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Inhibition of [³H]Thymidine Incorporation into DNA of Rat Esophageal Epithelium and Related Tissues by Carcinogenic N-Nitroso Compounds¹

Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, Nebraska 68105

We studied effects on [³H]thymidine incorporation into the DNA of rat esophageal epithelium measured 1 hr after the thymidine injection and expressed as cpm/µg DNA. When various doses of 8 N-nitroso compounds were injected into rats 4 hr before they were killed, the highest doses inhibited the incorporation by 65 to 82%. The dose causing 50% inhibition was 2.3 mg/kg for methyl-n-amylnitrosamine, which is a specific carcinogen for the rat esophagus, and 22 mg/kg for the esophageal noncarcinogen, dimethylnitrosamine (DMN). For all 8 compounds, the dose causing 50% inhibition was positively correlated with total carcinogenic dose and with total carcinogenic dose per percentage of incidence of esophageal tumors, as taken from published experiments in which the test compounds were administered chronically p.o.

Esophageal DNA radioactivity was maximal 60 to 90 min after the [³H]thymidine injection. Thymidine incorporation remained inhibited for 2 days after methyl-n-amylnitrosamine (2.2 mg/kg), but <1 day after DMN (20 mg/kg) was injected and was inhibited after continuous treatment for 2 weeks with methyl-n-amylnitrosamine (2 mg/liter drinking water) or DMN (20 mg/liter).

The inhibition by methyl-n-amylnitrosamine was similar in different regions of the esophagus and was reduced by pretreatment with 3-methylcholanthrene and phenobarbital. Thymidine incorporation, without methyl-n-amylnitrosamine treatment, was inhibited by fasting and by treatment with 3-methylcholanthrene and hydroxyurea, but not with urethan. The methyl-n-amylnitrosamine-DMN difference persisted when whole esophagi or esophageal epithelia were incubated in vitro with methyl-n-amylnitrosamine or DMN and [³H]thymidine. In vivo thymidine incorporation was also inhibited by methyl-n-amylnitrosamine, but only at high doses, in the hamster esophagus, hamster trachea, and rat trachea, but not in the rat forestomach. Similar results were observed for N-nitrosopiperidine in the hamster esophagus and trachea. These results were correlated with organ-specific carcinogenicity in the esophagus but not in the trachea, since nitrosamines mainly induce tracheal tumors in the hamster.

¹ Supported by USPHS Contract NO1 CP33278 from the National Cancer Institute, NIH.

² To whom requests for reprints should be addressed, at Eppley Institute for Research in Cancer, University of Nebraska Medical Center, 42nd Street and Dewey Avenue, Omaha, Nebr. 68105.

³ Present address: Fels Research Institute, Temple University School of Medicine, Philadelphia, Pa. 19140.

Received 3/ 7/77. Accepted 11/10/77.

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