MINIMAL ROLE OF ENHANCED CELL-PROLIFERATION IN SKIN TUMOR PROMOTION BY MIREX - A NONPHORBOL ESTER-TYPE PROMOTER

Mirex, a chlorinated hydrocarbon previously used as a systemic insecti cide and flame retardant, is a nongenotoxic hepatocarcinogen in both r ats and mice. In liver, mirex induced biochemical responses and hyperp lasia characteristic of increased cell proliferation, which is consist ent with its role as a liver tumor promoter. We have recently shown th at mirex is a potent nonphorbol ester-type skin tumor promoter in 7,12 -dimethylbenz[a]anthracene (DMBA)-initiated mice. However, unlike its effect in liver, a single topical application of mirex to skin does no t induce the acute biochemical responses, such as increased epidermal DNA synthesis and ornithine decarboxylase activity, indicative of incr eased cell proliferation. Multiple topical applications of mirex over a 1 month period induced only a minimal increase in the number of epid ermal nucleated cell layers, which contrasts with definitive hyperplas ia induced by a comparable tumor-promoting dose of 12-O-tetradecanoylp horbol-13-acetate (TPA). Collectively, these data indicated that mirex is promoting through a novel mechanism. Further evidence that mirex p romotes tumors through a mechanism distinct from that of the prototypi cal skin tumor promoter, TPA, was obtained by examining the effect of their simultaneous co-treatment. The co-application of mirex and TPA y ielded a tumor multiplicity greater than the sum of the responses of e ach promoter individually. In summary, our results demonstrate that mi rex, a carcinogenic and hyperplastic agent in liver, is also a very ef fective tumor promoter in mouse skin, but suggest that mirex operates via a novel mechanism in skin that may involve only a minimal role for enhanced cell proliferation.