期刊
SCIENCE TRANSLATIONAL MEDICINE
卷 2, 期 40, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.3000615
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资金
- Cancer Research UK [PH1/088, C2259/A9994]
- National Institute for Health Research Biomedical Research Centres at Oxford and Royal Marsden
- Protherics
- Canadian Institutes for Health Research [1097737]
- Canadian Foundation for Innovation
- Genome Canada through the Ontario Genomics Institute
- GlaxoSmithKline
- Karolinska Institutet, the Knut and Alice Wallenberg Foundation
- Ontario Innovation Trust
- Ontario Ministry for Research and Innovation
- Merck Co. Inc.
- Novartis Research Foundation
- Swedish Agency for Innovation Systems
- Swedish Foundation for Strategic Research
- Wellcome Trust
- Cancer Research UK [9994] Funding Source: researchfish
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.
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