CHEMOPREVENTION OF CANCER BY ORGANOSELENIUM

本项目的目标是开发有机硒化合物， 最高功效但毒性低，了解作用机制 这种药物在结肠和乳腺癌发生中的作用， 将结果应用于人类。我们早期的研究发现 1，4-亚苯基-双（亚甲基）硒氰酸酯（p-XSC）作为上级的那些 先前在乳腺癌和结肠癌中评价的有机硒化合物 模型我们的研究还表明，化学预防效果和 硒化合物的毒性取决于它们的化学形式， 这表明他们的新陈代谢正在输入 产生生物效应。初步研究表明谷胱甘肽 p-XSC（p-XSe-SG）的结合物在推定的中间代谢产物中， 四硒环蕃（TSC）是p-XSC的代谢物。我们假设 芳基硒醇，从这些代谢物形成的硒的活性形式是 可能负责p-XSC的化学预防活性。在这 p-XSe-SG和TSC的化学预防性能， 将在乳腺癌和结肠癌发生中评价与p-XSC的比较。 这些药剂将是合成的，最大耐受剂量（MTD）为 化合物将被确定，并且p-XSe-SG和TSC的40和80%MTD和 将评价p-XSC的80% MTD的潜在化学预防作用 在乳腺癌的开始和开始后阶段， 结肠癌发生 有机硒化合物显示最高 化学预防指数将进一步评估其有效性， 在乳腺和结肠促进/进展期间给药 致癌作用该试剂还将被表征为其 吸收、排泄和组织分布。抑制机制 结肠和乳腺肿瘤的这种代理将探索。统一 机制假说是（a）有机硒抑制氧化 应激和脂质过氧化调节转录因子， 从而下调环氧合酶（考克斯-2），而环氧合酶又可以增强 细胞凋亡和减少肿瘤发生和（B）有机硒诱导 通过增加DNA胞嘧啶甲基化在异常细胞中凋亡 通过抑制过量的DNA甲基转移酶。

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.