INHIBITION OF 7-BROMOMETHYLBENZ[A]ANTHRACENE-PROMOTED MOUSE SKIN TUMOR-FORMATION BY RETINOIC ACID AND DEXAMETHASONE

Abstract

Retinoic acid [RA], a potent inhibitor of mouse skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate [TPA], fails to inhibit tumor formation by the complete carcinogen, 7,12-dimethylbenz[a]anthracene (DMBA). To obtain further clues about the nature of the mechanism of the carcinogenic process as well as the mechanism of the effect of RA on tumor promotion, the effect of RA and 2 other modifiers (dexamethasone [dex] and 7,8-benzoflavone) of tumor formation on tumor promotion by 7-bromomethylbenz[a]anthracene (BrMBA) was determined. BrMBA, a structural analog of DMBA, is a weak mouse skin tumor-initiating agent but is a good skin tumor promoter. Application of 10, 100 and 200 nmol of BrMBA twice weekly to DMBA-initiated skin resulted in 0, 1.6 and 2.5 papillomas per mouse, and 0, 44 and 60% of mice had papillomas at the 25th wk of promotion treatment, respectively. Application of 17 nmol of RA or 76 nmol of dex 30 min prior to each twice weekly application of 100 nmol of BrMBA to DEMBA-initiated skin inhibited the formation of skin papillomas by 73 and 100%, respectively. 7,8-Benzoflavone, at a 367-nmol dose, did not inhibit tumor promotion by BrMBA. Application of 200 nmol of BrMBA to mouse skin induced epidermal ornithine decarboxylase (ODC) activity; a peak activity was observed between 8 and 18 h following BrMBA treatment. Application of 17 nmol of RA or 76 nmol of inhibited the induction of ODC activity by BrMBA. 7,8-Benzoflavone did not inhibit the induction of ODC activity by BrMBA. RA and dex, which inhibit tumor promotion by TPA, also inhibited tumor promotion by BrMBA, but the nature of the mechanism of tumor promotion by BrMBA is unclear; BrMBA did not inhibit specific binding of [3H]TPA to the cellular membrane fraction of mouse epidermis.