PREVENTION OF CRC BY iNOS AND COX-2 SELECTIVE INHIBITORS

通过 iNOS 和 COX-2 选择性抑制剂预防 CRC

• 批准号: 6952292
• 负责人: Chinthalapally V. Rao
• 金额: $ 30.03万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-23 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6952292
• 关键词: apoptosis; biomarker; cancer prevention; carcinogenesis; cell growth regulation; cell proliferation; chemoprevention; colorectal neoplasms; combination chemotherapy; disease /disorder model; dosage; drug design /synthesis /production; drug screening /evaluation; enzyme inhibitors; gene expression; gene expression profiling; laboratory rat; male; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; neoplastic cell; neoplastic process; nitric oxide synthase; nonhuman therapy evaluation; prostaglandin endoperoxide synthase

DESCRIPTION (provided by applicant): The overall objective of this proposal is to develop the use of inducible nitric oxide synthase (iNOS)-selective inhibitors in the chemoprevention of colorectal cancer, and to gain an understanding of the cellular and molecular mechanism(s) of tumor inhibition by these agents. In addition, we will design the strategies for improving the efficacy of colon cancer prevention and treatment by concurrent application of iNOS- and COX-2 selective inhibitors. Colorectal cancer is one of the most common human malignancies in the United States, anticipated to account for 140,000 new cases and about 56,000 deaths in the year 2003. Developing treatment strategies, aimed at a specific molecular target that facilitate(s) tumor cell growth, uncontrolled expansion and invasion, provide a rational approach. Nitric oxide, produced by isoforms of NOS, has been implicated in several pathophysiological conditions including colon carcinogenesis. Our studies and those of others indicate that iNOS activities were up-regulated several-fold in colon tumors compared to normal mucosa and, importantly, nitric oxide or its reactive molecules derived from these enzymes play a pivotal role in modulation of apoptosis and proliferation. Recent evidence from our laboratory suggests that iNOS-selective inhibitors suppress chemically-induced colon carcinogenesis and also tumor formation in transgenic APC min mice. Thus, it is important to systematically develop iNOS-selective inhibitors for colon cancer prevention/treatment and delineate the specific mechanisms that lead to inhibition of tumorigenesis by these agents. Specifically, we will 1) examine the chemopreventive efficacy of different iNOS-inhibitors [PBIT, NILT and BIPPA] on azoxymethane (AOM)-induced colon carcinogenesis in rats (maximum tolerated dose selection; dose-response effects; and effectiveness during promotion/progression stages of colon carcinogenesis; 2) establish strategies to improve efficacy of colon cancer prevention and treatment by a combination of COX-2- and iNOS-selective inhibitors and 3) assess the cellular and molecular biomarkers associated with iNOS inhibition/COX-2 inhibition (apoptotic and proliferation changes, nitric oxide, 3-nitrotyrosine, and expression and activities of isoforms of NOS and COX) and study the modulation of gene expression profiles to identify changes in functional groups of genes associated with apoptosis, cell-cycle regulation and iNOS and COX-2 mediated signals and 4) understand the mechanisms by which inhibitors of iNOS and COX-2 modulate colon tumor cell proliferation and apoptosis.

描述（由申请人提供）：本提案的总体目标是开发诱导型一氧化氮合酶（iNOS）选择性抑制剂在结直肠癌化学预防中的应用，并了解这些药物抑制肿瘤的细胞和分子机制。此外，我们将设计同时应用iNOS-和COX-2选择性抑制剂来提高结肠癌预防和治疗功效的策略。结直肠癌是美国最常见的人类恶性肿瘤之一，预计 2003 年将导致 140,000 例新发病例和约 56,000 例死亡。针对促进肿瘤细胞生长、不受控制的扩张和侵袭的特定分子靶标制定治疗策略，提供了一种合理的方法。一氧化氮由 NOS 亚型产生，与包括结肠癌发生在内的多种病理生理状况有关。我们和其他人的研究表明，与正常粘膜相比，结肠肿瘤中的 iNOS 活性上调数倍，重要的是，一氧化氮或其衍生自这些酶的反应分子在细胞凋亡和增殖的调节中发挥着关键作用。我们实验室的最新证据表明，iNOS 选择性抑制剂可抑制化学诱导的结肠癌发生以及转基因 APC min 小鼠中的肿瘤形成。因此，系统地开发用于结肠癌预防/治疗的iNOS选择性抑制剂并阐明这些药物抑制肿瘤发生的具体机制非常重要。 具体来说，我们将 1) 检查不同 iNOS 抑制剂 [PBIT、NILT 和 BIPPA] 对氧化偶氮甲烷 (AOM) 诱导的大鼠结肠癌发生的化学预防功效（最大耐受剂量选择；剂量反应效应；以及结肠癌发生促进/进展阶段的有效性；2）建立策略，通过以下方法提高结肠癌预防和治疗的功效： COX-2-和iNOS-选择性抑制剂的组合，3) 评估与iNOS抑制/COX-2抑制相关的细胞和分子生物标志物（凋亡和增殖变化、一氧化氮、3-硝基酪氨酸、NOS和COX亚型的表达和活性）并研究基因表达谱的调节，以确定与凋亡相关的基因功能组的变化， 细胞周期调节以及 iNOS 和 COX-2 介导的信号，4) 了解 iNOS 和 COX-2 抑制剂调节结肠肿瘤细胞增殖和凋亡的机制。