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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.
Footnotes
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Citation: M. R. Middleton, R. Knox, E. Cattell, U. Oppermann, R. Midgley, R. Ali, T. Auton, R. Agarwal, D. Anderson, D. Sarker, I. Judson, T. Osawa, V. J. Spanswick, S. Davies, J. A. Hartley, D. J. Kerr, Quinone oxidoreductase-2–mediated prodrug cancer therapy.Sci. Transl. Med. 2, 40ra50 (2010).
- Copyright © 2010, American Association for the Advancement of Science
