Cell‐specific Cytotoxicity of Human Pancreatic Adenocarcinoma Cells Using Rat Insulin Promoter Thymidine Kinase‐directed Gene Therapy

• Published in: World journal of surgery 2004-08, Vol.28 (8), p.826-833
• Main Authors: Tirone, Thomas A., Wang, Xaio‐Ping, Templeton, Nancy S., Lee, Tim, Nguyen, Liz, Fisher, William, Brunicardi, F. Charles
• Format: Article
• Language: English
• Subjects: Animals; beta-Galactosidase - genetics; Biological and medical sciences; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - therapy; Cell Line, Tumor; Cell Survival - genetics; Feasibility Studies; Female; Ganciclovir - administration & dosage; Gene Expression Regulation, Enzymologic - physiology; Gene Transfer Techniques; General aspects; Genetic Therapy - methods; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Human Pancreatic Adenocarcinoma Cell Line; Human Pancreatic Cancer Cell Line; Humans; Injections, Intraperitoneal; Liposomes; Liver - pathology; Medical sciences; Mice; Mice, Inbred ICR; Mice, SCID; Neoplasm Transplantation; Pancreas - pathology; Pancreatic Ductal Adenocarcinoma; Pancreatic Ductal Adenocarcinoma Cell; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - therapy; Rats; Simplexvirus - genetics; Thymidine Kinase; Thymidine Kinase - genetics; Trans-Activators - genetics; Trans-Activators - metabolism; Tumor Cells, Cultured - pathology
• ISSN: 0364-2313; 1432-2323
• DOI: 10.1007/s00268-004-7291-x

The formation of a normal pancreas and the activation of insulin production are, in part, dependent on the expression and activation of the pancreatic duodenal homeobox gene 1 (PDX‐1). The expression of PDX‐1 also has been detected in various human pancreatic ductal adenocarcinoma (PDA) cell lines. This has made it possible to generate a cancer cell‐specific gene expression system to treat human pancreatic cancer. In this study, we have developed a cell‐specific cytotoxic model of PDA cells using the expression of herpes simplex virus thymidine kinase (TK) under the control of the rat insulin promoter (RIP‐TK). We have shown that the cell‐specific cytotoxicity in human PDA cells depends on the presence of PDX‐1. Our results also demonstrate that in vivo PDA‐specific cytotoxicity can be achieved with RIP‐TK using an intraperitoneal liposomal gene delivery method followed by a short period of ganciclovir treatment in severe combined immunodeficient (SCID) mice. Furthermore, PDX‐1 protein was found in all six freshly isolated human pancreas cancer specimens and two liver metastasis samples that were group‐tested, suggesting the feasibility of using RIP‐TK gene therapy in humans. This study may provide an alternative strategy for the future treatment of pancreatic cancer.