Adeno-associated virus-mediated delivery of a mutant endostatin suppresses ovarian carcinoma growth in mice.
Earlier studies have shown that a point mutation in human endostatin at position 125 (human endostatin wherein proline 125 was substituted with alanine, P125A-endostatin) improves endothelial cell binding and antiangiogenic activity. In the present study, we investigated the effect of recombinant adeno-associated virus (rAAV)-mediated gene delivery of P125A-endostatin (rAAV-P125Aendo) in a mouse model of ovarian carcinoma. Intramuscular (i.m.) injection of rAAV-P125Aendo resulted in a dose-dependent increase in serum endostatin levels. Consequently, vascular endothelial growth factor- and basic fibroblast growth factor-mediated angiogenesis was significantly inhibited in mice injected with rAAV-P125Aendo as compared to control mice injected with rAAV-LacZ. Furthermore, gene therapy using rAAV-P125Aendo construct showed sustained secretion of P125A-endostatin for up to 9 weeks after a single i.m. administration. Recombinant AAV-P125Aendo injection significantly inhibited the growth of human ovarian cancer cells in athymic nude mice. Immunofluorescence studies of residual tumors surgically removed from the rAAV-P125Aendo-treated animals showed decreased number of vessel ends and vessel length, indicating inhibition of angiogenesis. These studies suggest that recombinant AAV-mediated antiangiogenic gene therapy methods can be used to inhibit ovarian cancer growth.
Subramanian
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Department of Obstetrics and Gynecology and Women's Health, University of Minnesota Medical School, Minneapolis, MN, USA.
Ghebre
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Ramakrishnan
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S
D000818:Animals; D002277:Carcinoma / Q000098:blood supply / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D000229:Dependovirus / Q000235:genetics*; D043169:Endostatins / Q000235:genetics*; D042783:Endothelial Cells / Q000166:cytology; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics; D006801:Humans; D051379:Mice; D023421:Models, Animal; D009389:Neovascularization, Pathologic; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000473:pathology / Q000628:therapy*; D017354:Point Mutation
D043169:Endostatins