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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA045164-10
Application #
2667901
Study Section
Cancer Centers and Research Programs Review Committee (CCRP)
Project Start
1987-09-01
Project End
2001-02-28
Budget Start
1998-03-01
Budget End
1999-02-18
Support Year
10
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Roswell Park Cancer Institute Corp
Department
Type
DUNS #
City
Buffalo
State
NY
Country
United States
Zip Code
14263
Dong, Yan; Ganther, Howard E; Stewart, Carleton et al. (2002) Identification of molecular targets associated with selenium-induced growth inhibition in human breast cells using cDNA microarrays. Cancer Res 62:708-14
Zhu, Zongjian; Jiang, Weiqin; Ganther, Howard E et al. (2002) Mechanisms of cell cycle arrest by methylseleninic acid. Cancer Res 62:156-64
Ganther, H E (2001) Selenotyrosine and related phenylalanine derivatives. Bioorg Med Chem 9:1459-66
Block, E; Birringer, M; Jiang, W et al. (2001) Allium chemistry: synthesis, natural occurrence, biological activity, and chemistry of Se-alk(en)ylselenocysteines and their gamma-glutamyl derivatives and oxidation products. J Agric Food Chem 49:458-70
Dong, Y; Lisk, D; Block, E et al. (2001) Characterization of the biological activity of gamma-glutamyl-Se-methylselenocysteine: a novel, naturally occurring anticancer agent from garlic. Cancer Res 61:2923-8
Ganther, H; Ip, C (2001) Thioredoxin reductase activity in rat liver is not affected by supranutritional levels of monomethylated selenium in vivo and is inhibited only by high levels of selenium in vitro. J Nutr 131:301-4
Jiang, W; Zhu, Z; Ganther, H E et al. (2001) Molecular mechanisms associated with Se-allylselenocysteine regulation of cell proliferation and apoptosis. Cancer Lett 162:167-73
Unni, E; Singh, U; Ganther, H E et al. (2001) Se-methylselenocysteine activates caspase-3 in mouse mammary epithelial tumor cells in vitro. Biofactors 14:169-77
Ganther, H E (2001) Selenium metabolism and mechanisms of cancer prevention. Adv Exp Med Biol 492:119-30
Medina, D; Thompson, H; Ganther, H et al. (2001) Se-methylselenocysteine: a new compound for chemoprevention of breast cancer. Nutr Cancer 40:12-7

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