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Urethan Carcinogenesis and Nucleic Acid Metabolism: Factors Influencing Lung Adenoma Induction¹

Department of Experimental Biology, Isaac Wolfson Building, Weizmann Institute of Science, Rehovoth, Israel

Experiments were performed (a) to test the validity of the proposal that urethan (ethyl carbamate) acts by virtue of its conversion to N-hydroxyurethan, and (b) to examine the generality of the reported observations that pyrimidines interfere with lung adenoma formation by urethan.

Conditions were obtained in adult and newborn SWR mice in which the average number of tumors per mouse increased linearly with urethan dose; the number of spontaneous tumors appearing in untreated mice was negligible compared with the number induced by urethan. A comparison of urethan and N-hydroxyure-than, as inducers of lung adenomas when injected into newborn mice, showed that, at low dose levels, N-hydroxyurethan is several times less effective than urethan as a carcinogen. Furthermore, the drug potentiator SKF-525A, which inhibits the activity of certain oxidation-reduction enzymes in liver microsomes, had no effect on the induction of lung adenomas by urethan, but significantly inhibited the carcinogenic action of N-hydroxyurethan.

Thymidine, thymine, and orotic acid were all found to be ineffective in reducing the number of lung adenomas per mouse induced by a single injection of urethan, while aminopterin did not show any enhancing effect on lung adenoma formation by urethan; nor did starvation influence the number of urethaninduced adenomas. However, the reported reduction in spontaneous lung adenoma formation in strain A mice, when these were fed thymine in their drinking water, was confirmed.

It was concluded that urethan rather than N-hydroxyurethan is the more likely proximal carcinogen and that no consistent or general direct effect of pyrimidines on urethan carcinogenesis has yet been established.

¹ This investigation was supported in part by USPHS Research Grant No. CA-05263 from the National Cancer Institute.

² Herbert Sidebotham Research Associate.

Received 4/ 7/65. Revised 3/30/66.

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