GENE-THERAPY FOR ALPHA-FETOPROTEIN-PRODUCING HUMAN HEPATOMA-CELLS BY ADENOVIRUS-MEDIATED TRANSFER OF THE HERPES-SIMPLEX VIRUS THYMIDINE KINASE GENE

We have developed a recombinant replication-defective adenovirus conta ining human alpha-fetoprotein (AFP) promoter/enhancer to direct cell t ype-specific expression of the herpes simplex virus thymidine kinase ( HSVtk) gene to AFP-producing hepatocellular carcinoma (HCC) cells, Aft er an in vitro infection by a recombinant adenovirus carrying the lacZ gene under the control of human AFP promoter/enhancer (AdAFPlacZ), an expression of the lacZ gene was demonstrated efficiently in AFP-produ cing HuH-7 and HepG2 cell lines, but not in AFP-nonproducing HLE and H LF cell lines, although lacZ gene expression was demonstrated in all t hese cell lines when infected with adenovirus vector carrying lacZ gen e driven by the beta-actin-based promoter. Expression of the HSVtk gen e by adenovirus from AFP promoter/enhancer (AdAFPtk) induced the cells sensitive to ganciclovir (GCV) in the AFP-producing cell line efficie ntly, but not in AFP-nonproducing HLF hepatoma cells, An in vitro byst ander effect was observed when only 10% of the cells were infected wit h AdAFPtk, These findings suggest that the AFP promoter/enhancer seque nce can provide the tumor-specific activity for the therapeutic gene e xpression, and that the AdAFPtk vector induces the selective growth in hibition by GCV in the adenovirus-infected human hepatoma cells in vit ro, Recombinant adenovirus transfer of the HSVtk gene under the contro l of tumor-specific promoter followed by GCV may have promise as a tar geted in situ treatment for solid neoplasms.