Preclin. model for prevention of NSCLC in former smokers

Preclin。

• 批准号: 7285066
• 负责人: Hildegard M. Schuller
• 金额: $ 3.16万
• 依托单位: UNIVERSITY OF TENNESSEE KNOXVILLE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7285066
• 关键词: adenocarcinoma; alternative medicine; beta antiadrenergic agent; bioassay; biological signal transduction; cancer prevention; carotene; cell growth regulation; cell line; chemoprevention; cyclic AMP; enzyme inhibitors; glucocorticoids; hamsters; human genetic material tag; inhibitor /antagonist; laboratory mouse; lipoxygenase; neoplastic cell; nonsmall cell lung cancer; prostaglandin endoperoxide synthase; retinoids; smoking; squamous cell carcinoma; tea; theophylline; therapy adverse effect; tobacco abuse

DESCRIPTION (provided by applicant) The central hypothesis of this application is that growth regulating pathways expressed in human and mouse alveolar type II cell pulmonary adenocarcinomas (PAC type II) and in human and hamster pulmonary squamous cell carcinomas (SQCs) are antagonistic to those expressed in human and hamster Clara cell type pulmonary adenocarcinomas (PACCs). Chemoprevention studies applicable to former smokers therefore need to use models representing these differently regulated cancer types. Non-invasive methods need to be developed that allow to monitor the expression levels of these pathways in former smokers to asses response to treatment and to ensure assignment of individuals to effective chemopreventive treatments while avoiding potentially cancer promoting agents. To achieve these goals in a preclinical setup, our specific aims are as follows: 1) We will characterize the effects of green tea, theophylline, beta-carotene, retinol, glucocorticoid beta- blockers, cAMP antaogonists, and inhibitors of cyclooxygenase-2 (COX-2) or 5-1ipooxygenase (5-.LOX) in human lung cancer cell lines derived from PAC type II, PACC or QSQC and in non-tumorigenic and tumorigenic mouse PAC type II cell lines. 2) We will synthesize iodine-125 and -123-labeled analogues of inhibitors of COX-2, cAMP-dependent PKA and 5-LOX for use in micro-photon emisssion tomography (micro-SPECT). We will verify the binding of these analogues to their cellular targets by in vitro binding assays, using human lung cancer cell lines characterized under aim 1 and by in vivo bio-distribution studies, using mice carrying xenographs of these human lung cancer cell lines. 3) We will study the chemopreventive effects of selected agents from aim 1 in bioassay experiments, using the A/J/mouse PAC type II model, the hamster PACC model and the hamster SQC model. The experimental designs will simulate chemoprevention in former smokers by starting the chemopreventive treatments at the time when tumor induction treatment has been discontinued and precancerous lesions are present in the animals. Evaluation of data will include histopathology, including immunostains for COX-2, PKA and 5-LOX as well as analysis of protein expression of these enzymes by Western blots in normal cells of origin of the induced tumors, premalignant lesions, and in lung cancers harvested by laser capture microscopy. 4) Using the iodine-125-1abeled analogues from aim 2, we will conduct micro-SPECT analysis of five randomly chosen animals per treatment group of aim 3 before, during and after completion of chemopreventive treatments and we will attempt to quantitate levels of COX-2, PKA, and 5-LOX in lung tissues and lung tumors.

描述（由申请人提供） 本申请的中心假设是，在人和小鼠肺泡II型细胞肺腺癌（PAC II型）和在人和仓鼠肺鳞状细胞癌（SQC）中表达的生长调节途径与在人和仓鼠Clara细胞型肺腺癌（PACC）中表达的生长调节途径是拮抗的。因此，适用于前吸烟者的化学预防研究需要使用代表这些不同调节的癌症类型的模型。需要开发非侵入性方法，以监测这些途径在前吸烟者中的表达水平，以评估对治疗的反应，并确保将个体分配到有效的化学预防治疗，同时避免潜在的癌症促进剂。为了在临床前设置中实现这些目标，我们的具体目标如下： 1)我们将描述绿色茶、茶碱、β-胡萝卜素、视黄醇、糖皮质激素β-受体阻滞剂、cAMP拮抗剂和环氧合酶-2（考克斯-2）或5-脂氧合酶（5-LOX）抑制剂在源自PAC II型、PACC或QSQC的人肺癌细胞系以及非致瘤性和致瘤性小鼠PAC II型细胞系中的作用。 2)我们将合成碘-125和碘-123标记的考克斯-2、cAMP依赖性PKA和5-LOX抑制剂的类似物，用于微光子发射断层扫描（micro-SPECT）。我们将通过体外结合试验（使用根据目标1表征的人肺癌细胞系）和体内生物分布研究（使用携带这些人肺癌细胞系异种移植物的小鼠）验证这些类似物与其细胞靶点的结合。 3)我们将在生物测定实验中使用A/J/小鼠PAC II型模型、仓鼠PACC模型和仓鼠SQC模型研究目标1中所选试剂的化学预防效应。实验设计将通过在肿瘤诱导治疗已停止且动物中存在癌前病变时开始化学预防治疗来模拟前吸烟者的化学预防。数据评价将包括组织病理学，包括考克斯-2、PKA和5-LOX的免疫染色，以及通过蛋白质印迹法分析诱导肿瘤、癌前病变起源的正常细胞和通过激光捕获显微镜收集的肺癌中这些酶的蛋白质表达。 4)使用目标2的碘-125-1标记类似物，我们将在化学预防治疗之前、期间和完成之后对目标3的每个治疗组随机选择的5只动物进行显微SPECT分析，我们将尝试定量肺组织和肺肿瘤中的考克斯-2、PKA和5-LOX水平。

项目成果

Gamma-aminobutyric acid, a potential tumor suppressor for small airway-derived lung adenocarcinoma.

• DOI: 10.1093/carcin/bgn041
• 发表时间: 2008-10
• 期刊: CARCINOGENESIS
• 影响因子: 4.7
• 作者: Schuller, Hildegard M.;Al-Wadei, Hussein A. N.;Majidi, Mourad
• 通讯作者: Majidi, Mourad

beta-Carotene promotes the development of NNK-induced small airway-derived lung adenocarcinoma.

• DOI: 10.1016/j.ejca.2008.10.035
• 发表时间: 2009-05
• 期刊: EUROPEAN JOURNAL OF CANCER
• 影响因子: 8.4
• 作者: Al-Wadei, Hussein A. N.;Schuller, Hildegard M.
• 通讯作者: Schuller, Hildegard M.

Antagonistic growth regulation of cell lines derived from human lung adenocarcinomas of Clara cell and aveolar type II cell lineage: Implications for chemoprevention.

• DOI: 10.3892/ijo.24.6.1467
• 发表时间: 2004-06
• 期刊: International journal of oncology
• 影响因子: 5.2
• 作者: H. Adissu;H. Schuller

Neuroendocrine lung carcinogenesis in hamsters is inhibited by green tea or theophylline while the development of adenocarcinomas is promoted: implications for chemoprevention in smokers.

绿茶或茶碱可抑制仓鼠神经内分泌肺癌的发生，同时促进腺癌的发展：对吸烟者化学预防的影响。

• DOI: 10.1016/j.lungcan.2003.12.007
• 发表时间: 2004
• 期刊: Lung cancer (Amsterdam, Netherlands)
• 作者: Schuller,HildegardM;Porter,B;Riechert,A;Walker,K;Schmoyer,R
• 通讯作者: Schmoyer,R