HERPES-SIMPLEX THYMIDINE KINASE GENE-TRANSFER IS REQUIRED FOR COMPLETE REGRESSION OF MURINE COLON ADENOCARCINOMA

The herpes simplex thymidine kinase (HStk) gene induces regression of epithelial tumors after ganciclovir (GCV) administration. This observa tion has been attributed to both gene transfer and metabolic cooperati on between cells (the bystander effect). This study evaluates the rela tive roles of the bystander effect and gene delivery of the HStk gene by the LTKOSN.2 vector. MC38 colon adenocarcinoma cells, syngeneic for C57/B16 mice, were used. Whereas in vitro proliferation assays demons trated a bystander effect, significantly greater inhibition of prolife ration occurred with HStk gene transfer. In mixtures containing 75 per cent MC38 cells with no vector (MC38 NV) and 25 per cent MC38 pretran sduced with LTKOSN.2 (MC38 TK), proliferation was inhibited by 62 +/- 5 per cent. In mixtures containing 75 per cent MC38 NV with 25 per cen t HStk vector-producing cells (LTKOSN.2 VPC), proliferation was inhibi ted by 97 +/- 1 per cent. In vivo subcutaneous mixture experiments uti lized MC38 NV cells inoculated at a 1:1 ratio with various treatment c ell groups followed by administration of GCV. Tumor volumes (mean +/- standard error) at 30 days were: 264 +/- 66 mm(3) for MC38 TK, 0 for L TKOSN.2 VPC, 1009 +/- 335 mm(3) for lacZ VPC (beta-galactosidase VPC), and 1012 +/- 212 mm(3) for NIH3T3 (nontransduced cells). These data s uggest that in vivo, the bystander effect alone causes tumor inhibitio n, but gene transfer is necessary for complete tumor elimination in im munocompetent mice.