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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 publication

DOI

10.1126/scitranslmed.3000615

Type

Journal article

Journal

Science translational medicine

Publication Date

07/2010

Volume

2

Addresses

Department of Medical Oncology, Churchill Hospital, Headington, Oxford OX3 7LJ, UK. mark.middleton@medonc.ox.ac.uk

Keywords

Humans, Neoplasms, Aziridines, Quinone Reductases, DNA, Neoplasm, Antineoplastic Agents, Prodrugs, Cross-Linking Reagents, Crystallography, X-Ray, Cell Death, Enzyme Activation, Models, Molecular, Adult, Aged, Middle Aged, Female, Male