Combination of cytosine deaminase suicide gene expression with DR5 antibody treatment increases cancer cell cytotoxicity

Cancer Gene Ther. 2006 Feb;13(2):203-14. doi: 10.1038/sj.cgt.7700874.


Combined treatment using adenoviral-directed enzyme/prodrug therapy and immunotherapy has the potential to become a powerful alternative method of cancer therapy. We have developed adenoviral vectors encoding the cytosine deaminase gene (Ad-CD) and cytosine deaminase:uracil phosphoribosyltransferase fusion gene (Ad-CD:UPRT). A monoclonal antibody, TRA-8, specifically binds to death receptor 5, one of two death receptors bound by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). The purpose of this study was to evaluate cytotoxicity in vitro and therapeutic efficacy in vivo of the combination of Ad-CD:UPRT and TRA-8 against human pancreatic cancer and glioma cell lines. The present study demonstrates that Ad-CD:UPRT infection resulted in increased 5-FC-mediated cell killing, compared with Ad-CD. Furthermore, a significant increase of cytotoxicity following Ad-CD:UPRT/5-FC and TRA-8 treatment of cancer cells in vitro was demonstrated. Animal studies showed significant inhibition of tumor growth of MIA PaCa-2 pancreatic and D54MG glioma xenografts by the combination of Ad-CD:UPRT/5-FC plus TRA-8 as compared with either agent alone or no treatment. The results suggest that the combination of Ad-CD:UPRT/5-FC with TRA-8 produces an additive cytotoxic effect in cancer cells in vitro and in vivo. These data indicate that combined treatment with enzyme/prodrug therapy and TRAIL immunotherapy provides a promising approach for cancer therapy.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenoviridae / genetics*
  • Analysis of Variance
  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / metabolism
  • Antibodies, Monoclonal / therapeutic use*
  • Blotting, Western
  • Cell Line, Tumor
  • Cytosine Deaminase / genetics*
  • Cytotoxicity Tests, Immunologic
  • Female
  • Flow Cytometry
  • Genes, Transgenic, Suicide / genetics*
  • Genetic Therapy / methods*
  • Glioma / immunology
  • Glioma / therapy*
  • Humans
  • Immunotherapy / methods*
  • Mice
  • Mice, Nude
  • Microscopy, Fluorescence
  • Pancreatic Neoplasms / immunology
  • Pancreatic Neoplasms / therapy*
  • Pentosyltransferases / genetics
  • Prodrugs / therapeutic use
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor / metabolism


  • Antibodies, Monoclonal
  • Prodrugs
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor
  • TNFRSF10B protein, human
  • Tnfrsf10b protein, mouse
  • Pentosyltransferases
  • uracil phosphoribosyltransferase
  • Cytosine Deaminase