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The Induction of Ornithine Decarboxylase as an Early, Possibly Obligatory, Event in Mouse Skin Carcinogenesis¹

McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, Wisconsin 53706

A single, topical application of croton oil or its active component, 12-O-tetracanoyl-phorbol-13-acetate (TPA), results in a rapid and substantial increase in mouse epidermal ornithine decarboxylase activity. At 5 hr after TPA application, this enzyme activity, which is the first and rate-limiting step in polyamine biosynthesis, is nearly 250 times greater than the control level. The 2nd enzyme in the polyaminebiosynthetic pathway, S-adenosyl-L-methionine decarboxylase, is also elevated after TPA or croton oil treatment but to a lesser extent and at a later time after treatment. These changes in enzyme activities lead to the accumulation of the polyamines, putrescine and spermidine. The results of experiments with inhibitors of protein and RNA synthesis indicate that the increased enzymatic activities are dependent on RNA and protein synthesis.

The magnitude of the enzyme inductions, especially ornithine decarboxylase, correlates well with the promoting activity of graded doses of TPA and also with the relative promoting abilities of a series of structurally similar phorbol esters. Other promoters, chemically different from the phorbol esters, also are capable of inducing these enzymes. On the other hand, hyperplastic agents such as acetic acid, cantharidin, and ethyl phenylpropriolate, which promote weakly or not at all, had little or no effect on ornithine decarboxylase activity, but did induce S-adenosyl-L-methionine decarboxylase in a manner similar to the active promoters, croton oil and TPA. Studies with 2 dose levels of carcinogenic hydrocarbons indicated that only a high, completely carcinogenic dose induced ornithine decarboxylase activity, while a subcarcinogenic, initiating dose was ineffective. High doses of noncarcinogenic hydrocarbons and urethan, an initiator of mouse skin carcinogenesis, were also without effect. Tumors produced by the 2-stage treatment procedure exhibited high levels of ornithine decarboxylase activity but, in contrast, S-adenosyl-L-methionine decarboxylase activity was not consistently higher in skin tumors than in normal epidermis.

These results strongly suggest that the induction of epidermal ornithine decarboxylase by tumor-promoting agents may be a phenotypic change essential for carcinogenesis in mouse skin.

¹ Presented at the Conference "Early Lesions and the Development of Epithelial Cancer," October 21 to 23, 1975, Bethesda, Md. This work was supported by Grant BC-14 from the American Cancer Society and Grants CA-07175 and CA-05002 from the National Cancer Institute.

² Present address: The Wistar Institute, Philadelphia, Pa. 19104.

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