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：
8270548
负责人：
Tong Chen
金额：
$ 30.19万
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 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8270548
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 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 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 products and to determine the cellular and molecular mechanisms of their actions; 3. To identify cellular and molecular biomarkers of 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. Project Narrative 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常见恶性肿瘤，其中 90% 以上为食管鳞状细胞癌 (SCC)。食管鳞状细胞癌的危险因素包括吸烟、饮酒、营养缺乏以及摄入受各种霉菌毒素污染的食物。食管鳞状细胞癌比其他类型的胃肠道恶性肿瘤生长更快，且患者预后很差。尽管单独或联合使用手术、化疗和放疗，但该病的总体5年生存率仍然很低，为5%至15%。为了降低食管癌的发病率，通过饮食和/或化学干预进行癌症化学预防将是一种合理且实用的方法。许多化合物已经过测试；然而，迄今为止的试验并未导致食道癌发病率下降。迫切需要找到可以预防与食道癌风险增加相关的个体的这种疾病的保护剂。我们研究的长期目标是制定机制驱动的安全有效的预防策略，以降低高危人群食管癌的发病率。 N-亚硝基甲基苄胺（NMBA）诱导的大鼠食管癌临床前模型已被广泛用于研究食管癌发生的机制并评估潜在化学预防剂的功效。食管鳞状细胞癌从正常到增生、不典型增生和乳头状瘤的多阶段演变，非常适合化学预防策略的应用。在本提案中，我们概述了开发食管癌化学预防组合方法的策略。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-亚苯基-双(1,2-乙二基)双异硫脲的组合(PBIT) 和冻干黑树莓 (BRB) 将提高抗肿瘤发展的功效，同时最大限度地减少 NMBA 大鼠临床前模型中的毒性。具体目标是： 1. 建立策略以提高COX-2和iNOS抑制剂联合预防食管癌的功效； 2. 制定策略，通过纯化合物和天然食品的组合来提高食道癌预防功效，并确定其作用的细胞和分子机制； 3. 鉴定 NMBA 诱导的大鼠食管肿瘤发生的细胞和分子生物标志物。总体而言，这项假设驱动的临床前研究的成功结果将为开发与在食管癌化学预防的人类临床试验中可能具有协同活性的药物的组合提供重要的信息和基本原理。项目叙述该项目的总体目标是评估针对食管癌的组合方法的疗效癌症的发展，研究这些药物的机制基础，并识别细胞和使用大鼠临床前模型研究食管肿瘤发生的分子生物标志物，该模型与人食管鳞状细胞癌。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Efficacy comparison of lyophilised black raspberries and combination of celecoxib and PBIT in prevention of carcinogen-induced oesophageal cancer in rats.

冻干黑树莓与塞来昔布和 PBIT 联合预防大鼠食道癌的功效比较。

DOI：
10.1016/j.jff.2016.08.044
发表时间：
2016
期刊：
Journal of functional foods
影响因子：
5.6
作者：
Shi,Ni;Riedl,KennethM;Schwartz,StevenJ;Zhang,Xiaoli;Clinton,StevenK;Chen,Tong
通讯作者：
Chen,Tong

Peroxiredoxin 1 promotes invasion and migration by regulating epithelial-to-mesenchymal transition during oral carcinogenesis.

过氧化还原蛋白 1 通过调节口腔癌发生过程中的上皮间质转化来促进侵袭和迁移