Cell-specific cytotoxicity of human pancreatic adenocarcinoma cells using rat insulin promoter thymidine kinase-directed gene therapy

World J Surg. 2004 Aug;28(8):826-33. doi: 10.1007/s00268-004-7291-x. Epub 2004 Aug 3.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • 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
  • Genetic Therapy / methods*
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism
  • Humans
  • Injections, Intraperitoneal
  • Liposomes
  • Liver / pathology
  • Mice
  • Mice, Inbred ICR
  • Mice, SCID
  • Neoplasm Transplantation
  • Pancreas / pathology
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / therapy*
  • Rats
  • Simplexvirus / genetics
  • Thymidine Kinase / genetics*
  • Trans-Activators / genetics*
  • Trans-Activators / metabolism
  • Tumor Cells, Cultured / pathology*
  • beta-Galactosidase / genetics


  • Homeodomain Proteins
  • Liposomes
  • Trans-Activators
  • pancreatic and duodenal homeobox 1 protein
  • Thymidine Kinase
  • beta-Galactosidase
  • Ganciclovir