Chemoprevention of Early Pulmonary Lesions in Mice

小鼠早期肺部病变的化学预防

• 批准号: 6604209
• 负责人: ALVIN M MALKINSON
• 金额: $ 52万
• 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 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6604209
• 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以及小鼠 致癌小组研究肺癌的临床前化学预防 前吸烟者。 我们的理由是抗炎药会抑制 化学诱导的肺部肿瘤发生，早期肺部病变是可逆的，并且 对于人类肺肿瘤，尚无经过验证的生物标志物。 小鼠增生 病灶和微腺瘤模拟了前人肺部存在的小结节 吸烟者，更好地了解癌症的进展将有助于 深入了解人类肺癌化学预防。 两阶段癌变 方案，其中腹腔注射 3-甲基胆蒽 (MCA)，然后注射四次 每周腹膜内注射丁基羟基甲苯 (BHT)，可诱发这些肺部病变 在雄性 BALB 小鼠中。布地奈德，一种合成糖皮质激素，和其他三种 每种抗炎药物都有独特的作用机制， 单独（口服）给药或在病灶和微腺瘤后联合给药 已经发展起来了。其他三种药物是 LM4111（一种 COX-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 胸膜表面腺瘤将在既定时间点进行量化，直至 MCA 注射后 20 周。 几种表达增加的蛋白质 在早期小鼠肺部病变中，将通过免疫组织化学检查，看看是否 他们可以预测化学预防的成功。这些包括促炎性 酶（COX-1、COX-2 和 iNOS）和 hnRNP 蛋白（AUF1、HuR 和 A1）。我们 结合了两种全球策略，基因组学和蛋白质组学，作为发现 新型替代标记的工具。 RNA 和蛋白质表达模式将 分别通过微阵列、LC/MS/MS 和 2D-​​PAGE/MS 分析进行检查。 将正常肺部的表达与可解剖的腺瘤进行比较，并且 那么我们的分析将转向更实际地检查样本 可从人体获得（支气管肺泡灌洗细胞和液体以及血清）。 我们的目标是：（1）成功抑制肺部肿瘤进展 早期病变形成后应用消炎药物； (2) 至 识别新的早期预测生物标志物。