CHEMOPREVENTION OF CANCER BY ORGANOSELENIUM

该项目的目标是开发有机硒化合物与 高效低毒，了解作用机理 这种物质在结肠癌和乳腺癌的发生中并最终翻译成 将结果转化为人类应用。我们早期的研究已经确定 1，4-苯亚甲基-双(亚甲基)硒氰酸酯(p-XSC)的性能优于 有机硒化合物在乳腺癌和结肠癌中的先前评估 模特们。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以何种化学形式存在 表明他们的新陈代谢正在进入 发挥生物效应的。初步研究表明，谷胱甘肽 P-XSC(p-XSE-SG)在一种可能的中间代谢物和 四硒环番(TSC)是p-XSC的代谢产物。我们假设 芳基硒醇，这些代谢物形成的硒的活性形式是 可能对p-XSC的化学预防活性负责。在这 P-XSe-SG和TSC的化学预防性能 与p-XSC的比较将在乳腺癌和结肠癌的发生中进行评估。 这些药物将被合成，最大耐受量(MTDS) 将测定化合物和对-XSe-SG和TSC的40%和80%的MTDS 80%的p-XSC的MTD将被评估其潜在的化学预防作用 乳房启动和启动后阶段的活动和 结肠癌的发生。有机硒化合物显示最高 化学预防指数将在下列情况下进一步评估其疗效 在乳房和结肠的提升/进展期间给药 致癌。该制剂还将根据其 吸收、排泄和组织分布。抑制机制的研究进展 该试剂可用于结肠癌和乳腺肿瘤的研究。统一 机理假说是：(A)有机硒抑制氧化 调节转录因子的应激和脂质过氧化， 从而下调环氧合酶(COX-2)，进而增强 细胞凋亡与减少肿瘤发生和(B)有机硒诱导 DNA胞嘧啶甲基化增加引起的异常细胞的凋亡 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.