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

Gene Therapy volume 12, pages 30–38 (2005)Cite this article

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.

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Acknowledgements

We thank Dr C Le and RL Bliss (Biostatistics Core, University of Minnesota Cancer Center) for statistical analysis. We also thank Dr Y Yokoyama for helpful suggestions. This work was supported in part by grants from the Minnesota Ovarian Cancer Alliance, Sparboe and Women's Health Fund Endowment and DAM 17-99-1-9564 from the USARMY.

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology and Women's Health, University of Minnesota Medical School, Minneapolis, MN, USA

    I V Subramanian, R Ghebre & S Ramakrishnan

  2. Department of Pharmacolgy, University of Minnesota Medical School, Minneapolis, MN, USA

    S Ramakrishnan

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  1. I V Subramanian
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  2. R Ghebre
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  3. S Ramakrishnan
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Subramanian, I., Ghebre, R. & Ramakrishnan, S. Adeno-associated virus-mediated delivery of a mutant endostatin suppresses ovarian carcinoma growth in mice. Gene Ther 12, 30–38 (2005). https://doi.org/10.1038/sj.gt.3302352

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