Gene therapy using apoptosis-inducer bax and suicide gene for chemically induced rat bladder cancer

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The effectiveness of in vivo electrogene transfer as a means of gene therapy for rat bladder cancers using the herpes simplex virus 1 thymidine kinase (HSVtk) gene in combination with ganciclovir (GCV) was investigated. In vitro studies demonstrated that 50-70% of the transitional cell carcinoma (TCC) cells died as a result of transfection with pHSVtk and GCV administration and that this treatment was associated with decreased DNA synthesis and elevated activities of caspase-3, -8 and -9. A significantly decreased mitochondrial membrane potential was also noted in TCC cells given pHSVtk+GCV. A direct single injection of HSVtk into bladder tumors using in vivo electrogene transfer followed by GCV administration resulted in significant increases in the levels of apoptosis and histopathological necrosis accompanied by marked inflammation. Active caspase-3 was strongly expressed in the cell death areas of the TCC in rats given pHSVtk/GCV therapy. In vivo electrogene transfer results in efficient gene transfer in chemically induced rat bladder tumors and the HSVtk/GCV producing system induces significant cell death which appears to be, at least, mediated via the mitochondrial apoptotic pathway.