Pancreatic carcinoma cell killing via adenoviral mediated delivery of the herpes simplex virus thymidine kinase gene.

Abstract

Use of adenoviral mediated delivery of the herpes simplex virus thymidine kinase (HSV-TK) gene as a gene therapy strategy for carcinoma of the pancreas. Expression of HSV-TK selectively sensitizes cells to the nucleoside analog ganciclovir (GCV). This strategy has been used to treat other compartmentalized tumor models. Therefore, the containment of pancreatic carcinoma makes it amenable to this gene therapy approach. A recombinant adenoviral vector encoding the HSV-TK gene was used to induce GCV sensitivity and test the potential bystander effect in established pancreatic carcinoma cell lines and patient-derived tumor material. Additionally, Balb/C nude mice were injected intraperitoneally with human pancreatic carcinoma cells and treated with GCV (50 mg/kg per day) for 14 days. Expression of the HSV-TK gene elicited a significant bystander effect in the presence of GCV. Pancreatic tumor cells injected intraperitoneally into nude mice resulted in significant tumor formation. Treatment of animals with AdCMVHSV/HSV-TK and GCV induced a dramatic decrease in overall tumor burden for up to 8 weeks post-GCV treatment. Pancreatic carcinoma cells are highly susceptible to transduction with recombinant adenoviral vector and elicit a potent bystander effect on neighboring tumor cells. Additionally, in vivo treatment of tumor-bearing animals results in dramatic reduction of overall tumor burden, thus providing the rationale for molecular chemotherapy of pancreatic carcinoma.