The overall goal of this multi-institutional program project is to develop novel selenium compounds with high anticarcinogenic activity and low toxicity, and to delineate the mechanisms of action by which selenium protects against tumorigenesis. Five independent laboratories will form a collaborative network in working towards this objective. The novel selenium compounds to be evaluated include both synthetic and naturally- occurring chemicals. With respect to the first category, our ongoing research suggests that a lipophilic selenonium ion has many attributes of an effective and desirable anticancer agent. Thus a major emphasis of the renewal will be focused on this class of compound. In view of the previous findings that a high selenium-garlic (cultivated with selenite fertilization) is capable of delivering selenium both as an anticarcinogen and an essential nutrient, the characterization of the chemical composition of selenium in the garlic is also targeted as a priority area. PROJECT 1 (Dr. Howard Ganther) will be charged with the task of supplying the novel synthetic selenium compounds to the other participating laboratories. In addition, it will study the in vivo metabolism of these compounds and the biochemistry underlying their metabolic reactions. PROJECT 2 (Dr. Eric Block) will be responsible for identifying the garlic selenium compounds, and for their synthesis so that they will be available for biological evaluation PROJECT 3 (Dr. Henry Thompson) will provide an in vitro mammary tumor cell model for screening the new compounds with the use of a number of cellular and molecular endpoints. The information obtained will guide the selection of candidate compounds for further investigation in the animal model. A second component of this project is to understand how selenium might modulate the pathogenetic pathway of mammary carcinogenesis by studying the processes of clonal expansion and clonal selection. PROJECT 4 (Dr. Clement Ip) will have the assignment of carrying out animal tolerance toxicity experiments, mammary cancer chemoprevention efficacy bioassays, as well as carcinogen activation and detoxification studies. PROJECT 5 (Dr. Daniel Medina) will examine the ability of selenium compounds to regulate gene expression in mammary cells by the mRNA differential display-PCR method. Subsequent characterization of the cDNAs will involve Northern blotting, nucleotide sequencing of full-length mRNA and functional analysis by transfection studies.
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