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 observation has been attributed to both gene transfer and metabolic cooperation between cells (the bystander effect). This study evaluates the relative 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 demonstrated a bystander effect, significantly greater inhibition of proliferation occurred with HStk gene transfer. In mixtures containing 75 per cent MC38 cells with no vector (MC38 NV) and 25 per cent MC38 pretransduced with LTKOSN.2 (MC38 TK), proliferation was inhibited by 62 +/- 5 per cent. In mixtures containing 75 per cent MC38 NV with 25 per cent HStk vector-producing cells (LTKOSN.2 VPC), proliferation was inhibited by 97 +/- 1 per cent. In vivo subcutaneous mixture experiments utilized MC38 NV cells inoculated at a 1:1 ratio with various treatment cell groups followed by administration of GCV. Tumor volumes (mean +/- standard error) at 30 days were: 264 +/- 66 mm3 for MC38 TK, 0 for LTKOSN.2 VPC, 1009 +/- 335 mm3 for lacZ VPC (beta-galactosidase VPC), and 1012 +/- 212 mm3 for NIH3T3 (nontransduced cells). These data suggest that in vivo, the bystander effect alone causes tumor inhibition, but gene transfer is necessary for complete tumor elimination in immunocompetent mice.
Nielsen
C S
CS
Department of Surgery Education, Iowa Methodist Medical Center, Des Moines, USA.
Moorman
D W
DW
Levy
J P
JP
Link
C J
CJ
D000230:Adenocarcinoma / Q000473:pathology / Q000628:therapy*; D000818:Animals; D002455:Cell Division; D003110:Colonic Neoplasms / Q000473:pathology / Q000628:therapy*; D004195:Disease Models, Animal; D005260:Female; D018014:Gene Transfer Techniques; D005814:Genes, Viral; D015316:Genetic Therapy; D005822:Genetic Vectors; D006561:Herpes Simplex / Q000201:enzymology* / Q000235:genetics; D051379:Mice; D008815:Mice, Inbred Strains; D013937:Thymidine Kinase / Q000235:genetics*; D014407:Tumor Cells, Cultured
D013937:Thymidine Kinase