Evaluation of herpes simplex thymidine kinase mediated gene therapy in experimental pancreatic cancer

Background Despite of recent improvements in the treatment of many malignan t diseases, pancreatic ductal adenocarcinoma is still a disease with an ext remely poor prognosis with current modes of treatment. Gene therapy has bee n suggested as a novel approach also against pancreatic cancer. Previous st udies have been carried out predominantly with immunodeficient animal model s and with tumors growing in environments other than the pancreas. We have attempted to mimic a more clinically relevant situation and investigated su icide gene therapy strategy for experimental pancreatic cancer in animals w ith an intact immune system. Methods We used herpes simplex virus thymidine kinase (HSV-tk) and ganciclo vir (GCV) strategy in both in vitro and in vivo settings. Results In vitro studies demonstrated that: retro- as well as adenovirally transduced HSV-tk-positive DSL-6A/C1 rat pancreatic carcinoma cells were se nsitive to low concentrations of GCV when compared with parental, nontransd uced. cells. In addition, a strong bystander effect was observed. In in viv o studies, subcutaneously transplanted HSV-tk-positive DSL-6A/C1 cells were killed after GCV treatment, whereas parental, HSV-tk-negative cells contin ued to grow and developed into ductal adenocarcinomas. In in vivo HSV-tk-tr ansduced. pancreatic tumors, GCV treatment caused tumor necrosis and the ne crosis volume was significantly more extensive when compared with control g roups. Conclusions HSV-tk gene transfer followed by GCV treatment is efficient in killing pancreatic cancer cells in vitro, in a transduced subcutaneous tumo r model, as well as in in vivo transduced pancreatic tumors using an immuno competent animal model. These results highlight the potential of gene thera py to treat experimental pancreatic cancer. Copyright (C) 2000 John Wiley & Sons, Ltd.