Dietary induction of NQO1 increases the antitumour activity of mitomycin C in human colon tumours in vivo.
The bioreductive antitumour agent, mitomycin C (MMC), requires activation by reductive enzymes like NAD(P)H:quinone oxidoreductase 1 (NQO1). We used a novel approach to increase MMC efficacy by selectively inducing NQO1 in tumour cells in vivo. CD-1 nude mice were implanted with HCT116 cells, and fed control diet or diet containing 0.3% of the NQO1 inducer, dimethyl fumarate (DMF). The mice were then treated with saline, 2.0, 3.5 or 2.0 mg kg(-1) MMC and dicoumarol, an NQO1 inhibitor. The DMF diet increased NQO1 activity by 2.5-fold in the tumours, but had no effect in marrow cells. Mice given control diet/2.0 mg kg(-1) MMC had tumours with the same volume as control mice; however, mice given DMF diet/2.0 mg kg(-1) MMC had significantly smaller tumours. Tumour volumes in mice given DMF/2.0 mg kg(-1) MMC were similar to those in mice given control diet/3.5 mg kg(-1) MMC. Tumour inhibition was partially reversed in mice given DMF/2.0 mg kg(-1) MMC and dicoumarol. DMF diet/2.0 mg kg(-1) MMC treatment did not increase myelosuppression and did not produce any organ toxicity. These results provide strong evidence that dietary inducers of NQO1 can increase the antitumour activity of bioreductive agents like MMC without increasing toxicity.
Department of Internal Medicine, Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, 675 McDermot Avenue, Winnipeg, Manitoba, Canada R3E 0V9. begleit@cc.umanitoba.ca
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Begleiter
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Leith
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Thliveris
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Digby
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D001853:Bone Marrow / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D001728:Dicumarol / Q000627:therapeutic use; D004035:Diet Therapy; D000069462:Dimethyl Fumarate; D004359:Drug Therapy, Combination; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D005650:Fumarates / Q000008:administration & dosage; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016685:Mitomycin / Q000627:therapeutic use*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D004791:Enzyme Inhibitors; D005650:Fumarates; D016685:Mitomycin; D001728:Dicumarol; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D000069462:Dimethyl Fumarate