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 journalArticle

    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

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    Prodrugs
    Oxidoreductases
    Neoplasms
    DNA
    Therapeutics
    Crystallography
    Niacinamide
    Maximum Tolerated Dose
    Alkylating Agents
    Alkylation
    Drug Combinations
    Transaminases
    Diarrhea
    Appointments and Schedules
    Magnetic Resonance Spectroscopy
    Pharmacokinetics
    Bone Marrow
    X-Rays
    benzoquinone
    Tissue Donors

    ASJC Scopus subject areas

    • Medicine(all)

    Cite this

    Middleton, M. R., Knox, R., Cattell, E., Oppermann, U., Midgley, R., Ali, R., ... Kerr, D. J. (2010). Quinone oxidoreductase-2-mediated prodrug cancer therapy. Science Translational Medicine, 2(40), [40ra50]. https://doi.org/10.1126/scitranslmed.3000615

    Quinone oxidoreductase-2-mediated prodrug cancer therapy. / Middleton, Mark R.; Knox, Richard; Cattell, Emma; Oppermann, Udo; Midgley, Rachel; Ali, Raghib; Auton, Tim; Agarwal, Roshan; Anderson, David; Sarker, Debashis; Judson, Ian; Osawa, Tsuyoshi; Spanswick, Victoria J.; Davies, Scot; Hartley, John A.; Kerr, David J.

    In: Science Translational Medicine, Vol. 2, No. 40, 40ra50, 14.07.2010.

    Research output: Contribution to journalArticle

    Middleton, MR, Knox, R, Cattell, E, Oppermann, U, Midgley, R, Ali, R, Auton, T, Agarwal, R, Anderson, D, Sarker, D, Judson, I, Osawa, T, Spanswick, VJ, Davies, S, Hartley, JA & Kerr, DJ 2010, 'Quinone oxidoreductase-2-mediated prodrug cancer therapy', Science Translational Medicine, vol. 2, no. 40, 40ra50. https://doi.org/10.1126/scitranslmed.3000615
    Middleton MR, Knox R, Cattell E, Oppermann U, Midgley R, Ali R et al. Quinone oxidoreductase-2-mediated prodrug cancer therapy. Science Translational Medicine. 2010 Jul 14;2(40). 40ra50. https://doi.org/10.1126/scitranslmed.3000615
    Middleton, Mark R. ; Knox, Richard ; Cattell, Emma ; Oppermann, Udo ; Midgley, Rachel ; Ali, Raghib ; Auton, Tim ; Agarwal, Roshan ; Anderson, David ; Sarker, Debashis ; Judson, Ian ; Osawa, Tsuyoshi ; Spanswick, Victoria J. ; Davies, Scot ; Hartley, John A. ; Kerr, David J. / Quinone oxidoreductase-2-mediated prodrug cancer therapy. In: Science Translational Medicine. 2010 ; Vol. 2, No. 40.
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