Chemoprevention of Early Pulmonary Lesions in Mice

小鼠早期肺部病变的化学预防

• 批准号: 6748167
• 负责人: ALVIN M MALKINSON
• 金额: $ 54.44万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-28 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6748167
• 关键词: adenoma; antiinflammatory agents; biomarker; butylated hydroxytoluene; cancer prevention; chemoprevention; functional /structural genomics; glucocorticoids; immunocytochemistry; laboratory mouse; lung neoplasms; methylcholanthrene; microarray technology; neoplastic process; proteomics

DESCRIPTION (provided by applicant): At UCHSC, we have assembled mature Genomics and Proteomics and mouse carcinogenesis groups to study preclinical chemoprevention of lung cancer in former-smokers. Our rationale is that anti-inflammatory drugs inhibit chemically-induced lung tumorigenesis, early lung lesions are reversible, and no verified biomarkers exist for human lung neoplasia. Mouse hyperplastic foci and microadenomas model the small nodules present in the lungs of former smokers, and a better understanding of the progression to cancer will lend insight into human lung cancer chemoprevention. A two-stage carcinogenesis regimen, in which 3-methylcholanthrene (MCA) is injected ip followed by four weekly ip doses of butylated hydroxytolulene (BHT), induces these lung lesions in male BALB mice. Budesonide, a synthetic glucocorticoid, and three other anti-inflammatory drugs, each with a unique mechanism of action, will be administered (orally) singly and in combination after foci and microadenomas have developed. The three other drugs are LM4111 (a COX-2 specific inhibitor), PBIT (an iNOS-specific inhibitor), and Iloprost (a stable prostacyclin agonist). The number of foci, and the number and sizes of microadenomas and pleural surface adenomas will be quantified at established time points up to 20 weeks after the MCA injection. Several proteins whose expression increases in early mouse lung lesions will be examined by immunohistochemistry to see if they can predict successful chemoprevention. These include pro-inflammatory enzymes (COX-1, COX-2, and iNOS) and hnRNP proteins (AUF1 , HuR, and A1). We have combined two global strategies, genomics and proteomics, as discovery tools for novel surrogate markers. RNA and protein expression patterns will be examined by microarray, LC/MS/MS, and 2D-PAGE/MS analyses, respectively. Expression in normal lungs will be compared with dissectable adenomas, and then our analyses will move proximally to examine samples more practically obtainable from humans (bronchoalveolar lavage cells and fluid, and serum). Our goals are: (1) to successfully inhibit lung tumor progression when anti- inflammatory drugs are applied after early lesions have forms; and (2) to identify novel early-stage predictive biomarkers.

描述（由申请人提供）： 在UCHSC，我们已经组装了成熟的基因组学和蛋白质组学， 研究肺癌的临床前化学预防， 前吸烟者 我们的理论是抗炎药抑制 化学诱导的肺肿瘤发生，早期肺部病变是可逆的， 对于人肺肿瘤，还没有经过验证的生物标志物。 小鼠增生性 病灶和微腺瘤模拟了前者肺部存在的小结节 吸烟者，更好地了解癌症的进展将有助于 人类肺癌化学预防研究进展 两阶段致癌作用 方案，其中3-甲基胆蒽（MCA）注射ip，然后是四个 每周ip剂量的丁基化羟基甲苯（BHT）诱导这些肺部病变 在雄性BALB小鼠中。布地奈德是一种合成糖皮质激素， 抗炎药，每一种都有独特的作用机制，将是 病灶和微腺瘤后单独和联合给药（口服） 已经发展。其他三种药物是LM 4111（一种考克斯-2特异性抑制剂）， PBIT（一种iNOS特异性抑制剂）和伊洛前列素（一种稳定的前列环素 激动剂）。 病灶的数量，微腺瘤的数量和大小， 胸膜表面腺瘤将在确定的时间点定量， MCA注射后20周。 几种表达增加的蛋白质 通过免疫组织化学检查早期小鼠肺损伤， 它们可以预测成功的化学预防。这些包括促炎性 酶（考克斯-1、考克斯-2和iNOS）和hnRNP蛋白（AUF 1、HuR和A1）。我们 结合了基因组学和蛋白质组学这两个全球战略， 新的替代标记的工具。 RNA和蛋白质表达模式将 分别通过微阵列、LC/MS/MS和2D-PAGE/MS分析进行检测。 将正常肺中的表达与可解剖腺瘤进行比较， 那么我们的分析将更接近实际地检查样本 可从人获得（支气管肺泡灌洗细胞和液体，以及血清）。 我们的目标是：（1）在抗肿瘤时成功抑制肺肿瘤进展 在早期病变形成后应用炎性药物;和（2） 识别新型早期预测生物标志物。

项目成果

Evidence that inflammation encourages pulmonary adenocarcinoma formation in mice: clinical implications.

炎症促进小鼠肺腺癌形成的证据：临床意义。

• DOI: 10.1378/chest.125.5_suppl.154s-a
• 发表时间: 2004
• 期刊: Chest
• 影响因子: 9.6
• 作者: Malkinson,AlvinM