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Effect of Inhibitors of Tumorigenesis on the Formation of O⁶-Methylguanine in the Colon of 1,2-Dimethylhydrazine-treated Rats¹

Wayne State University School of Medicine, Detroit, Michigan 48201

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 10⁶/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 their role in cancer prevention.

¹ Supported by the Matilda R. Wilson Fund.

Received 12/12/80. Accepted 8/24/81.