HMG CoA REDUCTASE AND COX2 INHIBITORS IN COLON CANCER

描述（由申请人提供）：本提案的总体目标是 为了确定洛伐他汀和阿司匹林的组合的化学预防功效， （3-羟基-3-甲基戊二酰辅酶A还原酶（HMG-R）抑制剂和塞来昔布 （考克斯-2-选择性抑制剂）治疗结肠癌，并获得了解 这些药物抑制肿瘤的机制。 结直肠癌是美国最常见的人类恶性肿瘤之一， 美国，预计将有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 细胞生长，但不是正常细胞生长，通过靶向特定基因/因子 提供了一个合理的方法。我们的研究 而其他研究结果表明，考克斯-2和HMG-R的活性均上调 结肠肿瘤中的肿瘤细胞数倍于正常粘膜，重要的是， 衍生自这些酶的代谢物/分子在 调节细胞凋亡和增殖。最近的临床证据 试验以及体内和体外实验室研究表明， HMG-R抑制剂（降胆固醇药物）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 开发HMG-R抑制剂及其与考克斯-2抑制剂的组合用于结肠 癌症预防和描绘的具体机制，导致调制 细胞凋亡和增殖。 具体来说，我们将研究1）洛伐他汀的化学预防功效， 氧化偶氮甲烷（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 促进/进展阶段，2）研究洛伐他汀的协同作用 和塞来昔布对AOM诱导的结肠癌发生的影响，并评估 这些药剂在促进/进展阶段的组合，和3） 通过确定洛伐他汀与或不与 塞来昔布联合用药对HMG-CoA还原酶、FPT酶、GGPT酶、p53 p21 CIP/WAF 1、半胱天冬酶-3和-6、Bax、Bcl-2、Fas和核纤层蛋白B、考克斯-2、PPAR-y、p53、 和肾上腺素水平。最后，我们将研究这些药剂的作用 对结肠不同阶段细胞增殖和凋亡的影响 致癌作用

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.