Journal article
The bioreductive prodrug PR-104A is activated under aerobic conditions by human aldo-keto reductase 1C3
CP Guise, MR Abbattista, RS Singleton, SD Holford, J Connolly, GU Dachs, SB Fox, R Pollock, J Harvey, P Guilford, F Doñate, WR Wilson, AV Patterson
Cancer Research | AMER ASSOC CANCER RESEARCH | Published : 2010
Abstract
PR-104, currently in phase II clinical trials, is a phosphate ester pre-prodrug which is converted in vivo to its cognate alcohol, PR-104A, a prodrug designed to exploit tumor hypoxia. Bioactivation occurs via one-electron reduction to DNA crosslinking metabolites in the absence of oxygen. However, certain tumor cell lines activate PR-104A in the presence of oxygen, suggesting the existence of an aerobic nitroreductase. Microarray analysis identified a cluster of five aldo-keto reductase (AKR) family members whose expressions correlated with aerobic metabolism of PR-104A. Plasmid-based expression of candidate genes identified aldo-keto reductase 1C3 as a novel nitroreductase. AKR1C3 protein ..
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Awarded by Health Research Council of New Zealand
Funding Acknowledgements
Health Research Council of New Zealand, Program grant 08/103 (C. P. Guise, G. U. Dachs, W. R. Wilson, and A. V. Patterson) and Proacta, Inc. (M. R. Abbattista, R. Pollock, J. Harvey, P. Guilford, S. Fox, F. Donate).