Meyer S A, Kim T W, Moser G J, Monteiro-Riviere N A, Smart R C
Department of Toxicology, North Carolina State University, Raleigh 27695-7633.
Carcinogenesis. 1994 Jan;15(1):47-52. doi: 10.1093/carcin/15.1.47.
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.
灭蚁灵是一种有机氯杀虫剂和非遗传毒性啮齿动物肝癌致癌物，也是小鼠皮肤肿瘤的一种强效非佛波酯型促癌剂。与大多数其他皮肤肿瘤促癌剂不同，即使在最大促癌剂量（200纳摩尔）下，灭蚁灵也不是显著的表皮增生剂。本文所述实验研究了灭蚁灵和12-O-十四烷酰佛波醇-13-乙酸酯（TPA）的促癌作用是否通过不同机制介导，这可由它们共同应用于7,12-二甲基苯并[a]蒽（DMBA，200纳摩尔）引发的雌性CD-1小鼠皮肤时的相加性来表明。对于分别用灭蚁灵（200纳摩尔）或TPA（2纳摩尔）促癌20周（每周2次）的小鼠，预计每只小鼠有14 + 5个肿瘤的相加反应，但它们共同应用时每只小鼠产生了35个肿瘤。与TPA的这种协同作用是灭蚁灵特有的，因为结构相关的化合物十氯酮（开蓬）没有活性。灭蚁灵加TPA促发的乳头状瘤中c-Ha-ras A182→T突变的频率（13/14）与单独用灭蚁灵或TPA促发的乳头状瘤一样高，这表明这些DMBA引发/共同促发的乳头状瘤在这个基因型标记上并非不典型。仅在2纳摩尔TPA的次最大促癌剂量下观察到与灭蚁灵的促癌协同作用；5或8纳摩尔TPA加灭蚁灵产生相加或更低的肿瘤发生率。灭蚁灵加2纳摩尔TPA的这种协同发生率（每只小鼠35个肿瘤）接近对200纳摩尔灭蚁灵（每只小鼠14个肿瘤）和TPA最大促癌剂量（12纳摩尔）的单独反应之和，即每只小鼠24个肿瘤，这表明灭蚁灵增强了TPA的促癌活性，以及通过一种灭蚁灵特异性机制发挥促癌作用。2纳摩尔TPA诱导的表皮DNA合成被灭蚁灵增强，进一步支持了灭蚁灵在增强表皮TPA活性方面的作用。总体而言，这些研究表明灭蚁灵影响两种可能相关的反应：（i）通过一种独特的灭蚁灵特异性机制发挥促癌作用，以及（ii）增强介导TPA促癌活性的一种机制。
