Adeno-associated virus-mediated delivery of a mutant endostatin suppresses ovarian carcinoma growth in mice

I. V. Subramanian, R. Ghebre, S. Ramakrishnan

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)30-38
Number of pages9
JournalGene Therapy
Volume12
Issue number1
DOIs
StatePublished - Jan 1 2005
Externally publishedYes

Keywords

  • Angiogenesis
  • Endostatin
  • Mouse model
  • Ovarian cancer
  • rAAV

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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