Regression of large tumors expressing a suicide gene

Using the HSV-tk/GCV system, complete remissions of tumors up to a size of 5 mm in diameter have been reported in mice and rats. In order to examine whether larger tumors of clinically relevant size can also be successfully treated, we established hepatic and peritoneal tumors consisting of retrovirally pretransduced tk-positive CC531 colon adenocarcinoma cells in syngenic Wag/Ola rats. In this model, we evaluated whether large tumors respond to therapy under the ideal condition of 100% gene transfer. Within 10 days, GCV treatment led to a marked regression of the adenocarcinomas. Tumors up to a size of 4000 mm3 could be completely eradicated. Passing through several stages of degeneration and cytolytic necrosis, a complete replacement by fibrous tissue was seen. There was no histological evidence for apoptosis and cell mediated immunity. These results suggest that complete regression of tumors of clinically relevant size can be achieved by direct toxic effects of the HSV-tk/GCV system if 100% of the cells are transduced.