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）：该提案的总体目的是开发使用诱导的一氧化氮合酶（INOS） - 选择性抑制剂在结直肠癌的化学预防中的选择，并了解细胞和分子机制（S）这些药物抑制肿瘤。此外，我们将设计通过同时应用Inos-和Cox-2选择性抑制剂来提高预防结肠癌和治疗功效的策略。结直肠癌是美国最常见的人类恶性肿瘤之一，预计在2003年将造成140,000例新病例和约56,000例死亡。制定治疗策略，旨在促进特定的分子靶标，以促进肿瘤细胞的生长，不受控制的扩张和入侵提供了一种理性的方法。由NOS的同工型产生的一氧化氮与包括结肠癌发生在内的几种病理生理条件有关。我们的研究和其他研究表明，与正常粘膜相比，结肠肿瘤中的iNOS活性被上调了几倍，重要的是，源自这些酶的一氧化氮或其反应性分子在调节凋亡和增殖中起着关键作用。我们实验室的最新证据表明，iNOS选择性抑制剂抑制了化学诱导的结肠癌发生以及在转基因APC Min小鼠中的肿瘤形成。因此，重要的是系统地开发用于预防结肠癌/治疗的iNOS选择性抑制剂，并描述导致这些药物抑制肿瘤发生的特定机制。 具体而言，我们将1）检查大鼠（最大剂量选择；剂量 - 反应效应；在促进/进展/进展过程中有效性，在促进/进展/进展过程中，在促促进剂剂量的剂量选择；最大耐受剂量的效果；最大的剂量选择效应；在促进/进展过程中有效性，在甲氧基甲烷（AOM）诱导的结肠癌上的化学预防疗效[PBIT，NILT和BIPPA]在甲氧甲烷（AOM）诱导的结肠癌上的化学疗效。结肠癌的阶段； 2）建立通过COX-2-和iNOS选择性抑制剂的结合以及3）评估与Inos抑制/COX-2抑制相关的细胞和分子生物标记的策略（凋亡和增殖的变化，一氧化氮，3-硝基酪氨酸以及NOS和COX的同工型的表达和活性），研究基因表达谱的调节以鉴定与凋亡，细胞周期调节和INOS和INOS和INOS和INOS和INOS和INOS和INOS和INOS和INOS和INOS的功能组变化COX-2介导的信号和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。