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Antiangiogenesis mediates cisplatin-induced peripheral neuropathy: attenuation or reversal by local vascular endothelial growth factor gene therapy without augmenting tumor growth.
Circulation. 2005 May 24; 111(20):2662-70.Circ

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.

Authors+Show Affiliations

Division of Cardiovascular Research, St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Mass 02135, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15897348

Citation

Kirchmair, Rudolf, et al. "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, 2005, pp. 2662-70.
Kirchmair R, Walter DH, Ii M, et al. Antiangiogenesis mediates cisplatin-induced peripheral neuropathy: attenuation or reversal by local vascular endothelial growth factor gene therapy without augmenting tumor growth. Circulation. 2005;111(20):2662-70.
Kirchmair, R., Walter, D. H., Ii, M., Rittig, K., Tietz, A. B., Murayama, T., Emanueli, C., Silver, M., Wecker, A., Amant, C., Schratzberger, P., Yoon, Y. S., Weber, A., Panagiotou, E., Rosen, K. M., Bahlmann, F. H., Adelman, L. S., Weinberg, D. H., Ropper, A. H., ... Losordo, D. W. (2005). Antiangiogenesis mediates cisplatin-induced peripheral neuropathy: attenuation or reversal by local vascular endothelial growth factor gene therapy without augmenting tumor growth. Circulation, 111(20), 2662-70.
Kirchmair R, et al. Antiangiogenesis Mediates Cisplatin-induced Peripheral Neuropathy: Attenuation or Reversal By Local Vascular Endothelial Growth Factor Gene Therapy Without Augmenting Tumor Growth. Circulation. 2005 May 24;111(20):2662-70. PubMed PMID: 15897348.
* Article titles in AMA citation format should be in sentence-case
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, Y1 - 2005/05/16/ PY - 2005/5/18/pubmed PY - 2006/1/13/medline PY - 2005/5/18/entrez SP - 2662 EP - 70 JF - Circulation JO - Circulation VL - 111 IS - 20 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. SN - 1524-4539 UR - https://www.unboundmedicine.com/medline/citation/15897348/Antiangiogenesis_mediates_cisplatin_induced_peripheral_neuropathy:_attenuation_or_reversal_by_local_vascular_endothelial_growth_factor_gene_therapy_without_augmenting_tumor_growth_ L2 - http://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.104.470849?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -