PANCREATIC-CARCINOMA CELL-KILLING VIA ADENOVIRAL MEDIATED DELIVERY OFTHE HERPES-SIMPLEX VIRUS THYMIDINE KINASE GENE

Objective Use of adenoviral mediated delivery of the herpes simplex vi rus thymidine kinase (HSV-TK) gene as a gene therapy strategy for carc inoma of the pancreas. Summary Background Data Expression of HSV-TK se lectively sensitizes cells to the nucleoside analog ganciclovir (GCV). This strategy has been used to treat other compartmentalized tumor mo dels. Therefore, the containment of pancreatic carcinoma makes it amen able to this gene therapy approach. Methods A recombinant adenoviral v ector encoding the HSV-TK gene was used to induce GCV sensitivity and test the potential bystander effect in established pancreatic carcinom a cell lines and patient-derived tumor material. Additionally, Balb/C nude mice were injected intraperitoneally with human pancreatic carcin oma cells and treated with GCV (50 mg/kg per day) for 14 days. Results Expression of the HSV-TK gene elicited a significant bystander effect in the presence of GCV. Pancreatic tumor cells injected intraperitone ally into nude mice resulted in significant tumor formation. Treatment of animals with AdCMVHSV-TK and GCV induced a dramatic decrease in ov erall tumor burden for up to 8 weeks post-GCV treatment. Conclusions P ancreatic carcinoma cells are highly susceptible to transduction with recombinant adenoviral vectors and elicit a potent bystander effect on neighboring tumor cells. Additionally, in vivo treatment of tumor-bea ring animals results in dramatic reduction of overall tumor burden, th us providing the rationale for molecular chemotherapy of pancreatic ca rcinoma.