CHEMOPREVENTION OF COLON CANCER BY SELECTED ORGANOSELENIUM COMPOUNDS

总体目标是开发一种有机硒化合物， 毒性和针对结肠癌的最大化学预防功效， 并了解这种药物抑制癌症的机制。我们 研究表明，1，4-亚苯基双（亚甲基）硒氰酸酯（p-XSC）是 上级于其他有机硒化合物，对结肠癌的预防作用。 我们假设谷胱甘肽对p-XSC的代谢导致了 推定谷胱甘肽结合物（p-XSe-SG）和/或代谢物的形成 p-XSC，四硒环蕃（TSC）负责其 化学预防活性最初，这两种药物的40%和80% MTD水平 药物和80% MTD的p-XSC（母体化合物）将评价其 在启动和启动后阶段的化学预防功效 AOM诱导的结肠癌发生。将喂食5周龄雄性F344大鼠 高脂饮食或40%和80% MTD水平的有机硒化合物， 7周龄时，除溶剂处理组外的所有动物将 皮下给药，AOM（15 mg/kg b.w.，每周一次，持续2周）和一次 一周后，对照饮食的动物将被转移到有机硒 饮食和有机硒饮食将被转移到控制 饮食，并继续该方案直至50周并处死。 将进行结肠肿瘤的组织学评价， 具有最高化学预防指数的有机硒将是 在晋升/进展阶段进行评估。5周龄雄性动物组 F344大鼠将喂食高脂肪饲料。在7周龄组的大鼠中， 每个饮食组将被s.c.处理。与上面一样。十四周 之后，高脂肪饮食的动物组将被转移到高脂肪饮食组， 饮食与不有机硒化合物，并继续在此 直至本研究终止。将在30时处死动物 和第二次AOM注射后50周（终止）。结肠肿瘤 饮食组之间的发病率和多样性将通过以下方式进行比较： 适当的统计方法。抑制结肠肿瘤的机制 也将对该化合物进行检测。这些方面将包括 结肠粘膜和肿瘤的测量（a）谷胱甘肽过氧化物酶（B） 环氧合酶（考克斯-1和考克斯-2）同工酶，（c）凋亡，和（d）F/2- 异前列烷作为脂质过氧化和氧化损伤指标; 和（e）DNA胞嘧啶甲基化和DNA甲基转移酶 不同的时间段。

The overall objective is to develop an organoselenium compound with lowest toxicity and yet maximal chemopreventative efficacy against colon cancer, and to understand the mechanisms of cancer inhibition by this agent. Our studies indicate that 1,4-phenylenebis(methylene)selenocyanate (p-XSC) is superior to other organoselenium compounds against colon carcinogenesis. We hypothesize that the metabolism of p-XSC by glutathione leading to the formation of putative glutathione conjugate (p-XSe-SG) and/or metabolite of p-XSC, tetraselenocyclophane (TSC) are responsible for its chemopreventative activity. Initially, 40 and 80% MTD levels of these two agents and 80% MTD of p-XSC (parent compound) will be evaluated for their chemopreventative efficacy during initiation and post-initiation phases of AOM-induced colon carcinogenesis. Five week old male F344 rats will be fed high-fat diet or 40 and 80% MTD levels of organoselenium compounds and at 7 weeks of age, all animals except vehicle-treated groups will be administered s.c., AOM (15 mg/kg b.w., once weekly for 2 weeks) and one week later, animals on control diet will be transferred to organoselenium diets and those on organoselenium diets will be transferred to control diet and continued on this regimen until 50 weeks and sacrificed. Histopathological evaluation of colon tumors will be performed and organoselenium exhibiting highest chemopreventative index will be evaluated during promotion/progression phase. Groups of 5-week old male F344 rats will be fed a high-fat diet. At 7 weeks of age groups of rats in each dietary group will be treated s.c. with AOM as above. Fourteen weeks later, groups of animals on high-fat diet will be transferred to high-fat diet with and without organoselenium compound and continued on this regimen until termination of this study. Animals will be sacrificed at 30 and 50 (termination) weeks after second AOM injection. Colon tumor incidence and multiplicity among the dietary groups will be compared by appropriate statistical methods. The mechanisms of colon tumor inhibition by this compound will also be examined. These aspects will include measurement of colonic mucosal and tumor (a) glutathione peroxidase (b) cyclooxygenase (COX-1 and COX-2) isozymes (c) apoptosis, and (d) F/2- isoprostane as an indicator of lipid peroxidation and oxidative damage; and (e) DNA cytosine methylation and DNA methyl transferase during different time periods.