LACK OF EFFECT OF RETINOIC ACID AND FLUOCINOLONE ACETONIDE ON MIREX TUMOR PROMOTION INDICATES A NOVEL MIREX MECHANISM

Mirex, a halogenated hydrocarbon, is a potent skin tumor promoter in 7 ,12-dimethylbenz[a]anthracene (DMBA)-initiated mouse skin, In the pres ent study retinoic acid (RA) and fluocinolone acetonide (FA), classica l inhibitors of phorbol ester- and non-phorbol ester-type skin tumor p romoters, were examined for their ability to inhibit mirex tumor promo tion, Female CD-1 mice were initiated with 200 nmol DMBA and promoted with equipotent promoting doses of either 5 nmol 12-O-tetradecanoylpho rbol-13-acetate (TPA) or 200 nmol mirex twice weekly for 25 weeks and RA (2 or 5 nmol), FA (0.5 or 2 nmol) or acetone were applied 30 min pr ior to each TPA or mirex dose, TPA-promoted papilloma formation was st rongly inhibited by >70% with both doses of RA and by >90% with both d oses of FA, In contrast, mirex-promoted papilloma formation was not in hibited by either dose of RA or 0.5 nmol FA and 2 nmol FA weakly inhib ited mirex-promoted papillomas by only 32%, TPA- and mirex-promoted pa pillomas that were refractory to RA and FA demonstrated the same incid ence of Ha ras mutation as TPA- or mirex-promoted papillomas without R A and FA treatment, further indicating that the inhibitory activity of RA and FA is promoter-dependent and not solely dependent on mutant Ha -ras, FA (2 nmol) treatment completely abolished TPA-induced epidermal hyperplasia and proliferating cell nuclear antigen (PCNA) S phase-pos itive cells, however, FA had no inhibitory effect on the weak prolifer ative response induced by mirex, Collectively, these results indicate that the promotional activity of mirex, as well as its weak proliferat ive response, result from a distinct promoter mechanism and/or that mi rex promotes a unique population of epidermal cells that are insensiti ve to FA and RA and cannot be distinguished by their mutant Ha-ras gen otype.