Evaluation of herpes simplex thymidine kinase mediated gene therapy in experimental pancreatic cancer.
BACKGROUND
Despite of recent improvements in the treatment of many malignant diseases, pancreatic ductal adenocarcinoma is still a disease with an extremely poor prognosis with current modes of treatment. Gene therapy has been suggested as a novel approach also against pancreatic cancer. Previous studies have been carried out predominantly with immunodeficient animal models and with tumors growing in environments other than the pancreas. We have attempted to mimic a more clinically relevant situation and investigated suicide gene therapy strategy for experimental pancreatic cancer in animals with an intact immune system.


METHODS
We used herpes simplex virus thymidine kinase (HSV-tk) and ganciclovir (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 sensitive to low concentrations of GCV when compared with parental, nontransduced cells. In addition, a strong bystander effect was observed. In in vivo studies, subcutaneously transplanted HSV-tk-positive DSL-6A/C1 cells were killed after GCV treatment, whereas parental, HSV-tk-negative cells continued to grow and developed into ductal adenocarcinomas. In in vivo HSV-tk-transduced pancreatic tumors, GCV treatment caused tumor necrosis and the necrosis volume was significantly more extensive when compared with control groups.


CONCLUSIONS
HSV-tk gene transfer followed by GCV treatment is efficient in killing pancreatic cancer cells in vitro, in a transduced subcutaneous tumor model, as well as in in vivo transduced pancreatic tumors using an immunocompetent animal model. These results highlight the potential of gene therapy to treat experimental pancreatic cancer.
Mäkinen
K
K
Department of Surgery, Kuopio University Hospital, Finland. kimmo.makinen@kuh.fi
Loimas
S
S
Wahlfors
J
J
Alhava
E
E
Jänne
J
J
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use; D003131:Combined Modality Therapy; D015774:Ganciclovir / Q000627:therapeutic use; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008297:Male; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D051381:Rats; D011917:Rats, Inbred Lew; D018139:Simplexvirus / Q000201:enzymology* / Q000235:genetics*; D013937:Thymidine Kinase / Q000235:genetics*; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
D000998:Antiviral Agents; D013937:Thymidine Kinase; D015774:Ganciclovir