CHEMOPREVENTION OF LUNG CANCER BY ORGANOSELENIUM

大量的流行病学研究、临床干预试验和实验室研究明确支持硒对肺癌发展的保护作用。富硒酵母是一种由不同形式的硒化合物组成的混合物，可降低肺癌的发病率和死亡率。化学预防功效取决于1）含硒化合物的化学形式，而不是元素本身;以及2）所用的剂量和种类。在我们的模型分析中，合成的1，4-亚苯基双（亚甲基）硒氰酸酯（pXSC）显着抑制由烟草特异性肺致癌物4-（甲基亚硝氨基）1-（3-吡啶基）1-丁酮（NNK），在雌性A/J小鼠中，而在富硒小鼠中发现的天然存在的硒代甲硫氨酸（SM）没有雌性A/J小鼠，而在富硒小鼠中发现的天然存在的硒代甲硫氨酸（SM）没有雌性A/J小鼠。富集的酵母在该动物模型中没有效果。在本申请中，我们提出了四个具体的目的，以获得重要的信息，这是必要的扩展从啮齿动物到人类的p-XSC的效用。在具体目标1中，我们将通过比较富硒酵母及其有前途的成分之一Se-甲基硒代半胱氨酸（MSC）与PXSC在NNK（长期给药）A/J小鼠模型中的疗效和化学预防的生化基础。具体目标2将探讨不同形式的硒对人气管支气管和外周肺培养外植体的代谢和DNA加合物形成的影响。在具体目标3中，我们将测试一个假设，该假设可能导致硒作为化学预防剂的因果关系的识别。具体地，基于我们的结果，我们假设p-XSC通过抑制NF-κ B（部分经由共价结合）从而下调考克斯-2和LOX（导致细胞凋亡）来抑制NNK诱导的肺肿瘤发生。然而，还将检查p-XSC影响lkappaB降解的替代机制，lkappaB降解反过来控制NF-κ B向细胞核的易位。这些研究将首先在体外使用人肺癌细胞培养物进行，随后在体内使用裸鼠进行。在具体目标2中，我们将确定不同水平的硒（如p-XSC和富硒酵母）以及维生素C和E作为抗氧化剂的作用，这些抗氧化剂可以抑制豚鼠肺中香烟烟雾诱导的氧化损伤;以及在某种程度上可以模拟人类生物化学的动物模型，因为这两个物种都缺乏合成抗氧化维生素C的能力。总的来说，该项目的结果将评估p-XSC在未来的临床试验中是否上级MSC或富硒酵母，以化学预防吸烟者和戒烟者的肺癌。

A number of epidemiological studies, clinical intervention trials, and investigations in laboratory clearly support the protective role of selenium against the development of lung cancer. Selenium-enriched yeast, used as a nutritional supplement by humans, is a mixture of different forms of selenium compounds that reduces lung cancer incidence and mortality. The chemopreventive efficacy depends on 1) the chemical form of the selenium-containing compound and not the element per se; and 2) the dose and species employed. In our model assays the synthetic 1,4- phenylenebis(methylene)selenocyanate (pXSC) significantly inhibited lung tumors induced by the tobacco-specific lung carcinogen, 4- (methylnitrosamino)1-(3-pyridyl)1-butanone (NNK), in female A/J mice while the naturally occurring selenomethionine (SM) found in selenium- enriched had no female A/J mice while the naturally occurring selenomethionine (SM) found in selenium-enriched yeast had no effect in this animal model. In the present application, we propose four specific aims to obtain important information that is requisite for extending the utility of p-XSC from rodents to humans. In Specific Aim 1, we will determine the efficacy and biochemical basis for chemoprevention by comparing selenium-enriched yeast and one of its promising components, Se-methylselenocysteine (MSC), with PXSC in the NNK (chronically administered) A/J mouse model. Specific Aim 2 will probe the effect of various forms of selenium on the metabolism and DNA adduct formation in cultured explants of human tracheobronchial and peripheral lung. In Specific Aim 3, we will test a hypothesis that could lead to the identification of casual relationships by which selenium acts as a chemopreventive agent. Specifically on the basis of our results, we hypothesize that p-XSC inhibits lung tumorigenesis induced by NNK by inhibiting NF-kappaB, in part via covalent binding, thereby down- regulating COX-2 and LOX leading to apoptosis. However, an alternative mechanism by which p-XSC influences lkappaB degradation which, in turn, controls the translocation of NF-kappaB to the nucleus, will also be examined. These studies will be conducted, initially, in vitro using human lung carcinoma cell cultures and, later, in vivo using nude mice. In Specific Aim 2, we will determine the effect of various levels of selenium (as p-XSC and selenium-enriched yeast) and vitamins C and E as anti- oxidants that can inhibit cigarette smoke-induced oxidative damage in the lung of guinea pigs; and animal model that, to some extent, may mimic human biochemistry in that both species lack the ability to synthesize the anti-oxidant vitamin C. Collectively, the results of this Project will assess whether p-XSC is superior to MSC or selenium-enriched yeast in future clinical trials toward the chemoprevention of lung cancer in smokers and ex-smokers.