Enhancement of the antineoplastic effect of mitomycin C by dietary fat.
In the present study, we investigated the effects of high dietary fat on the growth of MX-1 heterotransplanted in athymic mice and its response to mitomycin C (MC) treatment. We found that high fat intake (25% corn oil, w/w) significantly increased tumor growth, but at the same time it also increased the tumor response to MC treatment compared to the control low fat diet (5% corn oil, w/w). In the tumors from mice fed either low (5% w/w) or high (25% w/w) fat, MC treatment induced oxidative challenge, indicated by significantly increased tumor total superoxide dismutase, catalase, glutathione peroxidase, and glutathione S-transferase peroxidase activities, as well as increased tumor lipid peroxidation. On the other hand, glutathione reductase activity was inhibited by MC treatment. Some of the enzymes which are known to activate MC, such as cytochrome b5 reductase and DT-diaphorase, were also induced in the tumor by high dietary fat intake. The enzyme activities in hepatic tissues were also altered by dietary fat and MC treatment but to a lesser extent. We conclude that high dietary fat intake could enhance the chemotherapeutic effect of MC by increasing MC-activating enzyme activities. The observed increase in lipid peroxidation after MC treatment in MX-1 human mammary carcinoma implanted in the nude mice could result from the observed inhibited glutathione reductase activity. It is tempting to speculate that this might be another antineoplastic mechanism for MC in addition to its known role as a bioreductive alkylating agent. Alternatively, glutathione reductase may be a target for bioreductive alkylation.
Shao
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Allie M. Lee Laboratory for Cancer Research, Department of Biochemistry/330, University of Nevada, Reno 89557.
Pardini
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Pardini
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D000818:Animals; D003579:Cytochrome Reductases / Q000378:metabolism; D042966:Cytochrome-B(5) Reductase; D004041:Dietary Fats / Q000008:administration & dosage / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005260:Female; D005979:Glutathione Peroxidase / Q000378:metabolism; D015227:Lipid Peroxidation; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016685:Mitomycin / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D009245:NADH Dehydrogenase / Q000378:metabolism; D011897:Random Allocation; D014968:Xanthine Dehydrogenase / Q000378:metabolism; D014969:Xanthine Oxidase / Q000378:metabolism
D004041:Dietary Fats; D016685:Mitomycin; D005979:Glutathione Peroxidase; D014968:Xanthine Dehydrogenase; D014969:Xanthine Oxidase; D003579:Cytochrome Reductases; D042966:Cytochrome-B(5) Reductase; D016660:NAD(P)H Dehydrogenase (Quinone); D009245:NADH Dehydrogenase