CHEMOPREVENTION OF COLON CANCER BY SELECTED ORGANOSELENIUM COMPOUNDS

总体目标是开发一种最低成本的有机硒化合物。 对结肠癌的毒性和最大的化学预防效果， 并了解该药抑制肿瘤的机制。我们的 研究表明，1，4-亚苯基双(亚甲基)硒氰酸酯(p-XSC) 抗结肠癌作用优于其他有机硒化合物。 我们假设谷胱甘肽对p-XSC的新陈代谢导致 推定的谷胱甘肽结合物(p-XSE-SG)和/或代谢物的形成 在p-XSC中，四硒环芳烃(TSC)负责其 化学预防活动。最初，这两者的40%和80%的MTD水平 药剂和80%的p-XSC(母体化合物)的MTD将被评估其 启动和启动后阶段的化学预防效果 AOM诱导的结肠癌发生。饲喂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，除赋形剂处理组外，所有动物均将 皮下注射，AOM(15 mg/kg体重，每周1次，连续2周)和1 一周后，控制饮食的动物将被转移到有机硒 饮食和有机硒饮食将转移到对照 饮食，并继续这种养生法，直到50周，并牺牲。 将对结肠肿瘤进行组织病理学评估，并 化学预防指数最高的有机硒将是 在晋升/晋升阶段进行评估。一群5周大的雄性 F344大鼠将以高脂饮食喂养。7周龄组大鼠 每一饮食组都将接受S.C.AOM如上所述。十四周 稍后，高脂肪饮食的动物群体将转移到高脂肪饮食 含有机硒化合物和不含有机硒化合物的饮食 治疗方案，直至本研究结束。动物将在30岁时被献祭 第二次注射AOM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。结肠癌抑制作用机制的研究进展 还将对此化合物进行检测。这些方面将包括 结肠粘膜和肿瘤的测定(A)谷胱甘肽过氧化物酶(B) 环氧合酶(COX-1和COX-2)同工酶(C)细胞凋亡和(D)F/2- 异前列腺素作为脂质过氧化和氧化损伤的指示物； 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.