Combinational Approaches to the Chemoprevention of Esophageal Cancer

食管癌化学预防的组合方法

基本信息

批准号：
8332384
负责人：
Tong Chen
金额：
$ 7.91万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8332384
关键词：
1-Phosphatidylinositol 3-Kinase Adult Adverse effects Alcohol consumption Animals Area Biological Assay Biological Markers Carcinogenesis Mechanism Cell Proliferation Chemicals Chemoprevention Chemopreventive Agent China Clinical Trials Complement Factor B Coxibs Data Development Diet Disease Dose Down-Regulation Dysplasia Eating Environment Esophageal Esophageal Squamous Cell Carcinoma Esophageal Tissue Esophagus Evolution Exhibits Food Freeze Drying Future Goals Health Human Hyperplasia Incidence Individual Interdisciplinary Study Intervention Investigation JUN gene Laboratories Lesion Malignant Neoplasms Malignant neoplasm of esophagus Malnutrition Metabolic Pathway Mitogen-Activated Protein Kinases Modeling Molecular Mycotoxins Nuclear Ohio Operative Surgical Procedures Outcome Papilloma Pathway interactions Patients Phase Phase I Clinical Trials Play Population Pre-Clinical Model Prevention Prevention Research Prevention strategy Preventive Intervention Process Protective Agents Proteins Radiation therapy Raspberries Rattus Regimen Research Risk Factors Role S,S&apos -1,4-phenylene-bis(1,2-ethanediyl)bis-isothiourea Strawberries Survival Rate Testing Time Tissues Tobacco use Toxic effect Translating Universities Vascular Endothelial Growth Factors Work base cDNA Arrays cancer chemoprevention cancer prevention cancer risk carcinogenesis celecoxib chemotherapy cohort cyclooxygenase 2 dosage esophageal cancer prevention experience gastrointestinal high risk human NOS2A protein human study improved inhibitor/antagonist innovation laser capture microdissection nitrosobenzylmethylamine outcome forecast pre-clinical preclinical study prevent response tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Esophageal cancer is the 6th most common malignant neoplasm worldwide with more than 90% of all cases being esophageal squamous cell carcinoma (SCC). Risk factors for esophageal SCC include tobacco use, alcohol consumption, nutritional deficiency, and intake of food contaminated with various mycotoxins. Esophageal SCC grows more quickly than other kinds of gastrointestinal malignancies and patients with this disease have a very poor prognosis. Although surgery, chemotherapy, and radiotherapy alone or combined are used, the overall 5-year survival rate for this disease is still very low, ranging from 5% to 15%. To decrease the incidence of esophageal cancer, cancer chemoprevention through dietary and/or chemical intervention would be a logical and practical approach. Numerous compounds have been tested; however, the trails to date have not resulted in a decrease of esophageal cancer incidence. There is an urgent need to identify protective agents, which can prevent this disease in the individuals associated with increasing esophageal cancer risk. The long-term goal of our studies is to develop mechanism-driven safe and effective prevention strategies for reducing the incidence of esophageal cancer in high-risk populations. N-nitrosomethylbenzylamine (NMBA)- induced rat preclinical model of esophageal cancer has been used extensively to investigate the mechanisms of esophageal carcinogenesis and to evaluate the efficacy of potential chemopreventive agents. The multistage evolution of esophageal SCC, from normal to hyperplasia, dysplasia and papilloma, is ideal for the application of chemoprevention strategies. In this proposal, we outline our strategy to develop combinational approaches to the chemoprevention of esophageal cancer. Our central hypothesis is that combination of cyclooxygenase-2 (COX-2) inhibitor, celecoxib, inducible nitric oxide synthase (iNOS) inhibitor, S,S'-1,4- phenylene-bis(1,2-ethanediyl)bis-isothiourea (PBIT), and freeze-dried black raspberries (BRB) will increase efficacy against tumor development while minimizing toxicity in NMBA-rat preclinical model. The specific aims are: 1. To establish strategies to improve efficacy of esophageal cancer prevention by a combination of COX-2 and iNOS inhibitors; 2. To establish strategies to improve efficacy of esophageal cancer prevention by a combination of pure compound(s) and natural food product and to determine the cellular and molecular mechanisms of their actions; 3. To investigate the roles of mitogen-activated protein kinase (MAPK) and nuclear factor :B (NF:B) pathways in NMBA-induced tumorigenesis in the rat esophagus. Overall, a successful outcome of this hypothesis-driven preclinical study will provide important information and rationale to develop a combination with agents that may have synergistic activity in human clinical trials of chemoprevention of esophageal cancer. PUBLIC HEALTH RELEVANCE: The overall objective of this project is to evaluate the efficacy of combinational approaches against esophageal cancer development, to investigate the mechanistic basis of these agents, and to identify cellular and molecular biomarkers of esophageal tumorigenesis using a rat preclinical model, which is highly analogous to human esophageal squamous cell carcinoma.

描述（由申请人提供）：食管癌是全球第六大最常见的恶性肿瘤，所有病例中有90％是食管鳞状细胞癌（SCC）。食管SCC的危险因素包括烟草使用，饮酒，营养缺乏以及用各种霉菌毒素污染的食物摄入。食管SCC的生长速度比其他类型的胃肠道恶性肿瘤更快，患有这种疾病的患者的预后较差。尽管仅使用手术，化学疗法和放疗，但该疾病的总体5年生存率仍然很低，范围从5％到15％。为了降低食道癌的发生率，通过饮食和/或化学干预进行的癌症化学预防将是一种逻辑和实用的方法。已经测试了许多化合物；但是，迄今为止的步道并未导致食管癌发病率的降低。迫切需要识别保护剂，这可以防止与食管癌风险增加有关的个体中的这种疾病。我们研究的长期目标是开发机制驱动的安全有效的预防策略，以减少高危人群中食道癌的发生率。 N-亚硝基甲基苯胺（NMBA） - 已广泛使用了食管癌的大鼠临床前模型，以研究食道癌的机制，并评估潜在化学预防剂的疗效。食管SCC从正常到增生，发育不良和乳头状瘤的多阶段演变非常适合应用化学预防策略。在此提案中，我们概述了开发食管癌化学预防的组合方法的策略。我们的中心假设是环氧合酶-2（COX-2）抑制剂，塞来昔布，诱导型一氧化氮合酶（iNOS）抑制剂，S，S'-1,4-苯基烯基（1,2-乙基甲基）双ISOTHIOREA BIS-异硫酸酯）的组合（PBIT）和冷冻干燥的黑色覆盆子（BRB）将提高针对肿瘤发育的疗效，同时最大程度地减少NMBA-RAT临床前模型的毒性。具体目的是：1。建立通过COX-2和iNOS抑制剂组合来提高食道癌预防功效的策略； 2。建立通过纯化合物和天然食品的结合来提高食道癌预防功效的策略，并确定其作用的细胞和分子机制； 3。研究有丝分裂原激活的蛋白激酶（MAPK）和核因子的作用：B（NF：B）NMBA诱导的大鼠食道肿瘤发生中的作用。总体而言，这项假设驱动的临床前研究的成功结果将提供重要的信息和基本原理，以与可能具有协同活性的药物在人类的食管癌化学临床试验中具有协同活性。公共卫生相关性：该项目的总体目标是评估对食管癌发展的组合方法的疗效，调查这些药物的机械基础，并使用大鼠振荡模型鉴定食管肿瘤发生的细胞和分子生物标志物，这是与人类食管鳞状细胞癌高度类似。