Effects of the Irreversible Ornithine Decarboxylase Inhibitor,α-Difluoromethylornithine,Aflatoxin B 1,and Choline Deficiency on Hepatocarcinogenesis

Abstract

Liver carcinogenesis was induced in rats by aflatoxin B₁ (AFB₁) enhanced by a choline-deficient diet. In Experiment 1, the ornithine decarboxylase inhibitor, α-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 α-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 γ-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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