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Regression of solid tumors by engineered overexpression of von Hippel–Lindau tumor suppressor protein and antisense hypoxia-inducible factor-1α

Gene Therapy volume 10, pages 2081–2089 (2003)Cite this article

Abstract

The von Hippel–Lindau tumor suppressor protein (pVHL) suppresses tumor formation by binding the α subunits of hypoxia-inducible factors (HIFs) responsible for stimulating tumor angiogenesis and glycolysis, targeting them for ubiquitination and proteasomal destruction. Loss of pVHL leads to the development of sporadic renal cell carcinomas (RCCs). In the present study, we sought to determine whether engineered overexpression of pVHL in tumors other than RCC can inhibit tumor growth, either as a monotherapy, or in combination with antisense HIF-1α therapy. Intratumoral injection of subcutaneous EL-4 thymic lymphomas with an expression plasmid encoding pVHL resulted in the downregulation of HIF-1α and vascular endothelial growth factor (VEGF). There was a concomitant reduction in tumor angiogenesis and increased tumor cell apoptosis due in part to downregulation of Bcl-2 expression. VHL therapy resulted in the complete regression of small (0.1 cm diameter) tumors whereas, in contrast, large (0.4 cm diameter) EL-4 tumors were only slowed in their growth. Nevertheless, large tumors completely regressed in response to intratumoral injection of a combination of antisense HIF-1α and VHL plasmids. Combination therapy resulted in increased losses of HIF-1α, VEGF, and tumor blood vessels, and increased tumor cell apoptosis. These novel results suggest that synergistic therapies that simultaneously block the expression or function of HIF-1α, and enhance the expression or function of VHL may be beneficial in the treatment of cancer.

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Acknowledgements

This work was supported in part by grants from The Wellcome Trust, the Royal Society of New Zealand, the Health Research Council of New Zealand, and the Maurice and Phyllis Paykel Trust. XS is a recipient of a Wellcome Trust Research Leave Fellowship.

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Authors and Affiliations

  1. Department of Molecular Medicine & Pathology, Faculty of Medicine and Health Science, University of Auckland, Auckland, New Zealand

    X Sun, J R Kanwar, E Leung, M Vale & G W Krissansen

  2. Department of Surgery, Qilu Hospital of Shandong University, Jinan, Shandong Province, P.R. China

    X Sun

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Sun, X., Kanwar, J., Leung, E. et al. Regression of solid tumors by engineered overexpression of von Hippel–Lindau tumor suppressor protein and antisense hypoxia-inducible factor-1α. Gene Ther 10, 2081–2089 (2003). https://doi.org/10.1038/sj.gt.3302118

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