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

Cancer Gene Therapy volume 13, pages 203–214 (2006)Cite this article

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.

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Abbreviations

Ad:

adenovirus

CD:

cytosine deaminase

DR5:

death receptor 5

CMV:

cytomegalovirus

E. coli :

Escherichia coli

EGFP:

enhanced green fluorescent protein

5-FC:

5-fluorocytosine

5-FU:

5-fluorouracil

MOI:

multiplicity of infection

TRAIL:

tumor necrosis factor-related apoptosis-inducing ligand

TBS:

Tris-buffered solution

TCID50:

50% tissue culture infectious dose

TS:

thymidylate synthase

UPRT:

uracil phosphoribosyltransferase

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Acknowledgements

We thank Sankyo Co., Ltd for providing the TRA-8 antibody and Sally B Lagan for assistance in preparing the manuscript. Supported in part by NCI SPORE grants in Brain Cancer P50 CA97247 and Pancreatic Cancer P20 CA11905.

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Authors and Affiliations

  1. Department of Radiation Oncology, University of Alabama at Birmingham, 674 Wallace Tumor Institute, Birmingham, Alabama, USA

    S A Kaliberov, S Chiz, L N Kaliberova, V Krendelchtchikova, D Della Manna & D J Buchsbaum

  2. Department of Medicine, University of Alabama at Birmingham, 674 Wallace Tumor Institute, Birmingham, Alabama, USA

    T Zhou

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  1. S A Kaliberov
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Correspondence to D J Buchsbaum.

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Conflict of Interest

DJB has intellectual property interest related to the TRA-8 anti-DR5 antibody.

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Kaliberov, S., Chiz, S., Kaliberova, L. et al. Combination of cytosine deaminase suicide gene expression with DR5 antibody treatment increases cancer cell cytotoxicity. Cancer Gene Ther 13, 203–214 (2006). https://doi.org/10.1038/sj.cgt.7700874

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