Therapeutic Angiogenesis Inhibits or Rescues Chemotherapy-induced Peripheral Neuropathy: Taxol- and Thalidomide-induced Injury of Vasa Nervorum is Ameliorated by VEGF

doi:doi:10.1038/sj.mt.6300019

Subject Categories: Acquired and Multigenic Disease

Molecular Therapy (2007) 15, 69–75. doi:10.1038/sj.mt.6300019

Therapeutic Angiogenesis Inhibits or Rescues Chemotherapy-induced Peripheral Neuropathy: Taxol- and Thalidomide-induced Injury of Vasa Nervorum is Ameliorated by VEGF

Rudolf Kirchmair^1,2, Anne B Tietz¹, Eleftheria Panagiotou¹, Dirk H Walter¹, Marcy Silver¹, Young-Sup Yoon¹, Peter Schratzberger^1,2, Alberto Weber¹, Kengo Kusano¹, David H Weinberg³, Allan H Ropper³, Jeffrey M Isner^1,4 and Douglas W Losordo^1,4

¹Department of Cardiovascular Research, St Elizabeth's Medical Center – Tufts University School of Medicine, Boston, Massachusetts, USA
²Department of Internal Medicine, General Internal Medicine, Medical University Innsbruck, Innsbruck, Austria
³Department of Neurology, St Elizabeth's Medical Center – Tufts University School of Medicine, Boston, Massachusetts, USA
⁴Department of Vascular Medicine, St Elizabeth's Medical Center – Tufts University School of Medicine, Boston, Massachusetts, USA

Correspondence: Rudolf Kirchmair, Department of Internal Medicine, Medical University of Innsbruck, Anichstr., 35, 6020, Innsbruck, Austria; Feinberg Cardiovascular Research Institute, Northwestern University, 303 E Chicago Avenue, Taily 12-703, Chicago, Illinois 60611, USA. E-mails: Rudolf.kirchmair@uibk.ac.at; d-losordo@northwestern.edu

Received 22 December 2005; Accepted 11 July 2006.

Top

Abstract

Toxic neuropathy represents an important clinical problem in the use of the chemotherapeutic substances Taxol and thalidomide. Sensory neuropathy has a high incidence, lacks an effective treatment and is the dose-limiting factor for these drugs. The pathogenic basis of these neuropathies is unknown. We investigated the hypothesis that the experimental toxic neuropathies from Taxol and thalidomide results from destruction of vasa nervorum and can be reversed by the administration of an angiogenic cytokine. In animal models of Taxol- and thalidomide-induced neuropathy, nerve blood flow has been attenuated and the number of vasa nervorum has been reduced. Intramuscular gene transfer of naked plasmid DNA encoding VEGF-1 administered in parallel with Taxol injections completely inhibited deterioration of nerve function and diminution of the peripheral nerve vasculature. Gene therapy in animals with established Taxol- or thalidomide-induced neuropathies resulted in recovery of vascularity and improved nerve electrophysiology. These findings implicate microvascular damage as the basis for toxic neuropathy and suggest that angiogenic growth factors may constitute a novel treatment for this disorder.