SYNERGISTIC INTERACTION BETWEEN THE NONPHORBOL ESTER-TYPE PROMOTER MIREX AND 12-O-TETRADECANOYLPHORBOL-13-ACETATE IN MOUSE SKIN TUMOR PROMOTION

Mirex, an organochlorine pesticide and non-genotoxic rodent hepatocarc inogen, is also a potent non-phorbol ester-type promoter of mouse skin tumors. Mirex, unlike most other skin tumor promoters, is not a signi ficant epidermal hyper-plasiogen even at a maximally promoting dose (2 00 nmol). Experiments described here examined whether tumor promotion by mirex and 12-O-tetradecanoylphorbol-13-acetate (TPA) are mediated t hrough different mechanisms as indicated by their additivity when co-a pplied to 7,12-dimethyl-benz[a]anthracene (DMBA, 200 mmol)-initiated f emale CD-1 mouse skin. Instead of the additive response of 14 plus 5 t umors/mouse predicted from mice promoted for 20 weeks (2x/week) with e ither mirex (200 nmol) or TPA (2 nmol) respectively, their co-applicat ion yielded 35 tumors/mouse. This synergy with TPA was specific to mir ex since a structurally related compound, chlordecone (Kepone) was ina ctive. Mirex plus TPA-promoted papillomas contained a c-Ha-ras A(182) --> T mutation as frequently (13/14) as those promoted by mirex or TPA alone, suggesting that these DMBA-initiated/co-promoted papillomas we re not atypical in this genotypic marker. Promotional synergy with mir ex was only observed with a submaximal promoting dose of 2 nmol TPA; 5 or 8 nmol TPA plus mirex gave additive or less tumor multiplicities. This synergistic multiplicity with mirex plus 2 mmol TPA (35 tumors/mo use) approximated the sum of individual responses to 200 nmol mirex (1 4 tumors/mouse) and the maximally promoting dose of TPA (12 mmol), 24 tumors/mouse, suggesting that mirex potentiated the promotional activi ty of TPA, as well as promoted through a mirex-specific mechanism. Epi dermal DNA synthesis induced by 2 nmol TPA was potentiated by mirex, f urther supporting a role for mirex in potentiation of epidermal TPA ac tivity. Collectively, these studies suggest that mirex affects two pos sibly related responses: (i) promotion through a distinct mirex-specif ic mechanism, and (ii) potentiation of a mechanism mediating the promo tional activity of TPA.