Effects of a biomimetic superoxide dismutase on complete and multistage carcinogenesis in mouse skin

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Abstract
The effects of a selective detoxifer of the proximate oxygen radical, superoxide anion, on the induction of tumors in the skin of CD-1 mice by either the initiation-promotion regimen or the complete carcinogenesis process were investigated. The principle agent of interest, Cu (II) (3,5-diisopropylsalicylate)2 (CuDIPS), is a low MW, lipophilic CU coordination complex that catalytically disproportionates superoxide anion at a rate comparable to native Cu-Zn superoxide dismutase (SOD). The protocols used to elicit tumors were: a single application of 0.2 .mu.mol of 7,12-dimethylbenz[a]anthracene (DMBA) followed by twice-weekly applications of 12-O-tetradecanoylphorbol-13-acetate (TPA) in an initiation-promotion study and either a single application of 3.6 .mu.mol DMBA followed by no further treatment or weekly applications of 0.2 .mu.mol DMBA in complete carcinogenesis protocols. Application of 2 .mu.mol CuDIPS 15 min prior to the initiating dose of DMBA was without significant effect on tumor yield or incidence, whereas application prior to each dose of TPA substantially reduced tumor incidence and yield. This anti-promoting property of CuDIPS can be attributed to its SOD-mimetic activity in as much as the corresponding Zn coordination complex lacking in SOD activity, ZN (II) (3,5-diisopropylsalicylate)2, was non-inhibitory. Significant reductions in tumor yield were also observed when CuDIPS was applied prior to DMBA in either of the complete carcinogenesis protocols. Additionally, covalent binding of [3H]DMBA to epidermal DNA was markedly reduced by CuDIPS pre-treatment, suggesting that the anti-carcinogenic properties may reflect a perturbation in superoxide anion-dependent metabolic activation of DMBA. The induction by DMBA of ornithine decarboxylase activity, a biochemical marker of tumor promoter activity, was not affected by CuDIPS; however, induction of ornithine decarboxylase by TPA was potently blocked. Collectively, these effects of a biomimetic SOD further implicate reactive oxygen species at multiple stages in chemical carcinogenesis.

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