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

The effects of a selective detoxifier of the proximate oxygenradical, superoxide anion, on the induction of tumors in theskin of CD-1 mice by either the initiation-promotion regimenor the complete carcinogenesis process were investigated. Theprinciple agent of interest, copper (II) (3,5-diisopropylsalicylate)₂(CuDIPS), is a low molecular weight, lipophilic copper coordinationcomplex that catalytically disproportionates superoxide anionat a rate comparable to native CuZn superoxide dismutase (SOD).The protocols used to elicit tumors were: (i) a single applicationof 0.2 µmol of 7,12-dimethylbenz[a]anthracene (DMBA) followedby twice-weekly applications of 12-O-tetradecanoylphorbol-13-acetate(TPA) in an initiation-promotion study, and (ii) either a singleapplication of 3.6 µmol DMBA followed by no further treatmentor weekly applications of 0.2 µmol DMBA in complete carcinogenesisprotocols. Application of 2 µmol CuDIPS 15 min prior tothe initiating dose of DMBA was without significant effect ontumor yield or incidence, whereas application prior to eachdose of TPA substantially reduced tumor incidence and yield.This anti-promoting property of CuDIPS can be attributed toits SOD-mimetic activity in as much as the corresponding zinccoordination complex lacking in SOD activity, zinc (II) (3,5-diisopropylsalicylate)₂,was non-inhibitory. Significant reductions in tumor yield werealso observed when CuDIPS was applied prior to DMBA in eitherof the complete carcinogenesis protocols. Additionally, covalentbinding of [³H]DMBA to epidermal DNA was markedly reduced byCuDIPS pre-treatment, suggesting that the anti-carcinogenicproperties may reflect a perturbation in superoxide anion-dependentmetabolic activation of DMBA. The induction by DMBA of ornithinedecarboxylase activity, a biochemical marker of tumor promoteractivity, was not affected by CuDIPS; however, induction ofornithine decarboxylase by TPA was potently blocked. Collectively,these effects of a biomimetic SOD further implicate reactiveoxygen species at multiple stages in chemical carcinogenesis.