The goal of this Project is to define mechanisms by which organoselenium compounds inhibit carcinogenesis at the initiation and post-initiation stages. The compounds to be examined include 1, 4-phenylenebis(methylene) selenocyanate (p-XSC), the glutathione conjugate of p-XSC (p-XSe-SG), and tetraselenocyclophane (TSC), a metabolic product of p-XSC. To this end, our specific aims are: 1. To follow up on our preliminary finding that p-XSC, benzyl selenocyanate (BSC) and sodium selenite are potent inhibitors of DNA cytosine-C/5 methyltransferase (MTase) in extracts of human colon tumors and in cultures of human colon cancer cells. This finding was made using our improved method for determination of Mtase and global DNA methylation. We propose that inhibition of Mtase plays a central (and possibly sufficient) role in the mechanism of cancer chemoprevention by organoselenium and probably also be inorganic selenium. Human colon cancer cell lines HT29 and HCT116 will be used in conjunction with nude mouse xenografts to establish correlations among Mtase activity, global DNA methylation and inhibition of tumor growth. The azoxymethane model of colon cancer induction will be used to determine if changes in Mtase and DNA methylation that occur during carcinogenesis and its inhibition by organoselenium in rats are similar to the changes observed in human colon carcinogenesis. 2. To characterize p-XSe-SG and TSC with respect to their ability to induce or inhibit important enzymes of phase I and phase II metabolism in rodent liver and target tissues. Since chemopreventative agents may act in part by increasing the rate of carcinogen detoxication or by decreasing the rate of carcinogen activation, this information is critical for defining their effects at their initiation stage. 3. To characterize the organoselenium compounds with respect to absorption from the g.i. tract, excretion, and distribution in rodent tissues. Our previous work has shown that structurally similar organoselenium compounds differ dramatically with respect to these parameters. Since their effectiveness in chemoprevention depends on their bioavailability and tissue concentrations, information on absorption and distribution is essential to understanding the modes of action of chemopreventative organoselenium compounds.
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