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Correlation of the Inhibition by Retinoids of Tumor Promoter-induced Mouse Epidermal Ornithine Decarboxylase Activity and of Skin Tumor Promotion¹

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

Application of the potent tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA), to mouse skin leads to a more than 200-fold increase in epidermal ornithine decarboxylase (EC 4.1.1.17) activity, a phenotypic change proposed to be essential for skin tumor promotion. The correlation between TPA-induced ornithine decarboxylase activity and skin tumor promotion received additional support from our finding that vitamin A acid and its analogs inhibit both TPA-induced ornithine decarboxylase activity and formation of skin papillomas.

The induction of ornithine decarboxylase activity was investigated following multiple applications of TPA to mouse skin initiated with dimethylbenz[a]anthracene, the regimen followed in initiation-promotion experiments. Ornithine decarboxylase activity was increased to about 600-fold during repeated applications of 17 nmol of TPA. Application of 1.7 nmol of retinoic acid 1 hr prior to each treatment with TPA inhibited TPA-induced ornithine decarboxylase activity by 60 to 80%. In tumor induction experiments, application of 1.7 or 17 nmol of retinoic acid 1 hr before each promotion with 17 nmol of TPA reduced by 57 and 75%, respectively, the number of papillomas per mouse. In contrast, retinoic acid treatment 24 hr after each TPA treatment did not suppress the formation of skin papillomas. Furthermore, application of retinoic acid at various times relative to the time of initiation with dimethylbenz[a]anthracene did not alter the development of skin tumors.

The application of the trimethylmethoxyphenyl analog of ethyl retinoate, 13-cis-retinoic acid, or the dimethylmethoxyethylcyclopentenyl analog of retinoic acid 1 hr prior to each TPA application inhibited TPA-induced ornithine decarboxylase activity as well as formation of skin papillomas. The trimethylhydroxyphenyl analog of ethyl retinoate or the 13-trifluoromethyltrimethylmethoxyphenyl analog of ethyl retinoate altered neither TPA-induced ornithine decarboxylase activity nor development of skin papillomas. Treatment with retinoids did not result in any sign of local toxicity; also, the average weight of the control mice was identical to the average weight of those treated with retinoids. Furthermore, retinoid treatment specifically inhibited TPA-induced ornithine decarboxylase activity and the resultant increases in putrescine levels, but it did not inhibit TPA-induced S-adenosyl-L-methionine decarboxylase (EC 4.1.1.50) activity and the accumulation of spermidine and spermine.

The results indicate that the possible mechanism of prevention of skin papillomas by retinoids involves their ability to inhibit TPA-induced epidermal ornithine decarboxylase activity and the associated elevated putrescine levels. These findings suggest that the assay of the inhibition of TPA-induced ornithine decarboxylase activity by retinoids may be a simple, rapid screen for antipromoting properties of new synthetic retinoids.

¹ The work was supported by NIH Grants CA 07175 and CA 22484.

² To whom requests for reprints should be addressed.

Received 8/31/78. Accepted 10/30/78.