CHEMOPREVENTION OF CANCER BY ORGANOSELENIUM

这个项目的目标是开发毒性更小、更有效的 有机硒化合物的化学预防性优于无机硒， 那些以前在我们实验室合成的癌症抑制剂。 希望从这个程序中产生的数据将直接 相关的规划和评价这些新的化合物作为有效的 用于预防人类乳腺癌、结肠癌和其它器官癌的药物。 项目中有机硒化合物的选择 是基于苄基硒代糖（BSC）和1，4- 亚苯基双（亚甲基）硒氰酸酯（p-XSC），两个建立 大鼠结肠癌和乳腺癌的化学预防剂。 在这些 研究表明，有机硒化合物毒性较小， 比Na 2SeO 3更好的化学预防剂。 在拟议的研究中， 空间和/或电子因素在化学预防中的作用将被 通过比较p-XSC与其位置异构体m-XSC和o-XSC来检查。 结果表明，从两个碳原子延伸脂肪族侧链， 含硫化学预防剂（如异硫氰酸苯乙酯） 6个碳原子导致更好的化学预防效果。类似的 在拟议的方案项目中将采用的方法，即提高 亲油性我们将延长BSC中的脂肪族侧链。硒 是谷胱甘肽过氧化物酶（GSH-Px）的重要组成部分， 生物化学功能是保护细胞免受氧化损伤。 因此，具有GSH-Px样活性的化合物将被认为是 合成了上述三类有机硒化合物将被 在实验室程序#1中合成并测试其毒性。 显示最小毒性的有机硒化合物将被测试其 DMBA诱导的乳腺癌发生的有效性（实验室程序#1）， 氧化偶氮甲烷（AOM）诱导的结肠癌发生（实验室程序#2）， 实验动物模型。抑制结肠和乳腺肿瘤的机制 这些有机硒化合物将在实验室程序#1，2， 和3. 这些药物的药代动力学研究（代谢和处置） 将进行新的药物（实验室程序#3）。此外，BSC、p-XSO 和新型有机硒化合物，它们显示出最小的毒性， 测试了它们抑制细胞脂质氧化损伤的能力 和核酸并诱导（或抑制）细胞色素P45 O亚型， 异生物质代谢的第二阶段酶。这些化合物将进一步 测试了它们对2-硝基丙烷和三价铁的抑制作用 氨三乙酸诱导的肝和肾致癌作用（实验室计划 #3）。

The goal of this project is to develop less toxic and more effective chemopreventive organoselenium compounds than the inorganic selenium and those synthesized previously in our laboratory as inhibitors of Cancer. It is hoped that the data generated from this program will be directly relevant to planning and evaluation of these novel compounds as effective agents for preventing cancers of breast, colon and other organs in humans. Selection of the organoselenium compounds proposed in the Program Project is based on structural modification of benzyl selenosyanate (BSC) and 1,4- phenylenebis(methylene)selenocyanate (p-XSC), two established chemopreventive agents against colon and mammary cancer in rats. In these studies, we demonstrated that organoselenium compounds were less toxic and better chemopreventive agents than Na2SeO3. In the proposed study, the role of steric and/or electronic factors in chemoprevention will be examined by comparing p-XSC with its positional isomers, m-XSC and o-XSC. It was shown that extending the aliphatic side chain from two carbons in sulfur-containing chemopreventive agents (e.g. phenethyl isothiocyanate) to six carbon atoms resulted in a better chemopreventive effect. A similar approach will be adopted in the proposed program project i.e. to enhance lypophilicity. We will extend the aliphatic side chain in BSC. Selenium is an important component of glutathione peroxidase (GSH-Px) whose biochemical function is to protect the cell from oxidative damage. Accordingly, compounds possessing GSH-Px like activity will be synthesized. The above three classes of organoselenium compounds will be synthesized in and tested for their toxicity in Lab Program #1. Organoselenium compounds showing minimum toxicity will be tested for their efficacy in DMBA-induced mammary carcinogenesis (Lab Program #1) and azoxymethane (AOM)-induced colon carcinogenesis (Lab Program #2) in laboratory animal models. Mechanisms of colon and mammary tumor inhibition by these organoselenium compounds will be explored in Lab Programs #1, 2, and 3. Pharmacokinetic studies (metabolism and disposition) of these novel agents will be performed (Lab Program #3). In addition, BSC, p-XSO and novel organoselenium compounds, which show minimal toxicity will be tested for their ability to inhibit oxidative damage to cellular lipids and nucleic acids and to induce (or inhibit) cytochrome P45O isoforms and phase II enzymes of xenobiotic metabolism. These compounds will be further tested for their inhibitory effect on 2-nitropropane-and ferric nitrilotriacetic acid-induced liver and kidney carcinogenesis (Lab Program #3).