Gene Therapy for Advanced Hepatocellular Carcinoma using Transcriptional Control

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We have demonstrated the usefullness of tumor specific promoter as a tool of cancer gene therapy. The expression levels of such promoters, however, are generally low, and we have therefore develop a novel and general method to enhance the expression level of a tissuespecific promoter while maintaining specificity. We constructed a regulatory recombinant adenovirus (rAd) producing the site-specific recombinant Cre under the control of the hepatocellular carcinoma-specific a (AFP) promoter. The rAd was infected to AFP-producing cells together with a target rAd containing a Cre-activating potent expression unit. In in vitro experiments, the duble infection method gave about 50-fold higher expression than the single rAd infection directly driven by the AFP promoter, while maintaining strict specificity to AFP- producing cells. The enhanced and specific expression was also observed in in vivo tumor models. This method may contribute not only to the establishement of specific gene therapies but also to basic study for elucidating cell-type specific gene functions. As a next step, we have just made a rAd expressing herpes simplex virus thymidine kinase gene as a target rAd, and started testing the cytotoxicity in AFP producing cell lines and transplanted tumor on nude mice.