Humans are continually exposed to a wide variety of chemicals, some of which may act as initiators, promoters, cocarcinogens, and/or complete carciongens. Current evidence suggest that tumor promotion plays an important role in the etiology of human cancer. Although the phorbol ester promoters have been widely studied, much less is known about the mechanism of action of anthrone tumor promoters. While there are some similarities between phorbol esters and the anthrones we have obtained evidence that there are also some significant differences in their effects on mouse skin. In addition, indirect evidence which we hav obtained suggests that oxidation of anthrones and generation of free radicals is involved in their skin tumor promoting action. The current proposal will continue to explore the mechanism of skin tumor promotion by anthrones. Specifically, we will explore the role of anthrone oxidation and generation of free radicals in skin tumor promotion by this class of compounds. The specific amis of the proposal are as follows: (1) To further characterize skin tumor promotion and progression by anthrone derivatives as follows: a) to examine the regression kinetics of papillomas generated with various treatment protocols; b) to determine the ability of anthrone derivatives to enhance progression of pre- existing papillomas to carcinomas; and c) to further characterize the phenomenon of delayed promotion leading to enchanced promoting activity of anthrones; (2) To determine the ability of anthrones to induce or activate polyamine interconversion pathways in relation to epidermal toxicity and their skin tumor promoting activity; (3) To determine the relationship(s) between epidermal toxicity and anthrone mediated skin tumor promotion; (4) To examine the nonenzymatic and enzymatic mechanisms for oxidation of anthrones in mouse epidermis in relation to skin tumor promotion. Initial experiments indicate an excellent correlation between the ability to undergo base catalyzed oxidation and skin tumor promoting activity; (5) To determine the nature of the reactive products of anthrone oxidation; (6) To determine the ability of anthrones to modulate oxidant defense systems in mouse epidermis; and (7) To determine the ability of antioxidants to modulate skin tumor promotion by anthrones. This experimental approach will allow us to test the hypothesis that anthrone skin tumor promoters work by a mechanism which involves oxidation and subsequent generation of free radical intermediates.
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