CHEMOPREVENTION OF LUNG CANCER BY ORGANOSELENIUM--MODEL STUDIES

吸烟是肺癌的主要致病因素。 初级预防技术必须继续发挥突出作用 在我们减少烟草相关癌症的努力中。由于这些努力 在过去只取得了有限的成功，互补的方法是 来控制肺癌。化学预防是一种合理的 方法，使用合成或天然存在的试剂来抑制 发生临床可检测的肿瘤前事件 癌 流行病学和实验研究表明， 微量元素硒在癌症化学预防中的作用。但 无机硒的化学预防和毒性水平之间的范围 是狭窄的。我们是第一个报道，与无机物相比， 硒化合物、合成有机硒化合物较多 在几种动物的功效研究中有效且耐受性更好 模型系统（乳腺、结肠、肝脏）。最近， 代表性的合成有机硒化合物，1，4- 亚苯基双（亚甲基）硒氰酸酯（rho-XSC）已扩展到 烟草特有亚硝胺4-（甲基亚硝胺）-1 -（3-吡啶基）-1 - 丁酮（NNK）诱导的A/J小鼠肺肿瘤; rho-XSC抑制DNA 小鼠和大鼠肺中的甲基化。rho-XSC还抑制胸苷 蛋白激酶C和蛋白激酶A在体外和几种 细胞培养我们的假设是，饮食rho-XSC可以阻断 代谢活化NNK并抑制肿瘤促进， 进展为了验证我们的假设并模仿西方饮食 模式，我们将在拟议的实验中使用高脂肪饮食。 具体而言，我们的目标是：1）确定化学预防功效 饮食rho-XSC对NNK的起始和起始后阶段的影响- 在A/J小鼠中诱导肺肿瘤发生。除了功效 研究，我们将确定饮食rho-XSC对代谢的影响 NNK和小鼠肺和肝中DNA加合物的形成。（二） 测定饮食rho-XSC对NNK的化学预防功效- 诱发大鼠肺肿瘤。将进行生化调查 如目标1所述;饮食rho-XSC对加合物的影响 将确定肺的相关细胞类型中的形成。第三章 确定膳食rho-XSC对特定细胞色素P45 O的影响 同工酶、转移酶、水解酶和硒依赖型谷胱甘肽 过氧化物酶在大鼠和小鼠肺和肝脏。将优先 参与NNK代谢的酶。4)确定 rho-XSC对蛋白激酶C抑制作用的基础 利用硒-77核磁共振光谱法。我们将 检验rho-XSC与-SH基团的共价结合 可以破坏蛋白质的结构和功能。 的结果 该项目将提供深入了解使用rho-XSC在 未来的肺癌化学预防临床试验

Cigarette smoking is the major causative factor for lung cancer. Primary prevention techniques must continue to take a prominent role in our efforts to reduce tobacco-related cancers. Since such efforts had only limited success in the past, complementary approaches are needed to control lung cancer. Chemoprevention constitutes a plausible approach, using synthetic or naturally occurring agents to inhibit preneoplastic events before the occurrence of clinically detectable cancer. Epidemiological and experimental studies indicate the benefits of the micronutrient selenium in cancer chemoprevention. However, the range between chemopreventive and toxic levels of inorganic selenium is narrow. We were the first to report that, in contrast to inorganic selenium compounds, synthetic organoselenium compounds were more effective and better tolerated in efficacy studies in several animal model systems (mammary, colon, liver). Recently, the efficacy of a representative synthetic organoselenium compound, 1,4- phenylenebis(methylene)selenocyanate (rho-XSC) has been extended to the tobacco-specific nitrosamine 4-(methylnitrosamino)-1 -(3-pyridyl)-1 - butanone (NNK)-induced lung tumors in A/J mice; rho-XSC inhibited DNA methylation in mouse and rat lungs. rho-XSC also inhibited thymidine kinase, protein kinase C, and protein kinase A in vitro and in several cell cultures. Our hypothesis is that dietary rho-XSC can block the metabolic activation of NNK and suppress tumor promotion and progression. To test our hypothesis and to mimic the western dietary pattern, we will use a high-fat diet in the proposed experiments. Specifically, our aims are: 1) Determine the chemopreventive efficacy of dietary rho-XSC on the initiation and post-initiation phases of NNK- induced lung tumorigenesis in A/J mice. In addition to efficacy studies, we will determine the effect of dietary rho-XSC on metabolism of NNK and the formation of DNA-adducts in mouse lung and liver. 2) Determine the chemopreventive efficacy of dietary rho-XSC on NNK- induced lung tumors in rats. Biochemical investigations will be carried out as described in Aim 1; the effect of dietary rho-XSC on adducts formation in relevant cell types of the lung will be determined. 3) Determine the effect of dietary rho-XSC on specific cytochrome P45O isozymes, transferases, hydrolases, and selenium-dependent glutathione peroxidase in the rat and mouse lung and liver. Priority will be given to those enzymes involved in the metabolism of NNK. 4) Determine the basis for the inhibitory effect of rho-XSC on protein kinase C utilizing selenium-77 nuclear magnetic resonance spectroscopy. We will test the hypothesis that the covalent binding of rho-XSC to -SH groups can disrupt protein structure and function. The results of this project will provide insights into the feasibility of using rho-XSC in future clinical trials on lung cancer chemoprevention.