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Antiangiogenic cancer gene therapy by adeno-associated virus 2-mediated stable expression of the soluble FMS-like tyrosine kinase-1 receptor

Cancer Gene Therapy volume 12, pages 26–34 (2005)Cite this article

Abstract

Antiangiogenic gene transfer has the potential to be more efficacious than protein-based therapies or pharmacotherapies for the control of solid tumor growth, invasion and metastasis. For a sustained antiangiogenic effect, a vector capable of long-term expression without vector-associated immunity or toxicity is advantageous. The present study evaluated the potential of a recombinant adeno-associated virus-2 (rAAV) encoding the human soluble FMS-like tyrosine kinase receptor 1 (sFlt-1), which functions by both sequestering vascular endothelial growth factor (VEGF) and forming inactive heterodimers with other membrane-spanning VEGF receptors, in vitro and in vivo. Results indicated significant growth inhibitory activity of the transgenic factor in a human umbilical vein endothelial cell proliferation assay in vitro and protection against the growth of an angiogenesis-dependent human ovarian cancer cell line, SKOV3.ip1, xenograft in vivo with increased disease-free survival. Stable expression of the secretory factor and transgene persistence were confirmed by immunohistochemistry and in situ hybridization analyses, respectively. Increased therapeutic effects on both the growth index of the implanted tumor cells and tumor-free survival also correlated with an increasing dose of the vector used. These studies indicate that rAAV-mediated sFlt-1 gene therapy may be a feasible approach for inhibiting tumor angiogenesis, particularly as an adjuvant/therapy.

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Acknowledgements

This work was supported by a Career Development Award from NIH-Ovarian SPORE Grant CA83591, NIH Grants CA90850, CA98817, AR46031 and US Army Department of Defense Grants BC010494 and PC020372.

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Authors and Affiliations

  1. Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL, 35294, USA

    Gandham Mahendra, Sanjay Kumar, Tatyana Isayeva, David T Curiel, Cecil R Stockardt, William E Grizzle, Vidya Alapati, Raj Singh, Gene P Siegal & Selvarangan Ponnazhagan

  2. Department of Obstetrics and Gynecology, The University of Alabama at Birmingham, Birmingham, AL, 35294, USA

    Parameshwar J Mahasreshti

  3. Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL, 35294, USA

    David T Curiel & Sreelatha Meleth

  4. Gene Therapy Center, The University of Alabama at Birmingham, Birmingham, AL, 35294, USA

    Parameshwar J Mahasreshti, David T Curiel, Gene P Siegal & Selvarangan Ponnazhagan

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  1. Gandham Mahendra
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Correspondence to Selvarangan Ponnazhagan.

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Mahendra, G., Kumar, S., Isayeva, T. et al. Antiangiogenic cancer gene therapy by adeno-associated virus 2-mediated stable expression of the soluble FMS-like tyrosine kinase-1 receptor. Cancer Gene Ther 12, 26–34 (2005). https://doi.org/10.1038/sj.cgt.7700754

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