Comparison of the effects of 3-isobutyl-1-methylxanthine and adenosine cyclic 3':5' -monophosphate on the induction of skin tumors by the initiation-promotion protocol and by the complete carcinogenesis process

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Abstract
Topical application of either 5 .mu.mol of 3-isobutyl-1-methyl-xanthine (IBMX) or 0.25 .mu.mol of cAMP to the initiated skin of the mouse prior to each promotion with 8.5 nmol of 12-O-tetradecanoylphorbol-13-acetate (TPA) inhibited the formation of papillomas and carcinomas. Combined treatments including IBMX and cAMP caused additive reduction of the incidence of skin papillomas and carcinomas promoted by TPA. A good correlation existed between the reduction of the tumor incidence by IBMX and cAMP and their inhibition of TPA-stimulated polyamine, RNA, protein and DNA synthesis. Since repeated treatments with these agents before or after initiation with a single subcarcinogenic dose of 7,12-dimethylbenz[a]anthracene (DMBA) did not alter significantly the development of skin tumors (Curtis et al.; Perchellet and Boutwell). Apparently, in the 2-step initiation-promotion protocol, IBMX and cAMP treatments may decrease specifically the promoting stimulus of skin carcinogenesis. The same doses of IBMX and cAMP inhibited the accumulation of polyamines and the increase in marcromolecular synthesis observed in DMBA-treated skin, but their effect on DMBA-induced skin carcinogenesis was dependent upon the protocol used and the dose of carcinogen applied. IBMX and cAMP treatments failed to inhibit the induction of skin tumors by weekly applications of 0.2 .mu.mol of DMBA. In contrast to the inhibitory effect of cAMP treatment, IBMX enhanced the carcinogenic response to a single topical application of 3.6 .mu.mol of DMBA. The opposite effects of these agents on the carcinogenicity of DMBA correlated well with their different alteration of DMBA-induced unscheduled DNA synthesis in vitro. cAMP (0.5 mM) enhanced, whereas IBMX (0.5 mM) inhibited, the DMBA-induced incorporation of labeled precursor into DNA of isolated epidermal cells during incubation in the presence of hydroxyurea. Evidently the different modulation of DMBA carcinogenesis by IBMX and cAMP may result from concomitant effects on the initiating and promoting components of the carcinogen.