Synergistic interaction between the non-phorbol ester-type promoter mirex and 12-O-tetradecanoylphorbol-13-acetate in mouse skin tumor promotion.
Mirex, an organochlorine pesticide and non-genotoxic rodent hepatocarcinogen, is also a potent non-phorbol ester-type promoter of mouse skin tumors. Mirex, unlike most other skin tumor promoters, is not a significant epidermal hyperplasiogen even at a maximally promoting dose (200 nmol). Experiments described here examined whether tumor promotion by mirex and 12-O-tetradecanoylphorbol-13-acetate (TPA) are mediated through different mechanisms as indicated by their additivity when co-applied to 7,12-dimethyl-benz[a]anthracene (DMBA, 200 nmol)-initiated female CD-1 mouse skin. Instead of the additive response of 14 plus 5 tumors/mouse predicted from mice promoted for 20 weeks (2x/week) with either mirex (200 nmol) or TPA (2 nmol) respectively, their co-application yielded 35 tumors/mouse. This synergy with TPA was specific to mirex since a structurally related compound, chlordecone (Kepone) was inactive. Mirex plus TPA-promoted papillomas contained a c-Ha-ras A182-->T mutation as frequently (13/14) as those promoted by mirex or TPA alone, suggesting that these DMBA-initiated/co-promoted papillomas were not atypical in this genotypic marker. Promotional synergy with mirex 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 nmol TPA (35 tumors/mouse) approximated the sum of individual responses to 200 nmol mirex (14 tumors/mouse) and the maximally promoting dose of TPA (12 nmol), 24 tumors/mouse, suggesting that mirex potentiated the promotional activity of TPA, as well as promoted through a mirex-specific mechanism. Epidermal DNA synthesis induced by 2 nmol TPA was potentiated by mirex, further supporting a role for mirex in potentiation of epidermal TPA activity. Collectively, these studies suggest that mirex affects two possibly related responses: (i) promotion through a distinct mirex-specific mechanism, and (ii) potentiation of a mechanism mediating the promotional activity of TPA.
Meyer
S A
SA
Department of Toxicology, North Carolina State University, Raleigh 27695-7633.
Kim
T W
TW
Moser
G J
GJ
Monteiro-Riviere
N A
NA
Smart
R C
RC
D000225:Adenine / Q000502:physiology; D000818:Animals; D001483:Base Sequence; D002273:Carcinogens / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D011905:Genes, ras / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008815:Mice, Inbred Strains; D008917:Mirex / Q000633:toxicity*; D008969:Molecular Sequence Data; D009154:Mutation / Q000187:drug effects / Q000235:genetics; D010212:Papilloma / Q000139:chemically induced / Q000235:genetics; D012867:Skin / Q000187:drug effects; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000235:genetics; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity*; D013936:Thymidine / Q000235:genetics
D002273:Carcinogens; D000225:Adenine; D013755:Tetradecanoylphorbol Acetate; D013936:Thymidine; D008917:Mirex