Quinone oxidoreductase-2-mediated prodrug cancer therapy.

Science Translational Medicine
Mark R MiddletonDavid J Kerr

Abstract

DNA-damaging agents are widely used in cancer treatment despite their lack of tumor specificity. Human NQO2 (quinone oxidoreductase-2) is an atypical oxidoreductase because no endogenous electron donor has been identified to date. The enzyme converts CB1954 [5-(aziridin-1-yl)-2,4-dinitrobenzamide], in the presence of the synthetic nicotinamide cofactor analog EP0152R, to a cytotoxic bifunctional alkylating agent. NQO2 activity in hepatocellular tumor tissue is higher than that in other cancer types by a factor of 6 and higher than that in bone marrow by a factor of 20. Structural data from x-ray crystallography and nuclear magnetic resonance spectroscopy allowed us to construct a model of CB1954 and EP0152R binding to NQO2, which suggested an optimal infusion schedule for a phase I trial combining the two agents. Thirty-two patients were treated, and diarrhea and serum transaminase concentrations defined a maximum tolerated dose for the drug combination. There was a clear pharmacokinetic interaction, with EP0152R inducing a marked increase in clearance of CB1954, in keeping with model predictions. We detected DNA interstrand cross-links caused by nitroreduced CB1954 in tumor biopsies from treated patients, demonstrating that th...Continue Reading

References

Oct 8, 1999·Journal of Chromatography. B, Biomedical Sciences and Applications·D AndersonL W Seymour
Mar 8, 2000·Proceedings of the National Academy of Sciences of the United States of America·M FaigL M Amzel
Oct 8, 2003·Current Pharmaceutical Design·Richard J KnoxDavid J Kerr
Mar 31, 2004·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Daniel H PalmerDavid J Kerr
Dec 8, 2007·Journal of Medicinal Chemistry·Christian LudwigUlrich L Günther

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Citations

Jul 19, 2011·Free Radical Research·Karine ReybierFrançoise Nepveu
Aug 4, 2016·British Journal of Pharmacology·Ali Ryan
Dec 20, 2012·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Jenny WuJohn A Hartley

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