The induction of ornithine decarboxylase as an early, possibly obligatory, event in mouse skin carcinogenesis.

may be a phenotypic change essential for carcinogenesis in mouse skin. A single, topical application of croton oil or its active component , 12-O-tetracanoyl-phonbol-1 3-acetate (TPA), me suIts in a rapid and substantial increase in mouse epidermal omnithine decarboxylase activity. At 5 hr after TPA applica tion, this enzyme activity, which is the first and rate-limiting step in polyamine biosynthesis, is nearly 250 times greaten than the control level. The 2nd enzyme in the polyamine biosynthetic pathway, S-adenosyl-L-methionine decanbox ylase, 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 ex peniments with inhibitors of protein and RNA synthesis mdi date that the increased enzymatic activities are dependent on RNA and protein synthesis. The magnitude of the enzyme inductions, especially omni thine decanboxylase, 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 phor bol esters, also are capable of inducing these enzymes. On the other hand, hyperplastic agents such as acetic acid, canthanidin, and ethyl phenylpropniolate, which promote weakly on not at all, had little on no effect on omnithine decanboxylase activity, but did induce S-adenosyl-L-methio nine decamboxylase in a manner similar to the active pro motems, croton oil and TPA. Studies with 2 dose levels of carcinogenic hydrocarbons indicated that only a high, com pletely carcinogenic dose induced onnithine decarboxylase activity, while a subcamcinogenic, initiating dose was inef fective. High doses of noncarcinogenic hydrocarbons and unethan, an initiator of mouse skin cancinogenesis, were also without effect. Tumors produced by the 2-stage treat ment procedure exhibited high levels of ornithine decam boxylase 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 epi demmalonnithine decamboxylase by tumor-promoting agents I Presented at the Conference ‘‘Early Lesions and the Development of