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Oxygen-sensitive enzyme-prodrug gene therapy for the eradication of radiation-resistant solid tumours

Gene Therapy volume 9, pages 946–954 (2002)Cite this article

Abstract

Overwhelming clinical and experimental data demonstrate that tumour hypoxia is associated with aggressive disease and poor treatment outcome as hypoxic cells are refractive to radiotherapy and some forms of chemotherapy. However, hypoxia is rare in physiologically normal tissues representing a tumour-specific condition. To selectively target this therapeutically refractive cell population, we have combined bioreductive chemotherapy with hypoxia-directed gene therapy. We have transfected the human fibrosarcoma cell line, HT1080, with a hypoxia-regulated expression vector encoding the human flavoprotein cytochrome c P450 reductase (HRE-P450R). This conferred hypoxia-dependent sensitivity to the alkylating nitroimidazole prodrug RSU1069 in vitro, with a greater than 30-fold increase in oxic/hypoxic cytotoxicity ratio compared with controls. Xenografts of both the HRE-P450R and empty vector transfectants had comparable hypoxic fractions and were refractive to single dose radiotherapy of up to 15 Gy. However, combining a prodrug of RSU1069 with a reduced radiotherapy dose of 10 Gy represents a curative regimen (50% tumour-free survival; day 100) in the HRE-P450R xenografts. In complete contrast, 100% mortality was apparent by day 44 in the empty vector control xenografts treated in the same way. Thus, an oxygen-sensitive gene-directed enzyme prodrug therapy approach may have utility when incorporated into conventional radiotherapy and/or chemotherapy protocols for loco-regional disease in any tissue where hypoxia is a contra-indication to treatment success.

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Acknowledgements

The collaboration with Albert van der Kogel was initiated via the Biomed II Concerted Action Programme (Development of Methods for the Rapid Analysis of Tumour Oxygenation to Allow Treatment Stratification; contract BMH4983006). Many thanks are due to Hans Peters. The Medical Research Council funded this work.

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Authors and Affiliations

  1. School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, UK

    AV Patterson, KJ Williams, RL Cowen, M Jaffar, BA Telfer & IJ Stratford

  2. Paterson Institute for Cancer Research, Christie Hospital, Manchester, UK

    M Saunders

  3. School of Pharmacy and Chemistry, Liverpool John Moores University, Liverpool, UK

    R Airley

  4. The Gray Laboratory Cancer Research Trust, Mount Vernon Hospital, Northwood, UK

    D Honess

  5. Institute of Radiotherapy, University of Nijmegen, Nijmegen, The Netherlands

    AJ Van der Kogel

  6. Cancer Research UK Molecular Pharmacology Unit, University of Dundee, UK

    CR Wolf

  7. Auckland Cancer Society Research Centre, The University of Auckland, Auckland, New Zealand

    AV Patterson

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Patterson, A., Williams, K., Cowen, R. et al. Oxygen-sensitive enzyme-prodrug gene therapy for the eradication of radiation-resistant solid tumours. Gene Ther 9, 946–954 (2002). https://doi.org/10.1038/sj.gt.3301702

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  • DOI: https://doi.org/10.1038/sj.gt.3301702

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