Effects of the irreversible ornithine decarboxylase inhibitor, alpha-difluoromethylornithine, aflatoxin B1, and choline deficiency on hepatocarcinogenesis.
Liver carcinogenesis was induced in rats by aflatoxin B1 (AFB1) enhanced by a choline-deficient diet. In Experiment 1, the ornithine decarboxylase inhibitor, alpha-difluoromethylornithine (DFMO), was administered by gavage to one group only during AFB1 administration; another group received DFMO during AFB1 administration and for 2 months after carcinogen administration. These two groups were compared to two control groups, one given AFB1 and fed the choline-deficient diet and another fed the deficient diet only. In a second experiment, DFMO was administered at a concentration of 2% in the water for 3 weeks and then at 1% for the remainder of the study. Rats from each group in Experiment 1 were killed at 2, 8, and 10 months after AFB1 administration and the development of tumors was followed by histology; autoradiography of [3H]thymidine incorporation into DNA; enzyme histochemistry; and alpha-fetoprotein determination. The group given DFMO during AFB1 administration was not significantly different from the AFB1-treated control group at 2 and 8 months after AFB1 administration. However, at 10 months following AFB1 and DFMO administration, the [3H]thymidine-labeling index and glucose-6-phosphatase staining were significantly increased. This group had three animals bearing hepatocellular carcinomas as compared to none in the controls. The group given DFMO for 2 months after AFB1 administration had a significantly depressed growth rate 2 months later, but this difference was not apparent after 8 months. After 10 months, there was a significantly increased [3H] thymidine-labeling index and increased volume fraction of gamma-glutamyltranspeptidase in the AFB1-DFMO-treated group as compared to the controls. DFMO appeared to inhibit growth under some conditions, but if administration was discontinued after AFB1 exposure, it appeared to enhance tumorigenesis. In Experiment 2, where a larger dose of AFB1 was used and DFMO was administered in the water from start to finish of the experiment, DFMO inhibited tumor induction and depressed the appearance of markers examined during carcinogenesis. These data indicate that the regimen used for DFMO administration can markedly affect tumor induction.
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Sondergaard
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Taylor
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Newberne
D016604:Aflatoxin B1; D000348:Aflatoxins / Q000633:toxicity*; D000818:Animals; D002796:Choline Deficiency / Q000150:complications*; D004247:DNA / Q000096:biosynthesis; D000518:Eflornithine; D008099:Liver / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000209:etiology*; D008297:Male; D009952:Ornithine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D009955:Ornithine Decarboxylase / Q000502:physiology; D065108:Ornithine Decarboxylase Inhibitors; D051381:Rats; D011916:Rats, Inbred F344; D013936:Thymidine / Q000378:metabolism; D000509:alpha-Fetoproteins / Q000032:analysis; D005723:gamma-Glutamyltransferase / Q000032:analysis
D000348:Aflatoxins; D065108:Ornithine Decarboxylase Inhibitors; D000509:alpha-Fetoproteins; D004247:DNA; D016604:Aflatoxin B1; D009952:Ornithine; D005723:gamma-Glutamyltransferase; D009955:Ornithine Decarboxylase; D013936:Thymidine; D000518:Eflornithine