Correlation of the inhibition by retinoids of tumor promoter-induced mouse epidermal ornithine decarboxylase activity and of skin tumor promotion.

Application of the potent tumor promoter, 12-O-tetra decanoylphonbol-13-acetate (TPA), to mouse skin leads to a more than 200-fold increase in epidermal ornithine decan boxylase (EC 4.1.1.17) activity, a phenotypic change pro posed to be essential for skin tumor promotion. The come lation between TPA-induced omnithine decarboxylase activ ity and skin tumor promotion received additional support from our finding that vitamin A acid and its analogs inhibit both TPA-induced onnithine decanboxylase activity and for mation of skin papillomas. The induction of onnithine decarboxylase activity was investigated following multiple applications of TPA to mouse skin initiated with dimethylbenz[ajanthnacene, the regimen followed in initiation-promotion experiments. Or nithine decarboxylase activity was increased to about 600fold during repeated applications of 17 nmol of TPA. Appli cation of 1.7 nmol of netinoic acid 1 hr prior to each treatment with TPA inhibited TPA-induced omnithine decan boxylase activity by 60 to 80%. In tumor induction expeni ments, application of 1.7 or 17 nmol of netinoic acid 1 hr before each promotion with 17 nmol of TPA reduced by 57 and 75%, respectively, the number of papillomas per mouse. In contnast 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 dimethyl benz[ajanthracene did not alter the development of skin tumors. The application of the tnimethylmethoxyphenyl analog of ethyl retinoate, 13-cis-retinoic acid, or the dimethylmeth oxyethylcyclopentenyl analog of retinoic acid 1 hr prior to each TPA application inhibited TPA-induced omnithine de carboxylase activity as well as formation of skin papillomas. The tnimethylhydroxyphenyl analog of ethyl retinoate or the 13-tnifluoromethyltnimethylmethoxyphenyl analog of ethyl netinoate altered neither TPA-induced omnithine decarbox ylase activity nor development of skin papillomas. Treat ment with netinoids 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 neti noids. Furthermore, retinoid treatment specifically inhibited TPA-induced omnithine decarboxylase activity and the me sultant 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 spenmidine and Received August 31, 1978; accepted October 30, 1978. I The work was supported by NIH Grants CA 07175 and CA 22484. 2 Ta wham requests for reprints should be addressed. sperm me. The results indicate that the possible mechanism of prevention of skin papillomas by netinoids involves their ability to inhibit TPA-induced epidermal omnithine decar boxylase activity and the associated elevated putnescine levels. These findings suggest that the assay of the inhibi tion of TPA-induced onnithine decanboxylase activity by netinoids may be a simple, rapid screen for antipromoting properties of new synthetic retinoids.