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British Journal of Radiology (2008) 81, S45-S56
© 2008 British Institute of Radiology
doi: 10.1259/bjr/55070206
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British Journal of Radiology 81 (2008),S45-S56 ©2008 The British Institute of Radiology

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Gene therapy approaches to enhance bioreductive drug treatment

R L Cowen, PhD1, E J Garside, PhD1, B Fitzpatrick, BSc1, M V Papadopoulou, PhD2 and K J Williams, PhD1

1 Department of Pharmacy and Pharmaceutical Sciences, University of Manchester, Oxford Rd, Manchester M13 9PT, UK and 2 Department of Radiation Medicine, Evanston Northwestern Healthcare, Evanston, Illinois 60201, USA

Correspondence: R L Cowen, Department of Pharmacy and Pharmaceutical Sciences, University of Manchester, Oxford Rd, Manchester, M13 9PT, UK. E-mail: Rachel.cowen{at}manchester.ac.uk

Hypoxia, or a lack of oxygen, occurs in 50–60% of solid human tumours. Clinical studies have shown that the presence and extent of hypoxia in a tumour cannot be predicted by size or histopathological stage but it is predictive of a poor outcome following radiotherapy, chemotherapy and surgery. However, as a physiological feature of tumours, it can be exploited and researchers have developed many hypoxia-selective chemotherapies or bioreductive drugs that are in varying stages of clinical development. These agents are prodrugs that have two key requirements for their biological activation: they require the reductive environment of a hypoxic tumour cell and the appropriate complement of cellular reductase enzymes. To overcome tumour heterogeneity in reductase enzyme levels and enhance bioreductive drug metabolism a gene therapy strategy can be employed. We have reviewed this field and also present our own pre-clinical research using gene therapy to enhance bioreductive drug treatment for the treatment of cancer. We have specifically focused on studies enhancing lead clinical bioreductive drugs. We consider the metabolic requirements for their activation and we highlight the key in vivo studies supporting the future clinical development of hypoxia-targeted gene-directed enzyme prodrug therapy.






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