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The level of O6-methylguanine (O6MeGua) in the colonic DNA of rats treated with 1,2-dimethylhydrazine was determined. The effect of various tumorigenesis inhibitors on the formation of this modified base was also studied. Rats were given a single s.c. injection of 1,2-[14C]dimethylhydrazine. Six hr later, they were killed, and colonic DNA was extracted and analyzed by high-pressure liquid chromatography. The inhibitors tested were disulfiram (DSF), pyrazole, sodium selenite, butylated hydroxyanisole, butylated hydroxytoluene, potassium ascorbate, and 13-cis-retinoic acid. The level of O6MeGua in control rats was 29.9 [(O6MeGua X 10(6)/guanine)]. When rats were fed 0.25% (w/w) DSF, this value was reduced to 10.2, and at 0.5% DSF there was no detectable O6MeGua formed. Injection of pyrazole (40 mg/kg i.p.) 2 hr prior to 1,2-dimethylhydrazine treatment reduced the O6MeGua level to 2.4. All the other tumorigenesis inhibitors had no effect on either O6MeGua levels or the cpm/mg DNA in treated rats. With O6MeGua as a measure of the extent of initiation, these results confirm that DSF and pyrazole inhibit the initiation phase of carcinogenesis. This is to be expected as both have been shown to block the metabolism of azoxymethane, which is a crucial metabolite in the activation of 1,2-dimethylhydrazine. The other substances, all known tumorigenesis inhibitors, may act on the promotional phase of carcinogenesis and are worthy of further study for the role in cancer prevention.
The effect of the fecal stream on intestinal carcinogenesis with azoxymethane was studied in male rats. Colostomies were performed approximately 2 cm distal to the cecum in 50 Sprague-Dawley rats to produce a 20-cm segment of nonfunctional large bowel; an additional 50 animals were left intact. Each of these groups was divided equally and was fed a normal diet or a diet containing 2% cholestyramine by weight. All animals were given azoxymethan s.c. At the end of 7 months all rats were sacrificed. The animals with colostomies developed significantly fewer tumors in the defunctionalized bowel than did intact animals in the same bowel segment. Cholestyramine appeared to increase the tumor yield in the large bowel of the intact animals but had no effect on the number of tumors in the defunctionalized bowel. Further, the intact animals on both dietary regimens developed a greater number of large tumors in the distal 20 cm of bowel. The results show that the fecal stream alters the carcinogenic activity of azoxymethane in the large bowel of the rat. It also appears that the carcinogen can reach its target tissue by a route other than the fecal stream.
