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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：
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
项目类别：
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

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（由申请人提供）：我们研究的总体目标是评价塞来昔布-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。癌症是美国人死亡的第二大原因。正常结肠细胞转化为恶性病变需要几个步骤，并且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。然而，在2012年，据估计仅在美国就有约15万人将被诊断患有结直肠癌。环氧合酶（cyclooxygenase，考克斯）是研究其作用机制的重要分子靶点，也是筛选抗肿瘤新药的重要靶点。考克斯选择性抑制剂（COXIB）是一类选择性考克斯-2抑制剂化合物，其长期使用已显示出心脏毒性副作用。因此，迫切需要开发用于结肠癌预防方式的新药物。在这个修订后的申请中，我们将研究Secoxib-1GSH（一种新开发的塞来昔布的硒类似物）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有保护作用。我们假设，Secoxib-1 GSH具有最小或无心脏毒性，对多种机制途径具有抑制作用，包括抑制考克斯-2、PI 3 K/Akt和NF κ B的联合表达将成为一种安全有效的结肠癌化学预防剂。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的最大耐受剂量（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）诱导的粘蛋白耗竭灶（MUC）、结肠异常隐窝灶（ACF）、癌前病变和大鼠肿瘤负荷的抑制效力。我们还将研究Secoxib-1 GSH对雄性F344大鼠结肠癌、ACF和肿瘤样本中结肠癌重要机制途径的影响。