Comparative evaluation of the antitumor activity of antiangiogenic proteins delivered by gene transfer
Open Access
- 27 March 2001
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 98 (8) , 4605-4610
- https://doi.org/10.1073/pnas.081615298
Abstract
Although the systemic administration of a number of different gene products has been shown to result in the inhibition of angiogenesis and tumor growth in different animal tumor models, the relative potency of those gene products has not been studied rigorously. To address this issue, recombinant adenoviruses encoding angiostatin, endostatin, and the ligand-binding ectodomains of the vascular endothelial growth factor receptors Flk1, Flt1, and neuropilin were generated and used to systemically deliver the different gene products in several different preexisting murine tumor models. Single i.v. injections of viruses encoding soluble forms of Flk1 or Flt1 resulted in ≈80% inhibition of preexisting tumor growth in murine models involving both murine (Lewis lung carcinoma, T241 fibrosarcoma) and human (BxPC3 pancreatic carcinoma) tumors. In contrast, adenoviruses encoding angiostatin, endostatin, or neuropilin were significantly less effective. A strong correlation was observed between the effects of the different viruses on tumor growth and the activity of the viruses in the inhibition of corneal micropocket angiogenesis. These data underscore the need for comparative analyses of different therapeutic approaches that target tumor angiogenesis and provide a rationale for the selection of specific antiangiogenic gene products as lead candidates for use in gene therapy approaches aimed at the treatment of malignant and ocular disorders.Keywords
This publication has 42 references indexed in Scilit:
- Experimental subretinal neovascularization is inhibited by adenovirus-mediated soluble VEGF/flt-1 receptor gene transfection: a role of VEGF and possible treatment for SRN in age-related macular degenerationGene Therapy, 2000
- Blockade of Vascular Endothelial Cell Growth Factor Receptor Signaling Is Sufficient to Completely Prevent Retinal NeovascularizationThe American Journal of Pathology, 2000
- Vessel Cooption, Regression, and Growth in Tumors Mediated by Angiopoietins and VEGFScience, 1999
- Wide Spectrum of Antitumor Activity of a Neutralizing Monoclonal Antibody to Human Vascular Endothelial Growth FactorJapanese Journal of Cancer Research, 1999
- Regional Suppression of Tumor Growth byIn VivoTransfer of a cDNA Encoding a Secreted Form of the Extracellular Domain of theflt-1Vascular Endothelial Growth Factor ReceptorHuman Gene Therapy, 1998
- Patterns and Emerging Mechanisms of the Angiogenic Switch during TumorigenesisPublished by Elsevier ,1996
- Characterization of Novel Vascular Endothelial Growth Factor (VEGF) Receptors on Tumor Cells That Bind VEGF165 via Its Exon 7-encoded DomainJournal of Biological Chemistry, 1996
- Identification of Vascular Endothelial Growth Factor Determinants for Binding KDR and FLT-1 ReceptorsJournal of Biological Chemistry, 1996
- Angiostatin: A novel angiogenesis inhibitor that mediates the suppression of metastases by a lewis lung carcinomaCell, 1994
- Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivoNature, 1993