The overall goal of this collaborative chemoprevention project is to test the anticarcinogenic effectiveness of several synthetic selenium compounds and to delineate the mechanism of action by which selenium protects against tumorigenesis. Five independent research programs will interact in a concerted effort in achieving this objective. A multi-pronged approach is proposed, including animal carcinogenesis experiments, in vivo metabolism studies and biochemical investigations at the cellular and molecular level. Program 1 is designed to test the chemopreventive efficacy of novel synthetic selenium compounds, using the dimethylbenz(a)anthracene-induced mammary tumor model in female rats. The theme will be focused on the interaction between selenium and other dietary factors in the modification of mammary cancer risk. To tie in with the animal carcinogenesis data, Program 2 (Dr. Howard Ganther) is aimed at studying the metabolism of selenium compounds at high levels of administration. The emphasis will be on the speciation and quantitation of known metabolites and the identification of new selenium metabolites. In an attempt to delineate the mechanism of action at the molecular level, Dr. Ganther will also examine the incorporation of selenium metabolites into nucleic acids and proteins and the methylation of selenium in selenoproteins. The expression, distribution and localization of selenoproteins in the mammary gland and mammary tumors is the subject of program 3, which will be complemented by studies on the biochemical characterization of selenium in selenoproteins in Program 4. In addition, Dr. Sunde is going to investigate the tissue distribution of selenium and the effect of selenium in inhibiting protein synthesis. The impetus for Program 5 is based on the realization that polyamines are important regulators of neoplastic cell proliferation and that there is recent evidence showing that selenium may interfere with polyamine biosynthesis. Data generated by the different laboratories will be integrated to provide feed-back information for the design the synthesis of more effective selenium compounds. This coordinated approach will allow us to acquire basic knowledge in carcinogenesis/anticarcinogenesis and to translate new insights into practical means for chemoprevention.
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