Quinone oxidoreductase-2-mediated prodrug cancer therapy.
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.
Middleton
Mark R
MR
Department of Medical Oncology, Churchill Hospital, Headington, Oxford OX3 7LJ, UK. mark.middleton@medonc.ox.ac.uk
Knox
Richard
R
Cattell
Emma
E
Oppermann
Udo
U
Midgley
Rachel
R
Ali
Raghib
R
Auton
Tim
T
Agarwal
Roshan
R
Anderson
David
D
Sarker
Debashis
D
Judson
Ian
I
Osawa
Tsuyoshi
T
Spanswick
Victoria J
VJ
Davies
Scot
S
Hartley
John A
JA
Kerr
David J
DJ
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*
D000970:Antineoplastic Agents; D001388:Aziridines; D003432:Cross-Linking Reagents; D004273:DNA, Neoplasm; D011355:Prodrugs; C100099:tretazicar; C419642:NRH - quinone oxidoreductase2; D011808:Quinone Reductases