Combination of Gene Therapy and Chemotherapy Stops Kidney Cancer in Mouse Model

A novel therapeutic approach combining a modified viral vector and a small molecular weight drug produced promising results in a mouse model of human kidney cancer.

Investigators at the Virginia Commonwealth University (Richmond, USA) created a unique adenovirus vector by combining the tail and shaft domains of a serotype 5 virus and the knob domain of a serotype 3 virus. This Ad.5/3 adenovirus was then loaded with the gene needed to express the cancer-killing protein MDA-7/IL-24.

The viral vector was administered to mice bearing human renal carcinoma cells (RCCs), alone or together with the drug sorafenib, a small molecular weight inhibitor of several tyrosine protein kinases. Sorafenib, which is unique in targeting the Raf/Mek/Erk pathway (MAP Kinase pathway), has already been approved by the [US] Food and Drug Administration (FDA) for the treatment of renal carcinoma.

Results published in the December 15, 2010, issue of the journal Cancer Biology & Therapy revealed that infection with the Ad.5/3-mda-7 vector caused kidney cancer cells and normal cells lining the kidneys to secrete MDA-7/IL-24. MDA-7/IL-24 quickly stopped the growth of the primary tumor. As the infected cells continued to secrete MDA-7/IL-24, it entered the blood stream and eventually stopped the growth of a second, distinct tumor not directly infected by the adenovirus. Only renal carcinoma cells were destroyed by this "toxic bystander effect”; normal cells were unaffected. Sorafenib enhanced MDA-7/IL-24 toxicity and significantly increased its antitumor effects in the mouse model.

"While further research is needed, this therapy could be a novel and effective way to treat metastatic kidney cancer and prolong patient survival,” said senior author Dr. Paul Dent, professor of biochemistry at Virginia Commonwealth University. "This is the first study to clearly define that gene therapeutic delivery of MDA-7/IL-24 in kidney cancer should be explored in the clinic, especially since we have demonstrated an established, FDA-approved drug enhances its toxicity to cancer cells.”

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