Retrovirus-Mediated Herpes Simplex Virus Thymidine Kinase Gene Transfer in Pancreatic Cancer Cell Lines: An Incomplete Antitumor Effect

INTRODUCTION The transfer of drug-susceptible (suicide) genes to tumor cells by retroviral or adenoviral vectors is a novel approach to the treatment of human tumors. AIMS To ascertain the antitumor effect of retroviral transduction of the pancreatic cancer cell lines MIA PaCa 2, CAPAN-1, PANC1, and PSN1 with the herpes simplex virus thymidine kinase (HSV-TK) gene. METHODOLOGY The vector carried a neoselectable marker gene, the human interleukin-2 gene, an internal ribosome entry coding site, and the region coding HSV-TK. RESULTS Twenty micromoles or less of ganciclovir did not modify nontransduced TK- cell growth, whereas > or =100 micromol completely inhibited TK- cell growth, indicating that this dosage is cytotoxic per se. The 4 TK- and the 4 transduced cell lines were treated daily with 0.001, 0.01, 0.1, 1, 10, and 20 micromol of ganciclovir for 13 days. CAPAN-1 cell growth was completely inhibited by 0.1 micromol of ganciclovir; higher doses were required to kill PANC1 (10 micromol) and PSN1 (20 micromol). MIA PaCa 2 cell growth decreased following a 20-micromol ganciclovir dosing. The bystander effect was great in the CAPAN-1 cell line and moderate in PANC1; no bystander effect was recorded in MIA PaCa 2 and PSN1 cell lines. CONCLUSION Gene therapy with HSV-TK for pancreatic cancer seems effective in only a limited number of tumor-derived cell lines, and this limits its application in vivo.