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

Abstract

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.

• Authors: S A Kaliberov, S Chiz, L N Kaliberova, V Krendelchtchikova, D Della Manna, T Zhou, D J Buchsbaum
• Journal: Cancer gene therapy (Cancer Gene Ther) Vol. 13 Issue 2 Pg. 203-14 (Feb 2006) ISSN: 0929-1903 [Print] England
• PMID: 16082379 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

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

Topics

• Adenoviridae (genetics)
• Analysis of Variance
• Animals
• Antibodies, Monoclonal (immunology, metabolism, 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, therapy)
• Humans
• Immunotherapy (methods)
• Mice
• Mice, Nude
• Microscopy, Fluorescence
• Pancreatic Neoplasms (immunology, therapy)
• Pentosyltransferases (genetics)
• Prodrugs (therapeutic use)
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• Receptors, Tumor Necrosis Factor (metabolism)