CHEMOPREVENTION OF CANCER BY ORGANOSELENIUM

这个项目的目标是开发毒性更低、更有效的 具有化学预防作用的有机硒化合物比无机硒和 那些以前在我们实验室合成的抗癌药物。 希望从这个程序中产生的数据将直接 与规划和评估这些新化合物是否有效有关 用于预防人类乳腺癌、结肠癌和其他器官癌症的药物。 计划项目中有机硒化合物的选择 是基于硒氰酸苄酯(BSC)和1，4-氰基-1，4-氰基硫酸酯的结构修饰。 苯二亚甲基硒氰酸酯(p-XSC)，两个已建立的 预防大鼠结肠癌和乳腺癌的化学预防药物。在这些 研究表明，有机硒化合物毒性较小， 比Na_2SeO_3更好的化学预防药物。在拟议的研究中， 立体和/或电子因素在化学预防中的作用将是 通过比较p-xsc及其位置异构体m-xsc和o-xsc进行了验证。 结果表明，从两个碳原子上延伸出的脂肪族侧链 含硫化学防腐剂(如异硫氰酸苯乙酯) 对六个碳原子的化学预防效果较好。一种类似的 在拟议的计划项目中，将采取加强 嗜热性。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，其 生化功能是保护细胞免受氧化损伤。 因此，具有GSH-PX类似活性的化合物将是 合成的。上述三类有机硒化合物将被 在实验室计划1中合成并测试其毒性。 毒性最小的有机硒化合物将进行测试 对DMBA诱发的乳腺癌的疗效(实验计划1)和 偶氮甲烷(AOM)诱导的结肠癌(实验方案2) 实验动物模型。结肠癌和乳腺肿瘤的抑制机制 通过这些有机硒化合物将在实验计划1、2、 和3.这些药物的药代动力学研究(代谢和处置) 将进行新的代理(实验计划3)。此外，BSC、p-XSO 和新型有机硒化合物，毒性最小的将是 测试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P45O亚型和 异种代谢的II相酶。这些化合物将进一步 测试了它们对2-硝基丙烷和铁的抑制作用 氮三乙酸致肝肾癌(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).