Quinone oxidoreductase-2-mediated prodrug cancer therapy

Mark R. Middleton, Richard Knox, Emma Cattell, Udo Oppermann, Rachel Midgley, Raghib Ali, Tim Auton, Roshan Agarwal, David Anderson, Debashis Sarker, Ian Judson, Tsuyoshi Osawa, Victoria J. Spanswick, Scot Davies, John A. Hartley, David J. Kerr

Research output: Contribution to journalArticlepeer-review

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 the activated prodrug exerts its cytotoxic properties through DNA base alkylation.

Original languageEnglish (US)
Article number40ra50
JournalScience Translational Medicine
Volume2
Issue number40
DOIs
StatePublished - Jul 14 2010

ASJC Scopus subject areas

  • Medicine(all)

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