HMG CoA REDUCTASE AND COX2 INHIBITORS IN COLON CANCER

描述（由申请人提供）：该提案的总体目标是 确定洛伐他汀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 （COX-2-选择性抑制剂）对抗结肠癌并获得了解 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 各州预计将新增 137,000 例新病例，约 56,000 例死亡 2001年。开发旨在抑制肿瘤的化学预防剂 通过针对特定基因/因子来促进细胞生长，但不是正常细胞生长 负责肿瘤生长的研究提供了一种合理的方法。我们的研究 和其他人的研究表明 COX-2 和 HMG-R 活性上调 与正常粘膜相比，结肠肿瘤的数倍，重要的是， 来自这些酶的代谢物/分子在 细胞凋亡和增殖的调节。来自临床的最新证据 试验以及体内和体外实验室研究表明，应用 HMG-R 抑制剂（降胆固醇药物）和 COX抑制剂（非甾体抗炎药）产生协同作用 抑制结肠癌的作用。因此，系统地 开发用于结肠的 HMG-R 抑制剂及其与 COX-2 抑制剂的组合 癌症预防并描述导致调节的具体机制 这些试剂导致的细胞凋亡和增殖。 具体来说，我们将检查 1) 洛伐他汀对以下疾病的化学预防功效： 氧化偶氮甲烷（AOM）诱导大鼠结肠癌发生（最大耐受剂量 选择；剂量反应效应；以及期间的有效性 晋升/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其有效性 这些代理在晋升/进展阶段结合使用，以及 3) 通过确定洛伐他汀有或没有的作用来阐明机制 塞来昔布对 HMG-CoA 还原酶、FPTase、GGPTase、p53 的组合， p21CIP/WAF1、caspase-3 &- 6、Bax、Bcl-2、Fas 和核纤层蛋白 B、COX-2、PPAR-y、p53、 和前列腺素水平。最后，我们将研究这些药剂的效果 结肠不同阶段细胞增殖、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.