Chemoprevention of colon cancer by a novel COX-2 inhibitor

新型 COX-2 抑制剂对结肠癌的化学预防

• 批准号: 8833262
• 负责人: Dhimant Harkisan Desai
• 金额: $ 7.65万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-07 至 2016-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8833262
• 关键词: 1,2-Dimethylhydrazine; Aberrant crypt foci; Adenocarcinoma; Adverse effects; American; Anti-Inflammatory Agents; Anti-inflammatory; Antineoplastic Agents; Biological Assay; Cancer Etiology; Cause of Death; Cell Survival; Cells; Cessation of life; Chemoprevention; Chemopreventive Agent; Clinical Trials; Colon Carcinoma; Colonic Neoplasms; Colorectal Cancer; Coxibs; Critical Pathways; Development; Diagnosis; Diet; Dose; Equilibrium; Future; Goals; Health; Heart; Human; Inbred F344 Rats; Lesion; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Marketing; Maximum Tolerated Dose; Micronutrients; Modality; Modeling; Molecular Target; Mucins; Myocardium; Neoplasm Metastasis; New Agents; Normal Cell; Organ; Outcome; Pathway interactions; Pharmaceutical Preparations; Play; Preclinical Drug Evaluation; Prevention; Prostaglandin-Endoperoxide Synthase; Prostate; Rattus; Reporting; Role; Safety; Sampling; Selenium; Testing; Time; Toxic effect; Tumor Burden; United States; Vascular Endothelial Growth Factors; analog; angiogenesis; base; cancer cell; celecoxib; cyclooxygenase 1; cyclooxygenase 2; effective intervention; efficacy trial; feeding; gastrointestinal; inhibitor/antagonist; male; melanoma; mouse model; notch protein; novel; protective effect; tumor

DESCRIPTION (provided by applicant): Overall goal of our study is to evaluate the chemopreventive efficacy of Secoxib-1 GSH, a newly developed selenium analog of Celecoxib, against colon cancer. Cancer is the second leading cause of death among Americans. Conversion of normal colonic cells to malignant lesions requires several steps and often proceeds over considerable time periods, on average, 10-15 years, thus providing a window of opportunity for effective intervention and prevention. However, in 2012 it was estimated that in the United States alone about 150,000 people will be diagnosed with colorectal cancer. Earlier reports have established cyclooxygenase (COX) as an important molecular target for mechanistic studies and important target for new anticancer drugs screening. The long-term uses of COX selective inhibitor (COXIBs), a class of compounds that are selective COX-2 inhibitors, have shown cardio-toxic side effects. Therefore, there is an urgent need for the development of new agents for the prevention modality of colon cancer. In this revised application, we will investigate the inhibitory effects of Secoxib-1GSH, a newly developed selenium analog of Celecoxib, against colon cancer. In our preliminary studies, Secoxib-1 GSH has retained the selective shown protective effect to these cells. We hypothesize that Secoxib-1 GSH, having minimal or no cardio-toxicity; having inhibitory effects on multiple mechanistic pathways including inhibition of COX-2, PI3K/Akt, and NFkB will be a safe and potent chemopreventive agent for prevention of colon cancer. To test our hypothesis, we propose to determine maximum tolerated dose (MTD) of Secoxib-1 GSH when fed in the diet to male F344 rats for the assessment of major organ related systemic toxicity. Based on the outcome from the MTD study, we will examine and compare the inhibitory potency of Secoxib-1 GSH with Celecoxib in male F344 rats against 1, 2-Dimethylhydrazine (DMH) induced mucin depleted foci (MDF), colonic aberrant crypt foci (ACF), preneoplastic lesions; and tumor burden in rats. We will also examine the effects of Secoxib-1 GSH on the important mechanistic pathways of colon cancer in the MDF, ACF, and tumor samples from male F344 rats.

描述（由申请人提供）：我们研究的总体目标是评估塞氏菌针对结肠癌的新开发的塞氏菌类似物Secoxib-1 GSH的化学预防功效。癌症是美国人中死亡的第二大原因。正常的结肠细胞转换为恶性病变需要几个步骤，并且通常在相当长的时间段内进行10 - 15年，从而为有效的干预和预防提供了机会之窗。但是，据估计，仅在美国，大约有15万人将被诊断出患有大肠癌。较早的报告已将环氧合酶（COX）建立为机械研究的重要分子靶标，并且是新的抗癌药物筛查的重要靶标。 Cox选择性抑制剂（Coxibs）的长期用途是选择性COX-2抑制剂的一类化合物，已显示出心脏毒性的副作用。因此，迫切需要开发新药物以预防结肠癌。在此修订后的应用中，我们将研究Secoxib-1GSH的抑制作用，Secoxib-1Gsh是一种新开发的Celecoxib的硒类似物，对结肠癌。在我们的初步研究中，Secoxib-1 GSH保留了选择性 对这些细胞显示了保护作用。我们假设Secoxib-1 GSH具有最小或没有心脏毒性。对包括抑制的多种机械途径具有抑制作用 COX-2，PI3K/AKT和NFKB的of将是预防结肠癌的安全且有效的化学预防剂。为了检验我们的假设，我们建议在饮食中喂入雄性F344大鼠时，确定Secoxib-1 GSH的最大耐受剂量（MTD），以评估主要器官相关的系统性毒性。根据MTD研究的结果，我们将检查和比较雄性F344大鼠Secoxib-1 GSH与1，2-二甲基氢嗪（DMH）粘蛋白诱导的粘蛋白耗竭的灶（MDF），结肠异常的异常密码（ACF），Preneplostlostlostlostlastic laslastic laslastic laslastic laslastic lesions;和老鼠的肿瘤负担。我们还将研究Secoxib-1 GSH对雄性F344大鼠MDF，ACF和肿瘤样品中结肠癌重要机械途径的影响。