Combinational Chemoprevention of Esophageal Adenocarcin*

食管腺癌的联合化学预防*

• 批准号: 6830932
• 负责人: NAVTEJ S BUTTAR
• 金额: $ 7.38万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-06 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6830932
• 关键词: Barretts esophagus; adenocarcinoma; carcinogenesis inhibitor; chemical carcinogenesis; chemoprevention; cholanate compound; combination cancer therapy; drug screening /evaluation; enzyme inhibitors; esophagus neoplasm; histopathology; laboratory rat; neoplastic process; nonhuman therapy evaluation; nuclear factor kappa beta; physical chemical interaction; prostaglandin E; prostaglandin endoperoxide synthase; reflux esophagitis; statistics /biometry; ursodeoxycholate; western blottings

DESCRIPTION (provided by applicant): Barrett's esophagus is a pre-malignant condition that predisposes to esophageal adenocarcinoma, which has one of the fastest rising incidence rates in the United States and has limited therapeutic options. THE LONG-TERM GOAL of our lab is to develop mechanism-based, safe chemopreventive agents to prevent carcinogenesis in Barrett's esophagus. The mechanisms of carcinogenesis in Barrett's esophagus is not completely understood but esophageal refluxate containing bile salts is implicated in this process. Bile salts can activate several cellular pathways including the NFKB survival pathway and cyclooxygenase-2 (COX-2) leading to high levels of prostaglandins in the esophagus. We have shown that certain prostaglandins, in particular PGE2, are associated with the development of neoplasia in Barrett's esophagus and their inhibition by COX-2 inhibitors results in prevention of esophageal cancer in an animal model of Barrett's esophagus. Human studies are underway to assess the chemopreventive effect of COX-2 inhibitors. Combinational chemoprevention, whereby synergism can be achieved between two chemopreventive agents, represents an important development in the field of cancer prevention. Ursodeoxycholic acid (Urso) is another potential chemopreventive agent, which is a tertiary bile salt with an established safety profile. It inhibits NFKB activation as well as phospholipase A2 both of which act upstream of COX-2 enzyme and can therefore be a novel combinational chemopreventive agent with COX-2 inhibitors. We recently observed that Urso increases apoptosis, inhibits cell proliferation and decreases PGE2 production in Barrett's epithelial cells as well as potentiates the effect of COX-2 inhibitors on these parameters. Urso also inhibits PGE2 production and reduces the concentration of carcinogenic bile salts in the duodenum of an animal model with esophageal reflux. Based on these observations, we propose the novel and mechanistic HYPOTHESIS that inhibition of carcinogenic bile salt mediated PGE2 production by Urso will compliment the chemopreventive action of COX-2 inhibitors in Barrett's esophagus via a negative regulation of NFKappaB activation. To test this hypothesis, we have two SPECIFIC AIMS. First we will assess the rate of adenocarcinoma and PGE2 levels in the esophagus with a combination of Urso + COX-2 inhibitor treatment and compare it to either Urso or COX-2 inhibitor treatment alone. Secondly, we will examine if a decline in the levels of activated NFkB in the esophagus results in decreased levels of PGE2 and decreased risk of adenocarcinoma in the esophagus and assess whether the association is explained by Urso and or COX-2 inhibitor treatment. We propose an in vivo study using an established model of Barrett's esophagus and adenocarcinoma. A successful outcome of this hypothesis-driven preclinical study will provide adequate information and rationale to initiate clinical trials involving the use of combinational Urso and COX-2 inhibitors in prevention of esophageal adenocarcinoma and to explore mechanistic steps involved in this process.

描述（由申请人提供）： 巴雷特的食管是一种结构性疾病，易于食管腺癌，它是美国发病率最快的发病率之一，并且治疗方案有限。我们实验室的长期目标是开发基于机制的，安全的化学预防剂，以防止巴雷特食管中的致癌作用。巴雷特食管中癌变的机制尚未完全理解，但食管含有胆汁盐的食管反流含量与此过程有关。胆汁盐可以激活几种细胞途径，包括NFKB存活途径和环氧合酶-2（COX-2），导致食管中的前列腺素很高。我们已经表明，某些前列腺素，尤其是PGE2，与Barrett食管中肿瘤的发展及其对COX-2抑制剂的抑制作用导致在Barrett食管动物模型中导致食道癌的抑制作用。人类研究正在进行评估COX-2抑制剂的化学预防作用。结合化的化学预防，可以在两种化学预防剂之间达到协同作用，代表了预防癌症领域的重要发展。乌索氧化胆酸（URSO）是另一种潜在的化学预防剂，它是具有既定安全性的三级胆汁盐。它抑制NFKB激活以及磷脂酶A2，两者都在COX-2酶的上游作用，因此可以用COX-2抑制剂成为一种新型的组合化学预防剂。我们最近观察到，URSO会增加凋亡，抑制细胞增殖并降低Barrett上皮细胞中的PGE2产生，并增强COX-2抑制剂对这些参数的影响。 URSO还抑制PGE2的产生，并降低了用食管反流的动物模型的十二指肠中致癌胆汁盐的浓度。基于这些观察结果，我们提出了一种新的和机械假说，即URSO抑制致癌性胆汁盐介导的PGE2产生将通过NFKAPPAB激活的负调节来补充Cox-2抑制剂在Barrett食管中的化学预防作用。为了检验这一假设，我们有两个具体的目标。首先，我们将通过URSO + COX-2抑制剂治疗的结合评估食道中腺癌和PGE2水平的速率，并将其与URSO或COX-2抑制剂治疗进行比较。其次，我们将检查食道中活化NFKB的水平是否下降会导致PGE2水平降低，并且食管中腺癌的风险降低，并评估是否通过URSO和或COX-2抑制剂治疗来解释这种关联。我们建议使用Barrett食管和腺癌的既定模型进行体内研究。这项假设驱动的临床前研究的成功结果将提供足够的信息和理由，以启动临床试验，涉及使用组合URSO和COX-2抑制剂预防食管腺癌，并探索与此过程有关的机械步骤。