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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

基本信息

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
项目类别：
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

项目摘要

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(申请人提供)：本研究的总体目标是评估新开发的塞来昔布硒类似物Secoxib-1 GSH对结肠癌的化学预防效果。癌症是美国人的第二大死因。将正常结肠细胞转化为恶性病变需要几个步骤，通常需要相当长的时间，平均为10-15年，从而为有效干预和预防提供了机会之窗。然而，2012年，据估计，仅在美国就有大约15万人被诊断出患有结直肠癌。早期报道已将环氧合酶(COX)确立为机制研究的重要分子靶点和抗癌新药筛选的重要靶点。COX选择性抑制剂(COXIBS)是选择性COX-2抑制剂的一类化合物，长期使用已显示出心脏毒性副作用。因此，迫切需要开发新的结肠癌预防药物。在这个修订的应用中，我们将研究新开发的塞来昔布的硒类似物Secoxib-1GSH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对心脏的毒性很小或没有；对包括抑制在内的多种机制途径具有抑制作用 COX-2、PI3K/Akt和NFkB可能是一种安全有效的预防结肠癌的化学预防药物。为了验证我们的假设，我们建议确定在饲料中喂养雄性F344大鼠时Secoxib-1 GSH的最大耐受量(MTD)，以评估主要器官相关的全身毒性。基于MTD研究的结果，我们将在雄性F344大鼠身上检测并比较塞科昔布-1 GSH和塞来昔布对1，2-二甲基肼(DMH)诱导的粘蛋白耗竭灶(MDF)、结肠异常隐窝灶(ACF)、癌前病变和肿瘤负担的抑制效力。我们还将在雄性F344大鼠的MDF、ACF和肿瘤样本中检测Secoxib-1 GSH对结肠癌重要机制途径的影响。