Humans are continually exposed to a wide variety of chemicals, some of which may act as initiators, promoters, cocarcinogens and/or complete carcinogens. Current evidence suggests that tumor promotion plays an important role in the etiology of human cancer. The proposed research is designed to investigate the mechanism of action of the anthracene-derived mouse skin tumor promoters using 1,8-dihydroxy-3-methyl-9-anthrone (chrysarobin) as the prototype. Although much is known about the mechanism of skin tumor promotion by phorbol esters, little is known about the mechanism of action of the anthracene-derived compounds.
The specific aims of the proposal are as follows. The ability of chrysarobin to interact directly or indirectly with phorbol ester bindng sites will be determined. Our preliminary data indicates that chrysarobin does not interact competitively with the phorbol ester receptor. We will examine the ability of chrysarobin to activate a partially purified protein kinase C in vitro and/our to stimulate production of 1,2-diacylglycerol in cultures of mouse epidermal cells. We will also determine the ability of chrysarobin to interact with the Ah-receptor (also called the TCDD-receptor) of mouse epidermal cells. A major emphasis will be to determine if specific, saturable receptors exist for chrysarobin. In this regard, chrysarobin will be radioactively labeled and assayed for specific binding to mouse epidermal particulate and soluble fractions and mouse epidermal cells in culture. After binding assays have been developed the affinity of other structural analogs will be determined by competition experiments. We will als determine the subcellular localization and distribution of specific binding for chrysarobin. Finally, if appropriate, we will further characterize the induction of epidermal ornithine decarboxylase by chrysarobin and its relationship to skin tumor promotion by this class of compounds. This experimental approach will allow us to further test the hypothesis that anthracene derived mouse skin tumor promoters work by a mechanism different than the phorbol esters.
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