Antiangiogenesis mediates cisplatin-induced peripheral neuropathy attenuation or reversal by local vascular endothelial growth factor gene therapy without augmenting tumor growth

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

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)2662-2670
Number of pages9
JournalCirculation
Volume111
Issue number20
DOIs
Publication statusPublished - 2005 May 24

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Poisons
Peripheral Nervous System Diseases
Genetic Therapy
Vascular Endothelial Growth Factor A
Cisplatin
Vasa Nervorum
Growth
Neoplasms
Endothelial Cells
Apoptosis
Genes
Peripheral Nerves
Plasmids
Therapeutics
Animal Models
Drug Therapy
DNA
Incidence
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Kirchmair, Rudolf ; Walter, Dirk H. ; Ii, Masaaki ; Rittig, Kilian ; Tietz, Anne B. ; Murayama, Toshinori ; Emanueli, Costanza ; Silver, Marcy ; Wecker, Andrea ; Amant, Carole ; Schratzberger, Peter ; Yoon, Young Sup ; Weber, Alberto ; Panagiotou, Eleftheria ; Rosen, Kenneth M. ; Bahlmann, Ferdinand H. ; Adelman, Lester S. ; Weinberg, David H. ; Ropper, Allan H. ; Isner, Jeffrey M. ; Losordo, Douglas W. / Antiangiogenesis mediates cisplatin-induced peripheral neuropathy attenuation or reversal by local vascular endothelial growth factor gene therapy without augmenting tumor growth. In: Circulation. 2005 ; Vol. 111, No. 20. pp. 2662-2670.
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abstract = "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.",
author = "Rudolf Kirchmair and Walter, {Dirk H.} and Masaaki Ii and Kilian Rittig and Tietz, {Anne B.} and Toshinori Murayama and Costanza Emanueli and Marcy Silver and Andrea Wecker and Carole Amant and Peter Schratzberger and Yoon, {Young Sup} and Alberto Weber and Eleftheria Panagiotou and Rosen, {Kenneth M.} and Bahlmann, {Ferdinand H.} and Adelman, {Lester S.} and Weinberg, {David H.} and Ropper, {Allan H.} and Isner, {Jeffrey M.} and Losordo, {Douglas W.}",
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Kirchmair, R, Walter, DH, Ii, M, Rittig, K, Tietz, AB, Murayama, T, Emanueli, C, Silver, M, Wecker, A, Amant, C, Schratzberger, P, Yoon, YS, Weber, A, Panagiotou, E, Rosen, KM, Bahlmann, FH, Adelman, LS, Weinberg, DH, Ropper, AH, Isner, JM & Losordo, DW 2005, 'Antiangiogenesis mediates cisplatin-induced peripheral neuropathy attenuation or reversal by local vascular endothelial growth factor gene therapy without augmenting tumor growth', Circulation, vol. 111, no. 20, pp. 2662-2670. https://doi.org/10.1161/CIRCULATIONAHA.104.470849

Antiangiogenesis mediates cisplatin-induced peripheral neuropathy attenuation or reversal by local vascular endothelial growth factor gene therapy without augmenting tumor growth. / Kirchmair, Rudolf; Walter, Dirk H.; Ii, Masaaki; Rittig, Kilian; Tietz, Anne B.; Murayama, Toshinori; Emanueli, Costanza; Silver, Marcy; Wecker, Andrea; Amant, Carole; Schratzberger, Peter; Yoon, Young Sup; Weber, Alberto; Panagiotou, Eleftheria; Rosen, Kenneth M.; Bahlmann, Ferdinand H.; Adelman, Lester S.; Weinberg, David H.; Ropper, Allan H.; Isner, Jeffrey M.; Losordo, Douglas W.

In: Circulation, Vol. 111, No. 20, 24.05.2005, p. 2662-2670.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Antiangiogenesis mediates cisplatin-induced peripheral neuropathy attenuation or reversal by local vascular endothelial growth factor gene therapy without augmenting tumor growth

AU - Kirchmair, Rudolf

AU - Walter, Dirk H.

AU - Ii, Masaaki

AU - Rittig, Kilian

AU - Tietz, Anne B.

AU - Murayama, Toshinori

AU - Emanueli, Costanza

AU - Silver, Marcy

AU - Wecker, Andrea

AU - Amant, Carole

AU - Schratzberger, Peter

AU - Yoon, Young Sup

AU - Weber, Alberto

AU - Panagiotou, Eleftheria

AU - Rosen, Kenneth M.

AU - Bahlmann, Ferdinand H.

AU - Adelman, Lester S.

AU - Weinberg, David H.

AU - Ropper, Allan H.

AU - Isner, Jeffrey M.

AU - Losordo, Douglas W.

PY - 2005/5/24

Y1 - 2005/5/24

N2 - 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.

AB - 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.

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