2670.)
© 2005 American Heart Association, Inc.

Vascular Medicine

Antiangiogenesis Mediates Cisplatin-Induced Peripheral Neuropathy

Attenuation or Reversal by Local Vascular Endothelial Growth Factor Gene Therapy Without Augmenting Tumor Growth

Rudolf Kirchmair, MD; Dirk H. Walter, MD; Masaaki Ii, MD; Kilian Rittig, MD; Anne B. Tietz, BS; Toshinori Murayama, MD, PhD; Costanza Emanueli, MD; Marcy Silver, BS; Andrea Wecker, BS; Carole Amant, PhD; Peter Schratzberger, MD; Young-Sup Yoon, MD, PhD; Alberto Weber, MD; Eleftheria Panagiotou, BS; Kenneth M. Rosen, MD; Ferdinand H. Bahlmann, MD; Lester S. Adelman, MD; David H. Weinberg, MD; Allan H. Ropper, MD; Jeffrey M. Isner, MD; Douglas W. Losordo, MD

From the Departments of Cardiovascular Research (R.K., D.H.W., M.I., K.R., A.B.T., T.M., C.E., M.S., A.W., C.A., P.S., Y.-S.Y., A.W., E.P., F.H.B., J.M.I., D.W.L.), Vascular Medicine (J.M.I.), and Neurology (K.M.R., L.S.A, D.H.W., A.H.R.), St Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, Mass.

Correspondence to Douglas W. Losordo, MD, Division of Cardiovascular Research, St. Elizabeth’s Medical Center, 736 Cambridge St, Boston, MA 02135. E-mail douglas.losordo{at}tufts.edu

Received April 28, 2004; revision received January 13, 2005; January 20, 2005.

Background— Toxic neuropathies induced by cisplatin and other chemotherapeutic agents are important clinical problems because of their high incidence, their lack of effective treatment, and the fact that neuropathy represents a dose-limiting factor for these therapies. The pathogenic basis for toxic neuropathies induced by chemotherapeutic agents has not been completely elucidated.

Methods and Results— We investigated the hypothesis that experimental toxic neuropathy results from an antiangiogenic effect of these drugs, resulting in destruction of the vasa nervorum, and accordingly that the neuropathy could be prevented or reversed by locally administered VEGF gene transfer without augmenting tumor growth. In an animal model of cisplatin-induced neuropathy, nerve blood flow was markedly attenuated, and there was a profound reduction in the number of vasa nervorum associated with marked endothelial cell apoptosis, resulting in a severe peripheral neuropathy with focal axonal degeneration characteristic of ischemic neuropathy. After intramuscular gene transfer of naked plasmid DNA encoding VEGF-1 in animals with an established neuropathy, vascularity and blood flow returned to levels similar to those of control rats, peripheral nerve function was restored, and histological nerve architecture was normalized. Gene therapy administered in parallel with cisplatin chemotherapy completely attenuated endothelial cell apoptosis and inhibited destruction of nerve vasculature, deterioration of nerve function, and axonal degeneration. In a rat tumor model, VEGF gene transfer administered locally did not alter tumor growth or vascularity.

Conclusions— These findings implicate microvascular damage as the basis for toxic neuropathy induced by cisplatin and suggest that local angiogenic gene therapy may constitute a novel prevention or treatment for this disorder without augmenting tumor growth or vascularization.

Key Words: angiogenesis • endothelium • gene therapy • vasa nervorum

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