Gene therapy for hepatocellular carcinoma: augmentation of thymidine kinase gene/ganciclovir system using chemical modulators of nuclear proteins

Abstract

A Moloney murine leukemia virus-derived retroviral vector carrying the herpes simplex virus (HSV) thymidine kinase (TK) gene was constructed and subsequently transfected into Ψ2 packaging cells, with resultant retrovims being transduced into XC rat hepatoma cells. Using HSV-TK gene-transduced XC (XCtkn) cells, we studied the effects of treatment with GCV, as well as with GCV and anticancer drugs or chemical modulators of nuclear proteins. GCV treatment was also examined in co-cultures of XCtkn cells and genetically unmodified XC, PLC/PRF/5 and Huh1 hepatoma cells, respectively. The growth of HSV-TK gene-transduced XC (XCtkn) cells either in vivo or in vitro was suppressed by treating with ganciclovir (GCV). In addition, the proliferation of genetically unmodified XC, PLC/PRF/5 and Huhl hepatoma cells was inhibited on co-culturing in vitro with the XCtkn cells and GCV, indicating that bystander effect operated in the present experimental system. Anticancer drugs and chemical modulators of nuclear proteins acted additively with GCV in inhibiting the proliferation of XCtkn cells. These suggest that the use of HSV-TK/GCV system in combination with other drugs may be a promising therapy for hepatocellular carcinoma.