The goal of this project is to develop organoselenium compound with highest efficacy but with low toxicity, understand the mechanism of action of this agent in colon and mammary carcinogenesis and ultimately translate the results into human application. Our earlier studies have identified 1,4-phenylene-bis(methylene)selenocyanate (p-XSC) as superior to those organoselenium compounds evaluated previously in mammary and colon cancer models. Our studies also indicated that the chemopreventative efficacy and toxicity of selenium compounds depend on the chemical form in which they are administered, suggesting that their metabolism is importing in exerting biological effects. Preliminary studies suggest that glutathione conjugate of p-XSC (p-XSe-SG) in a putative intermediary metabolite and tetraselenocyclophane (TSC) is a metabolite of p-XSC. We hypothesize that arylselenol, active form of selenium formed from these metabolites is likely to be responsible for p-XSC's chemopreventative activity. In this proposal, the chemopreventative properties of p-XSe-SG and TSC in comparison to p-XSC will be evaluated in mammary and colon carcinogenesis. These agents will be synthesized, maximum tolerated doses (MTDs) of the compounds will be determined and 40 and 80% MTDs of p-XSe-SG and TSC and 80% MTD of p-XSC will be evaluated for their potential chemopreventative activities during initiation and post-initiation phases of mammary and colon carcinogenesis. Organoselenium compound showing highest chemopreventative index will be further evaluated for its efficacy when administered during promotion/progression in mammary and colon carcinogenesis. This agent will also be characterized with respect to its absorption, excretion and tissue distribution. Mechanisms of inhibition of colon and mammary tumors by this agent will be explored. Unified mechanistic hypothesis is that (a) organoselenium inhibits oxidative stress and lipid peroxidation which modulated transcription factors, thereby down regulating cyclooxygenase (COX-2) which in turn can enhance apoptosis and decrease tumorigenesis and (b) organoselenium induces apoptosis in the abnormal cells by increasing DNA cytosine methylation through inhibition of excess DNA methyl transferase.
