BYSTANDER EFFECT CAUSED BY SUICIDE GENE-EXPRESSION INDICATES THE FEASIBILITY OF GENE-THERAPY FOR HEPATOCELLULAR-CARCINOMA

In the field of gene therapy using retroviral vectors, it appears impo ssible to introduce a foreign gene into all target cells. Therefore ad jacent cell killing, the so-called bystander effect, caused by genetic ally modified cells provides therapeutic advantages for gene therapy a gainst cancers. We retrovirally transduced the herpes simplex virus th ymidine kinase (HSV-th) gene into murine and rat hepatocellular carcin oma (HCC) cells. These Hm-th gene-transduced HCC cells were cocultured with the corresponding parental cells in the presence of ganciclovir, at a concentration not at all cytotoxic to the parental cells, When p arental HCC cells were cocultured with their HSV-fh gene-transduced co unterparts at a high density at which most cells were in contact with one another, they were markedly eliminated. Conversely, when coculture d at a low density at which none of the cells were in contact, a weak but statistically significant bystander effect was observed. Addition of lysates of HSV-th gene-transduced cells in the presence of ganciclo vir did not cause any killing of parental cells. Furthermore, media co nditioned by transduced cells with ganciclovir exhibited weak cytotoxi c effects on parental cells. These results indicate that cell-cell con tact plays a major causative role in the bystander effect and that min or contributors to this phenomenon are some cytotoxic substance releas ed from transduced cells, Importantly, the bystander effect was induce d in vivo as well as in vitro. When mixtures of transduced and untrans duced HCC cells were implanted into the flank region of mice, intraper itoneal ganciclovir administration considerably inhibited tumor develo pment, indicating the feasibility of gene therapy with HSV-tk gene and ganciclovir against HCC.