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Mutation of Escherichia coli cytosine deaminase significantly enhances molecular chemotherapy of human glioma

Gene Therapy volume 14, pages 1111–1119 (2007)Cite this article

A Corrigendum to this article was published on 05 February 2008

Abstract

Combined treatment using adenoviral (Ad)-directed enzyme/prodrug therapy and radiation therapy has the potential to become a powerful method of cancer therapy. We have developed an Ad vector encoding a mutant bacterial cytosine deaminase (bCD) gene (AdbCD-D314A), which has a higher affinity for cytosine than wild-type bCD (bCDwt). The purpose of this study was to evaluate cytotoxicity in vitro and therapeutic efficacy in vivo of the combination of AdbCD-D314A with the prodrug 5-fluorocytosine (5-FC) and ionizing radiation against human glioma. The present study demonstrates that AdbCD-D314A infection resulted in increased 5-FC-mediated cell killing, compared with AdbCDwt. Furthermore, a significant increase in cytotoxicity following AdbCD-D314A and radiation treatment of glioma cells in vitro was demonstrated as compared to AdbCDwt. Animal studies showed significant inhibition of subcutaneous or intracranial tumor growth of D54MG glioma xenografts by the combination of AdbCD-D314A/5-FC with ionizing radiation as compared with either agent alone, and with AdbCDwt/5-FC plus radiation. The results suggest that the combination of AdbCD-D314A/5-FC with radiation produces markedly increased cytotoxic effects in cancer cells in vitro and in vivo. These data indicate that combined treatment with this novel mutant enzyme/prodrug therapy and radiotherapy provides a promising approach for cancer therapy.

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Abbreviations

Ad:

adenovirus

CD:

cytosine deaminase

CMV:

cytomegalovirus

E. coli :

Escherichia coli

5-FC:

5-fluorocytosine

5-FU:

5-fluorouracil

GDEPT:

gene-directed enzyme/prodrug therapy

IC50:

50% inhibitory concentration

MOI:

multiplicity of infection

TCID50:

50% tissue culture infectious dose

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Acknowledgements

We thank Catherine P Langford for expert technical assistance in the intracranial tumor studies and Sally B Lagan for assistance in preparing the paper. This work was supported in part by NCI SPORE in Brain Cancer Grant P50 CA97247.

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Authors and Affiliations

  1. Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, USA

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

  2. Department of Surgery, Division of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA

    J M Market & G Y Gillespie

  3. Department of Pharmaceutical Sciences and the School of Molecular Biosciences, Washington State University, Pullman, WA, USA

    M E Black

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  1. S A Kaliberov
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Correspondence to D J Buchsbaum.

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Kaliberov, S., Market, J., Gillespie, G. et al. Mutation of Escherichia coli cytosine deaminase significantly enhances molecular chemotherapy of human glioma. Gene Ther 14, 1111–1119 (2007). https://doi.org/10.1038/sj.gt.3302965

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