Prodrug-activated gene therapy: involvement of an immunological component in the "bystander effect".

The integration and expression of the herpes simplex virus type 1 thymidine kinase (HSV1-TK) gene in localized tumors results in tumor regression after the administration of the specific nucleoside analogue ganciclovir (GCV). Although only 10% to 20% of the tumor cells take up the HSV1-TK gene, the neighboring cells also die, a phenomenon termed "bystander effect.". In the present study, coinjection of the MC26 mouse colon carcinoma cell line and the HSV1-TK expressing retroviral packaging cell line followed after 7 days by the intraperitoneal administration of GCV resulted in almost total tumor regression in the immunocompetent BALB/c mice but not in immunocompromised athymic BALB/c mice. This suggested a strong cell-mediated immune component to the bystander effect.