HSV thymidine kinase gene transduction enhances tumor growth rate, neovascularization and cyclooxygenase-2 expression in murine colon cancer xenografts.

Proc Amer Assoc Cancer Res, Volume 45, 2004 3424 Transduction of tumor cells with Herpes Simplex virus type I thymidine kinase (HSV-tk) gene and subsequent treatment with the prodrug ganciclovir (GCV) is the most common system studied for “suicide” gene therapy of cancer. However, the HSV-tk/GCV strategy has several limitations that, to some extent, plague all the cancer gene therapy strategies. Limitations include low transduction efficiency, vector cytotoxicity, high immunogenicity of transduced cells and resistance or loss of GCV sensitivity. In the present report we show that HSV-tk gene transduction significantly augments tumor growth rate (1.63±0.15 fold increase in mean tumor volume) and neovascularization (1.83±0.32 increase in mean intratumor microvessel density) in xenografts of murine colon cancer cells. Transduction of tumor cells with control vector carrying the neomycin resistance gene alone did not increase tumor growth rate but even decreased it, indicating that the observed phenomenon is related to the presence of the HSV-tk sequence insert in the retroviral vector used for HSV-tk gene delivery. Additionally, we demonstrate herein that HSV-tk gene transduction significantly enhances cyclooxygenase-2 (COX-2) expression and leads to 2.5±0.17 fold increase in prostaglandin E2 release in tumors ex vivo. Tumor growth rate of HSV-tk transduced murine colon cancer xenografts was significantly inhibited by treatment with the selective COX-2 inhibitor nimesulide. This observation may suggest a causal relationship between COX-2 overexpression and the enhanced growth rate of tumors expressing HSV-tk gene. It is further shown that the enhanced tumor growth rate observed in HSV-tk transduced murine colon cancer xenografts persists upon the development of GCV resistance, characterized by decreased susceptibility of resistant cells to the antiproliferative effect of GCV. Thus, one may expect the prognosis of HSV-tk transduced tumors to seriously deteriorate when they become resistant to GCV since tumor growth rate is enhanced, without a benefit of a prodrug to accomplish the suicide mission of this treatment. Taken together, these results may provide an insight to further understanding of the direct effect of HSV-tk gene transduction on tumor cell biology as well as to potential harmful effects of “suicide” gene therapy using retroviral vectors.