HMG CoA REDUCTASE AND COX2 INHIBITORS IN COLON CANCER

描述(申请人提供)：本建议书的总体目标是 测定洛伐他汀联合应用的化学预防效果 (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)抗结肠癌和了解 这些药物抑制肿瘤的机制(S)。 结直肠癌是美国最常见的人类恶性肿瘤之一。 各州，预计#年新增病例137,000例，死亡约56,000例 2001年。开发以抑制肿瘤为目的的化学预防药物(S) 细胞生长，但不是正常的细胞生长，通过靶向特定的基因/因子 为肿瘤的生长提供了一条合理的途径。我们的研究 而其他研究表明，COX-2和HMG-R活性上调 与正常粘膜相比，结肠肿瘤中的几倍，更重要的是， 由这些酶衍生的代谢物/分子在 对细胞凋亡和增殖的调控。临床最新证据 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 环氧合酶抑制剂(非类固醇抗炎药)产生协同作用 抑制结肠癌的作用。因此，重要的是要系统地 HMG-R抑制剂及其与COX-2抑制剂联用治疗结肠癌的研究进展 癌症预防和描述导致调节的特定机制 这些药物对细胞凋亡和增殖的抑制作用。 具体地说，我们将检查1)洛伐他汀的化学预防效果 偶氮甲烷(AOM)诱发大鼠结肠癌(最大耐受量 选择；剂量-反应效应； 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诱导的结肠癌形成的影响及疗效评价 这些代理组合在促销/晋升阶段，以及3) 通过测定洛伐他汀与洛伐他汀合用或不合用来阐明其作用机制(S) 塞来昔布对HMG-CoA还原酶、FPTase、GGPTase、p53、 P21CIP/WAF1、caspase-3和-6、Bax、Bcl2、Fas和lamin B、COX-2、PPAR-y、p53、 和前列腺素水平。最后，我们将研究这些制剂的影响。 结肠不同发育阶段细胞增殖和凋亡的研究 致癌。

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.