Long-term survival of immunocompetent rats with intraperitoneal colon carcinoma tumors using herpes simplex thymidine kinase/ganciclovir and IL-2 treatments

Abstract

We evaluated the gain in long-term survival of BDIX rats bearing DHDProB colon cancer developed in the peritoneal cavity after in vivo therapy with the tk gene and GCV. The sensitivity and the bystander effect of DHDProB cells stably transduced with the tk gene evaluated in vitro were low, as one tk⁺ cell killed two tk⁻ cells. This correlated with the low ability of a fluorescent dye to diffuse through gap junctions. In vivo, more than 75% of tk-transduced cells were required and at least 100 mg/kg/day of GCV had to be injected no later than day 5 after tumor implantation to obtain a curative effect. A partial protection of the cured animals against rechallenge with the parental cells was also observed. Based on these results, a protocol of in vivo gene therapy was designed in which the tk/GCV treatment was combined with IL-2 gene expression. When the tk- and IL-2 encoding plasmids were injected twice i.p. with DOTAP and the animals treated with GCV, three of five rats were cured. This antitumoral activity resulted from the combined toxic effects of DNA/DOTAP and tk/GCV plus a potential immune response mediated by IL-2.