On the role of superoxide anion radicals in skin tumour promotion.
The effect of phorbol ester tumour promoters on the release of superoxide anion radicals .O2- by human peripheral leukocytes and the role of such radicals in tumour promotion of mouse skin was studied. No significant difference was found between complete [12-O-tetradecanoylphorbol-13-acetate (TPA)] as compared with incomplete [12-O-retinoylphorbol-13-acetate (RPA), 12-O-(2Z,4E,6,8)tetradecatetraenoylphorbol-13-acetate (Ti8), mezerein] tumour promoters upon induction of .O2- when measured by the reduction of ferricytochrome c. The semisynthetic phorbol esters 12-O-ethacrynylphorbol-13-acetate (EPA) and 4-O-methyl-TPA were less active, and phorbol diacetate, phorbol and ionophore A 23187 were found to be inactive in stimulating superoxide anion radicals. TPA-induced .O2- release from leukocytes was strongly inhibited by Cu(II)-(diisopropylsalicylate)2 (CuDIPS), and, to a lesser extent, by ethacrynic acid, nordihydroguaiaretic acid and quercetin. Retinoic acid exhibited only a moderate inhibitory effect. No .O2- release was observed in epidermal cell cultures upon TPA treatment. When analysed by the alkaline elution technique, TPA-induced .O2- release from leukocytes did not lead to measurable DNA damage in co-cultivated keratinocytes even in the presence of DNA repair inhibitors. In multi-stage-tumourigenesis experiments including two-stage promotion, retinoic acid, ethacrynic acid and CuDIPS were unable to inhibit tumour promotion in mouse skin when applied in combination with TPA in first stage promotion. gamma-Irradiation at a dose level shown to cause DNA damage in vitro could not replace TPA as a stage I-promoting agent. It is concluded that superoxide anion radicals--if related to promotion at all--may play a role in stage II rather than in stage I of mouse skin tumour promotion.
D000818:Animals; D002478:Cells, Cultured; D002869:Chromosome Aberrations; D004247:DNA; D005260:Female; D005609:Free Radicals; D007962:Leukocytes / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D012459:Salicylates / Q000494:pharmacology; D012878:Skin Neoplasms / Q000139:chemically induced*; D013481:Superoxides / Q000633:toxicity*; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity
D005609:Free Radicals; D012459:Salicylates; D013481:Superoxides; C030865:copper bis(3,5-diisopropylsalicylate); D004247:DNA; D013755:Tetradecanoylphorbol Acetate