copper-bis(3-5-diisopropylsalicylate) and Skin-Neoplasms

The ability of a biomimetic superoxide dismutase agent, copper(II)(3,5-diisopropylsalicylate)2 (CuDIPS), to modulate benzoyl peroxide (BzPo)-induced tumor promotion and progression in mouse skin multistage carcinogenesis was evaluated. The results showed a significant inhibition of tumor incidence by CuDIPS pretreatment during promotion-progression. Different types of tumors were developed: papillomas, keratoacanthomas and squamous cell carcinomas. There was a significant increase in the keratoacanthoma-papilloma ratio when the period of treatment with BzPo was prolonged, which was inhibited by CuDIPS pretreatment. CuDIPS induced a significant inhibition of malignant conversion. Our results suggest that reactive oxygen species could be important in BzPo-induced promotion and progression.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Antineoplastic Agents; Benzoyl Peroxide; Carcinoma, Squamous Cell; Cocarcinogenesis; Female; Incidence; Keratoacanthoma; Mice; Papilloma; Salicylates; Skin Neoplasms

A keratinocyte-mediated mutagenesis assay, and the murine skin multistage carcinogenesis tumor model were used to survey the chemopreventive properties of Cu(II)(3,5-diisopropylsalicylate)2 [CuDIPS] and its analogs. Supplementation of cocultures of newborn SENCAR keratinocytes and Chinese hamster lung fibroblasts (V79 cells) with CuDIPS, 3,5-diisopropylsalicylate (DIPS), and CuSO4 resulted in dose-dependent killings of V79 cells (LD50 of 34, 75, 960 microM, respectively), and inhibitions of benzo[a]pyrene (BP) and 7,12-dimethylbenz[a]anthracene (DMBA) mutagenesis (ED50 of 13, 95, 80 microM, and 40, 125, 110 microM, respectively). Analyses of dose-response curves suggest (i) CuDIPS preferentially inhibits BP mutagenesis; (ii) the antimutagenic activity of CuDIPS towards DMBA and the cytotoxicity of the copper complex are derived from the DIPS component of the chelate; (iii) the antimutagenic activity of CuDIPS towards BP requires both copper and DIPS; and (iv) DIPS and CuDIPS induced cytotoxicity is required for inhibition of mutagenesis. Inhibition of mutagenesis by CuDIPS was not mediated by modulation of promutagen metabolism because antimutagenic concentrations of the chelate had no significant effects on DMBA- and BP-dependent cytotoxicities. Topical pretreatment of SENCAR mice with CuDIPS (100-4000 nmol) 15 min prior to initiation with DMBA or BP resulted in small (38% maximum) non-dose-responsive reductions of papillomas/mouse following 20 weeks of promotion.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Antineoplastic Agents; Benzo(a)pyrene; Cell Line; Cell Survival; Cells, Cultured; Copper; Copper Sulfate; Epidermal Cells; Epidermis; Mice; Mice, Inbred Strains; Mutation; Papilloma; Salicylates; Skin Neoplasms

The present study was designed to compare the skin tumor promoting and epidermal ornithine decarboxylase (ODC) inducing activities of various structural analogs of anthralin (1,8-dihydroxy-9-anthrone) and chrysarobin (1,8-dihydroxy-3-methyl-9-anthrone). Groups of 30 SENCAR mice each were initiated with 7,12-dimethylbenz[a]anthracene and 2 weeks later promoted with once- or twice-weekly applications of various doses of these anthrone derivatives. Carbon-10 (C10)-acyl derivatives of anthralin were active skin tumor promoters in the range of 25-440 nmol per mouse. 10-Acetylanthralin was significantly more active than 10-myristoyl-anthralin at low doses (e.g. 25 and 50 nmol per mouse) and nearly as potent as the unsubstituted compound. Higher doses (greater than or equal to 100 nmol per mouse) of this derivative were toxic, hence, reducing the final papilloma response. On a relative activity scale where anthralin is 1.0, these derivatives had activities that were approximately 0.7 and 0.2, respectively. 10,10-Dipropylanthralin was totally inactive at the doses tested. C6-Substituted derivatives of chrysarobin demonstrated diverse tumor promoting activities when tested in the range of 25-440 nmol per mouse. On a relative activity scale where chrysarobin is 1.0, 6-methoxychrysarobin (physcion anthrone) was approximately 0.9, whereas 6-hydroxychrysarobin (emodin anthrone) had no activity. Chrysophanic acid (1,8-dihydroxy-3-methyl-9,10-anthraquinone) was also inactive as a tumor promoter at the doses tested. In general, the tumor promoting activities of these anthrone derivatives correlated very well with their ability to induce epidermal ODC after a single topical application indicating an important role for this enzyme in skin tumor promotion by anthones. The ability of C10-substituted derivatives of anthralin to undergo base catalyzed oxidation in vitro correlated with both ODC inducing and tumor promoting activities. In addition, copper(II)bis(diisopropylsalicylate) was found to inhibit both ODC induction and skin tumor promotion by chrysarobin. These latter data, when taken together, suggest a role for oxidation at C10 in skin tumor promotion by anthrone derivatives.

Topics: Animals; Anthracenes; Anthralin; Enzyme Induction; Female; Free Radicals; Mice; Ornithine Decarboxylase; Salicylates; Skin; Skin Neoplasms; Structure-Activity Relationship

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.

Topics: Animals; Cells, Cultured; Chromosome Aberrations; DNA; Female; Free Radicals; Leukocytes; Mice; Mice, Inbred Strains; Salicylates; Skin Neoplasms; Superoxides; Tetradecanoylphorbol Acetate

Cu(II) (3,5-diisopropyl salicylate)2 (CuDIPS) which is an anti-inflammatory copper coordination compound (mol. wt. 503) possessing superoxide dismutase (SOD) activity was tested to determine its effect on 7,12-dimethylbenz[a]anthracene (DMBA)-induced initiation of tumors in mouse skin and on mutagenicity to 6-thioguanine resistance in a mouse keratinocyte mediated Chinese hamster V-79 cell system. A single application of CuDIPS (0.4 mg/mouse) administered at a short interval before DMBA application when followed by 20 weeks of promotion by TPA reduced the mouse skin tumor yield by 55%. When DMBA-induced cell-mediated mutagenesis was tested in the presence of CuDIPS a significant reduction in the number of V-79 6-thioguanine resistant mutants was observed.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Benz(a)Anthracenes; Biotransformation; Cocarcinogenesis; Cricetinae; Female; Mice; Salicylates; Skin Neoplasms

A low molecular weight, lipophilic, copper coordination complex with superoxide dismutase-mimetic activity inhibited biochemical and biological actions of a tumor promoter in mouse epidermis. Such inhibitory effects implicate reactive oxygen species in the tumor promotion process.

Topics: Animals; Antineoplastic Agents; Carcinogens; Female; Mice; Ornithine Decarboxylase; Papilloma; Salicylates; Skin Neoplasms; Superoxide Dismutase; Tetradecanoylphorbol Acetate