title: Quinone oxidoreductase-2-mediated prodrug cancer therapy.
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.
authors.affiliation: Department of Medical Oncology, Churchill Hospital, Headington, Oxford OX3 7LJ, UK. mark.middleton@medonc.ox.ac.uk
authors.forename: Mark R
authors.initials: MR
authors.lastname: Middleton
authors.forename: Richard
authors.initials: R
authors.lastname: Knox
authors.forename: Emma
authors.initials: E
authors.lastname: Cattell
authors.forename: Udo
authors.initials: U
authors.lastname: Oppermann
authors.forename: Rachel
authors.initials: R
authors.lastname: Midgley
authors.forename: Raghib
authors.initials: R
authors.lastname: Ali
authors.forename: Tim
authors.initials: T
authors.lastname: Auton
authors.forename: Roshan
authors.initials: R
authors.lastname: Agarwal
authors.forename: David
authors.initials: D
authors.lastname: Anderson
authors.forename: Debashis
authors.initials: D
authors.lastname: Sarker
authors.forename: Ian
authors.initials: I
authors.lastname: Judson
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Osawa
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Spanswick
authors.forename: Scot
authors.initials: S
authors.lastname: Davies
authors.forename: John A
authors.initials: JA
authors.lastname: Hartley
authors.forename: David J
authors.initials: DJ
authors.lastname: Kerr
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001388:Aziridines / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016923:Cell Death / Q000187:drug effects; D003432:Cross-Linking Reagents / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004273:DNA, Neoplasm / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy*; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D011808:Quinone Reductases / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D001388:Aziridines; D003432:Cross-Linking Reagents; D004273:DNA, Neoplasm; D011355:Prodrugs; C100099:tretazicar; C419642:NRH - quinone oxidoreductase2; D011808:Quinone Reductases