HMG CoA REDUCTASE AND COX2 INHIBITORS IN COLON CANCER

HMG CoA 还原酶和 COX2 抑制剂在结肠癌中的作用

• 批准号: 6864445
• 负责人: Chinthalapally V. Rao
• 金额: $ 32.6万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6864445
• 关键词: HMG coA reductases; apoptosis; cancer prevention; cell proliferation; chemical carcinogen; chemical carcinogenesis; chemoprevention; colon neoplasms; enzyme activity; laboratory rat; lovastatin; nonsteroidal antiinflammatory agent; oxidoreductase inhibitor; prostaglandin endoperoxide synthase

DESCRIPTION (provided by applicant): The overall objective of this proposal is to determine the chemopreventive efficacy of a combination of lovastatin (3-hydroxy-3-methylglutaryl CoA reductase (HMG-R) inhibitor and celecoxib (COX-2-selective inhibitor) against colon cancer and to gain an understanding of the mechanism(s) of tumor inhibition by these agents. Colorectal cancer is one of the most common human malignancies in the United States, anticipated to account for 137,000 new cases and about 56,000 deaths in the year 2001. Developing chemopreventive agent(s) that aim to suppress tumor cell growth, but not normal cell growth, by targeting specific genes/factors that are responsible for tumor growth provides a rational approach. Our studies and those of others indicate that COX-2 and HMG-R activities were up-regulated several-fold in colon tumors compared to normal mucosa and, importantly, the metabolites/molecules derived from these enzymes play a pivotal role in modulation of apoptosis and proliferation. Recent evidence from clinical trials, and in vivo and in vitro laboratory studies suggest that application of a combination of HMG-R inhibitors (cholesterol-lowering drugs) and COX-inhibitors (nonsteroidal anti-inflammatory drugs) produces synergistic colon cancer-inhibiting effects. Thus, it is important to systematically develop HMG-R inhibitors and their combination with COX-2 inhibitors for colon cancer prevention and delineate the specific mechanisms that lead to modulation of apoptosis and proliferation by these agents. Specifically, we will examine 1) the chemopreventive efficacy of lovastatin on azoxymethane (AOM)-induced colon carcinogenesis in rats (maximum tolerated dose selection; dose-response effects; and effectiveness during promotion/progression stages, 2) study the synergistic effects of lovastatin and celecoxib on AOM-induced colon carcinogenesis and assess effectiveness of these agents in combination on the promotion/progression stages, and 3) elucidate mechanisms by determining the effect(s) of lovastatin with or without combination of celecoxib on HMG-CoA reductase, FPTase, GGPTase, p53, p21CIP/WAF1, caspase-3 &- 6, Bax, Bcl-2, Fas and lamin B, COX-2, PPAR-y, p53, and prostaglandins levels. Finally, we will study the effects of these agents on cell proliferation, and apoptosis during different stages of colon carcinogenesis.

描述（由申请人提供）：该提案的总体目标是 确定lovastatin结合的化学预防功效 （3-羟基-3-甲基戊二酰COA还原酶（HMG-R）抑制剂和塞来昔布 （COX-2选择性抑制剂）针对结肠癌并获得了解 这些药物的肿瘤抑制机制。 大肠癌是曼联最常见的人类恶性肿瘤之一 各州预计将占137,000例新病例和约56,000例死亡 2001年。开发旨在抑制肿瘤的化学预防剂 通过靶向特定基因/因素，细胞生长，但不是正常细胞生长 负责肿瘤生长的那些提供了一种合理的方法。我们的研究 其他的表明COX-2和HMG-R活动被上调 与正常粘膜相比，结肠肿瘤的几倍，重要的是 源自这些酶的代谢产物/分子在 凋亡和增殖的调节。临床的最新证据 试验以及体内和体外实验室研究表明，应用 HMG-R抑制剂（降低胆固醇的药物）和 Cox抑制剂（非甾体抗炎药）产生协同作用 结肠癌抑制作用。因此，系统地很重要 开发HMG-R抑制剂及其与COX-2抑制剂的结合 预防癌症并描述导致调节的特定机制 这些药物的凋亡和增殖。 具体而言，我们将检查1）lovastatin在 甲氧基甲烷（AOM）诱导的大鼠结肠癌发生（最大耐受剂量 选择；剂量反应效应；和有效性 促进/进步阶段，2）研究洛伐他汀的协同作用 和塞来昔布在AOM诱导的结肠癌发生并评估的有效性 这些代理在促进/进展阶段结合在一起，3） 通过确定lovastatin的效果，有或没有，阐明机制 Celecoxib在HMG-COA还原酶，FPTase，GGPTASE，p53，p53， P21CIP/WAF1，CASPASE-3＆-6，BAX，BCL-2，FAS和LAMIN B，COX-2，PPAR-Y，P53， 和前列腺素水平。最后，我们将研究这些试剂的影响 在细胞增殖和结肠不同阶段的凋亡中 致癌作用。