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

Sun, X., Kanwar, J.R., Leung, E., Vale, M. and Krissansen, G.W. 2003, Regression of solid tumors by engineered overexpression of von Hippel-Lindau tumor suppressor protein and antisense hypoxia-inducible factor-1alpha, Gene Therapy, vol. 10, no. 25, pp. 2081-2089.

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Title Regression of solid tumors by engineered overexpression of von Hippel-Lindau tumor suppressor protein and antisense hypoxia-inducible factor-1alpha
Author(s) Sun, X.
Kanwar, J.R.
Leung, E.
Vale, M.
Krissansen, G.W.
Journal name Gene Therapy
Volume number 10
Issue number 25
Start page 2081
End page 2089
Publisher Nature Publishing Group
Place of publication London, England
Publication date 2003-12
ISSN 0969-7128
1476-5462
Summary The von Hippel-Lindau tumor suppressor protein (pVHL) suppresses tumor formation by binding the alpha 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-1alpha therapy. Intratumoral injection of subcutaneous EL-4 thymic lymphomas with an expression plasmid encoding pVHL resulted in the downregulation of HIF-1alpha 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-1alpha and VHL plasmids. Combination therapy resulted in increased losses of HIF-1alpha, 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-1alpha, and enhance the expression or function of VHL may be beneficial in the treatment of cancer.
Language eng
Field of Research 110702 Applied Immunology (incl Antibody Engineering, Xenotransplantation and T-cell Therapies)
111204 Cancer Therapy (excl Chemotherapy and Radiation Therapy)
HERDC Research category C1.1 Refereed article in a scholarly journal
Copyright notice ©2003, Nature Publishing Group
Persistent URL http://hdl.handle.net/10536/DRO/DU:30026570

Document type: Journal Article
Collection: Institute of Biotechnology
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Created: Thu, 01 Apr 2010, 14:00:01 EST by Jagat Kanwar

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