Carcinogenesis in the skin can be induced by the sequential application of a subthreshhold dose of a carcinogen followed by repetitive treatment with a noncarcinogenic tumor promoter. The latter stage, promotion, can be subsequently divided into two stages, conversion and propagation. This multi-stage system has not only provided an important model for studying mechanisms of carcinogenesis, but is also one of the best systems for investigating the effects of inhibitors of chemical carcinogenesis. It is the objective of this proposal to utilize this system to probe the role of reactive oxygen species in the promotion process by assessing the action of a novel class of compounds, biomimetic superoxide dismutase, as antitumor promoters. Low molecular weight, lipophilic, copper complexes catalyze the disproportionation of the oxygen radical, superoxide anion, in chemical as well as cellular systems and are effective inhibitors of tumor promotion in mouse skin.
The specific aims of this proposal are to define the stage(s) of antipromoter activity for biomimetic superoxide dismutase as well as the specificity of inhibition by examining its action against phorbol ester, benzoyl peroxide, anthralin, phenol and dihydroteleocidin B tumor promoters. Biochemical effects of biomimetic superoxide dismutases on factors influencing oxygen radical metabolism and reactivity in epidermis will also be assessed. Finally, a series of biomimetic superoxide dismutases will be synthesized to define the importance of lipophilicity and stability in vivo in their anticarcinogenic action. These studies should lead to a better understanding of antioxidant mechanisms for the inhibition of carcinogenesis and will provide a new perspective in the development of chemopreventive agents.
