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: 8704070
• 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 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8704070
• 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; 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; public health relevance; 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 Secoxib-1 GSH（一种新开发的塞来昔布硒类似物）对结肠癌的化学预防功效。癌症是美国人的第二大死因。正常结肠细胞向恶性病变的转化需要几个步骤，并且通常需要相当长的时间，平均10-15年，从而为有效干预和预防提供了机会之窗。然而，据估计，2012 年仅在美国就有约 150,000 人被诊断患有结直肠癌。早期报道已将环氧合酶（COX）确定为机制研究的重要分子靶点和新抗癌药物筛选的重要靶点。 COX选择性抑制剂（COXIBs）是一类选择性COX-2抑制剂，长期使用已显示出心脏毒性副作用。因此，迫切需要开发用于预防结肠癌的新药剂。在此修订后的申请中，我们将研究 Secoxib-1GSH（一种新开发的塞来昔布硒类似物）对结肠癌的抑制作用。在我们的初步研究中，Secoxib-1 GSH 保留了选择性 对这些细胞显示出保护作用。我们假设 Secoxib-1 GSH 具有最小或没有心脏毒性；对多种机制途径具有抑制作用，包括抑制 COX-2、PI3K/Akt 和 NFkB 的组合将成为预防结肠癌的安全有效的化学预防剂。为了检验我们的假设，我们建议确定雄性 F344 大鼠饮食中 Secoxib-1 GSH 的最大耐受剂量 (MTD)，以评估主要器官相关的全身毒性。根据 MTD 研究的结果，我们将检查并比较 Secoxib-1 GSH 与塞来昔布在雄性 F344 大鼠中对 1, 2-二甲基肼 (DMH) 诱导的粘蛋白耗尽病灶 (MDF)、结肠异常隐窝病灶 (MDF) 的抑制效力。 ACF)，癌前病变；和大鼠的肿瘤负荷。我们还将检查 Secoxib-1 GSH 对 MDF、ACF 和雄性 F344 大鼠肿瘤样本中结肠癌重要机制途径的影响。