INDUCTION OF SENSITIVITY TO GANCICLOVIR IN HUMAN HEPATOCELLULAR-CARCINOMA CELLS BY ADENOVIRUS-MEDIATED GENE-TRANSFER OF HERPES-SIMPLEX VIRUS THYMIDINE KINASE

We have analyzed the ability of a recombinant replication-defective adenovirus to transfer the thymidine kinase gene of herpes simplex virus (HSV-tk) into hepato cellular carcinoma (HCC) cells to confer sensitivity to ganciclovir. Three HCC cell lines (Hep3B, PLC/PRF/5, and HepG2) were efficiently infected in vitro by a recombinant adenovirus carrying lacZ reporter gene (AdCMVlacZ). Expression of HSV-tk in HCC cells infected with a recombinant adenovirus carrying HSV-tk gene (AdCMVtk) induced sensitivity to ganciclovir in a dose-dependent manner. A bystander killing effect was observed when 90% of uninfected tumor cells were mixed with only 10% of AdCMVtk-infected cells. These data show that recombinant adenoviruses are efficient vectors for transduction of drug-sensitizing genes to HCC cells in vitro. We suggest that a gene therapy approach to hepatocellular carcinoma can be established using adenoviral transfer of HSV-tk to tumor cells and subsequent administration of ganciclovir.