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Effects of 3-Isobutyl-1-methylxanthine and Cyclic Nucleotides on the Biochemical Processes Linked to Skin Tumor Promotion by 12-O-Tetradecanoylphorbol-13-acetate¹

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

The phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX), which enhances 12-O-tetradecanoylphorbol-13-acetate (TPA)-stimulated cyclic nucleotide levels and ornithine decarboxylase (L-ornithine carboxy-lyase, EC 4.1.1.17) activity in mouse epidermis in vivo, was tested for its ability to modify the process of skin carcinogenesis using the initiation-promotion (two-step) model system for the production of skin tumor in mice.

Topical application of 10 µmol of IBMX prior to each promotion with 8.5 nmol of TPA reduced by 78% the number of papillomas per mouse. The inhibition was dose dependent. All phosphodiesterase inhibitors tested inhibited the development of skin papillomas. Topical applications of guanosine cyclic 3':5'-monophosphate and/or adenosine cyclic 3':5'-monophosphate before each treatment with TPA were also very effective in inhibiting the formation of skin papillomas. Combined treatments including IBMX, guanosine cyclic 3':5'-monophosphate, and adenosine cyclic 3':5'-monophosphate reduced by 98% the incidence of skin papillomas promoted by TPA. However, IBMX treatment 24 hr after each promotion with TPA did not suppress the formation of skin papillomas. Furthermore, repeated applications of IBMX before or after initiation with 7,12-dimethylbenz[a]anthracene did not alter the development of skin tumors.

These results indicate that phosphodiesterase inhibitors and cyclic nucleotides inhibit the promotion of skin papillomas. Indeed, these modifiers act on some of the biochemical events proposed to be necessary components of the carcinogenesis process. They inhibit dramatically both TPA-increased polyamine levels and TPA-stimulated RNA, protein, and DNA synthesis. Combined treatments including IBMX and cyclic nucleotides produced additive inhibitions of polyamine, RNA, protein, and DNA synthesis in relation with their greater reduction of the formation of skin papillomas. Since IBMX and cyclic AMP block the usual accumulation of putrescine and spermidine produced by TPA in mouse epidermis in vivo and inhibit the activity of ornithine decarboxylase when added in the assay mixture, these compounds may actually interact directly with the enzyme in situ as other ornithine decarboxylase inhibitors do.

¹ This material was presented in part at the Annual Meeting of the American Association for Cancer Research, San Diego, Calif., May 1980 (28). This investigation was sponsored by Grants CA-07175 and CA-22484 from the NIH. This is Paper 2 in a series exploring the role of cyclic nucleotides in the mechanism of action of TPA. Ref. 29 is the preceding paper in this series.

Received 3/18/81. Accepted 7/15/81.

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