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重要作用。 在我们努力减少与烟草相关的癌症方面。因为这样的努力 过去只取得了有限的成功，互补的方法是 需要控制肺癌。化学预防构成了一个看似合理的 方法，使用合成或自然产生的试剂来抑制 临床可检测的癌前事件发生前的事件 癌症。流行病学和实验研究表明， 微量营养素硒在癌症化学预防中的应用。然而， 无机硒的化学预防水平和中毒水平之间的范围 很窄。我们是第一个报道这一点的，与无机 硒化合物、合成有机硒化合物较多 在几种动物的疗效研究中有效且耐受性更好 模型系统(乳腺、结肠、肝脏)。最近，阿司匹林的疗效 代表性的合成有机硒化合物，1，4- 苯二亚甲基硒氰酸酯(Rho-XSC)已扩展到 烟草特有的亚硝胺4-(甲基亚硝基)-1-(3-吡啶)-1- 丁酮诱发A/J小鼠肺癌；Rho-XSC抑制DNA 小鼠和大鼠肺中的甲基化。Rho-XSC还抑制胸腺嘧啶核苷 蛋白激酶C和蛋白激酶A在体外和几种 细胞培养。我们的假设是饮食中的Rho-XSC可以阻断 NNK的代谢激活和抑制肿瘤的促癌作用 进步。来检验我们的假设并模仿西方的饮食 模式，我们将在拟议的实验中使用高脂肪饮食。 具体地说，我们的目标是：1)确定化学预防的效果 日粮Rho-XSC对NNK-1启动和启动后各阶段的影响 诱导A/J小鼠肺肿瘤形成。除了疗效之外 研究，我们将确定饮食中Rho-XSC对代谢的影响 NNK和DNA加合物在小鼠肺和肝脏的形成。2) 测定膳食Rho-XSC对NNK-1的化学预防效果 诱发大鼠肺肿瘤。将进行生化调查 如目标1所述；膳食中Rho-XSC对加合物的影响 将确定肺中相关细胞类型的形成。3) 测定日粮Rho-XSC对特定细胞色素P45O的影响 同工酶、转移酶、水解酶和硒依赖的谷胱甘肽 大鼠和小鼠肺和肝中的过氧化物酶。将优先考虑 与NNK代谢有关的那些酶。4)确定 Rho-XSC抑制蛋白激酶C作用的基础 利用硒-77核磁共振波谱。我们会 Rho-XSC与-SH基团的共价结合假设检验 会破坏蛋白质的结构和功能。这样做的结果 该项目将深入了解Rho-XSC在 未来肺癌化学预防的临床试验。

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.