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Direct retroviral delivery of human cytochrome P450 2B6 for gene-directed enzyme prodrug therapy of cancer

Cancer Gene Therapy volume 8, pages 473–482 (2001)Cite this article

Abstract

Human cytochrome P450 2B6 (CYP2B6) metabolizes the prodrug cyclophosphamide (CPA) to produce phosphoramide mustard that cross-links DNA leading to cell death. We have constructed a novel retroviral vector encoding CYP2B6 (designated “MetXia-P450”) and used it to transduce the human tumor cell lines HT29 and T47D. MetXia-P450 transduction sensitised these cells to the cytotoxic effects of the prodrug CPA. Results from in vitro experiments demonstrated adverse effects on the clonogenic survival of cyclophosphamide-treated cells transduced with MetXia-P450. Cytotoxic activity accompanied by bystander effect was particularly evident in 3-D multicellular spheroid models suggesting that this in vitro system may be a more appropriate model for assessing the efficacy of gene directed-enzyme prodrug therapy (GDEPT). We have applied this approach in a clinically relevant gene therapy protocol on established subcutaneous tumor xenografts. These studies show for the first time the efficacy of a P450-based GDEPT strategy mediated by a direct retroviral gene transfer in vivo. Cancer Gene Therapy (2001) 8, 473–482

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Acknowledgements

The authors thank David Waxman for scientific advice, CAMR, Salisbury, UK for performing the in vivo studies, Richard Jones and colleagues at Covance Laboratories Ltd, Harrogate, UK for conducting the toxicological studies to GLP, Emma Carter for technical assistance, Diana Cusack and Rachel Harrison for secretarial assistance.

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  1. Oxford Biomedica (UK) Ltd., Medawar Centre, Oxford Science Park, Oxford, OX4 4GA, UK

    On Kan, Leigh Griffiths, Dilair Baban, Sharifah Iqball, Mark Uden, Hayley Spearman, Jason Slingsby, Toby Price, Margaret Esapa, Susan Kingsman, Alan Kingsman, Andrew Slade & Stuart Naylor

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  1. On Kan
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  2. Leigh Griffiths
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  3. Dilair Baban
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  13. Stuart Naylor
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Correspondence to Stuart Naylor.

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Kan, O., Griffiths, L., Baban, D. et al. Direct retroviral delivery of human cytochrome P450 2B6 for gene-directed enzyme prodrug therapy of cancer. Cancer Gene Ther 8, 473–482 (2001). https://doi.org/10.1038/sj.cgt.7700329

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