The goal of this project is to develop less toxic and more effective chemopreventive organoselenium compounds than the inorganic selenium and those synthesized previously in our laboratory as inhibitors of Cancer. It is hoped that the data generated from this program will be directly relevant to planning and evaluation of these novel compounds as effective agents for preventing cancers of breast, colon and other organs in humans. Selection of the organoselenium compounds proposed in the Program Project is based on structural modification of benzyl selenosyanate (BSC) and 1,4- phenylenebis(methylene)selenocyanate (p-XSC), two established chemopreventive agents against colon and mammary cancer in rats. In these studies, we demonstrated that organoselenium compounds were less toxic and better chemopreventive agents than Na2SeO3. In the proposed study, the role of steric and/or electronic factors in chemoprevention will be examined by comparing p-XSC with its positional isomers, m-XSC and o-XSC. It was shown that extending the aliphatic side chain from two carbons in sulfur-containing chemopreventive agents (e.g. phenethyl isothiocyanate) to six carbon atoms resulted in a better chemopreventive effect. A similar approach will be adopted in the proposed program project i.e. to enhance lypophilicity. We will extend the aliphatic side chain in BSC. Selenium is an important component of glutathione peroxidase (GSH-Px) whose biochemical function is to protect the cell from oxidative damage. Accordingly, compounds possessing GSH-Px like activity will be synthesized. The above three classes of organoselenium compounds will be synthesized in and tested for their toxicity in Lab Program #1. Organoselenium compounds showing minimum toxicity will be tested for their efficacy in DMBA-induced mammary carcinogenesis (Lab Program #1) and azoxymethane (AOM)-induced colon carcinogenesis (Lab Program #2) in laboratory animal models. Mechanisms of colon and mammary tumor inhibition by these organoselenium compounds will be explored in Lab Programs #1, 2, and 3. Pharmacokinetic studies (metabolism and disposition) of these novel agents will be performed (Lab Program #3). In addition, BSC, p-XSO and novel organoselenium compounds, which show minimal toxicity will be tested for their ability to inhibit oxidative damage to cellular lipids and nucleic acids and to induce (or inhibit) cytochrome P45O isoforms and phase II enzymes of xenobiotic metabolism. These compounds will be further tested for their inhibitory effect on 2-nitropropane-and ferric nitrilotriacetic acid-induced liver and kidney carcinogenesis (Lab Program #3).
