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Bioreductive GDEPT using cytochrome P450 3A4 in combination with AQ4N

Cancer Gene Therapy volume 10, pages 40–48 (2003)Cite this article

Abstract

The bioreductive drug, AQ4N, is metabolized under hypoxic conditions and has been shown to enhance the antitumor effects of radiation and chemotherapy drugs. We have investigated the role of cytochrome P450 3A4 (CYP3A4) in increasing the metabolism of AQ4N using a gene-directed enzyme prodrug therapy (GDEPT) strategy. RIF-1 murine tumor cells were transfected with a mammalian expression vector containing CYP3A4 cDNA. In vitro AQ4N metabolism, DNA damage, and clonogenic cell kill were assessed following exposure of transfected and parental control cells to AQ4N. The presence of exogenous CYP3A4 increased the metabolism of AQ4N and significantly enhanced the ability of the drug to cause DNA strand breaks and clonogenic cell death. Cotransfection of CYP reductase with CYP3A4 showed a small enhancement of the effect in the DNA damage assay only. A single injection of CYP3A4 into established RIF-1 murine tumors increased the metabolism of AQ4N, and when used in combination with radiation, three of nine tumors were locally controlled for >60 days. This is the first demonstration that CYPs alone can be used in a GDEPT strategy for bioreduction of the cytotoxic prodrug, AQ4N. AQ4N is the only CYP-activated bioreductive agent in clinical trials. Combination with a GDEPT strategy may offer a further opportunity for targeting radiation-resistant and chemo-resistant hypoxic tumor cells.

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Acknowledgements

We would like to thank the Cancer Research, UK (Grant no. SP2423/0101), for supporting this research.

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Author notes

  1. Helen O McCarthy, Anita Yakkundi and Verna McErlane: These authors contributed equally to this manuscript.

Authors and Affiliations

  1. Radiation Science Research Group, School of Biomedical Sciences, University of Ulster at Jordanstown, Newtownabbey, County Antrim, UK

    Helen O McCarthy, Anita Yakkundi, Verna McErlane, Ciara M Hughes, Gillian Keilty, Margaret Murray, David G Hirst, Stephanie R McKeown & Tracy Robson

  2. Department of Pharmaceutical and Biological Chemistry, School of Pharmacy, University of London, London, UK

    Laurence H Patterson

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  1. Helen O McCarthy
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Correspondence to Tracy Robson.

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McCarthy, H., Yakkundi, A., McErlane, V. et al. Bioreductive GDEPT using cytochrome P450 3A4 in combination with AQ4N. Cancer Gene Ther 10, 40–48 (2003). https://doi.org/10.1038/sj.cgt.7700522

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