CYCLOOXYGENASE 2 ABD PREVENTION OF HEAD AND NECK CANCER

这项提案的总体目标是确定是否 环氧合酶-2(COX-2)是COX的诱导形式，是治疗的靶点 用于预防头颈部鳞状细胞癌(HNSCC)。几个 一系列证据表明，COX-2在癌症发生中起着重要作用。COX-2是 在转化细胞和包括结肠在内的几种恶性肿瘤中上调表达 癌症。此外，COX-2缺乏保护肿瘤的发生。 实验动物。申请人发现，COX-2的水平是 在HNSCC中升高。这一发现增加了选择性COX-2 抑制剂可以预防HNSCC，就像最近对结肠癌所显示的那样。 这项提案的目的之一是定义COX-2上调的阶段 在人类正常鳞状上皮向HNSCC发展的过程中。几个 包括定量RT-PCR、免疫印迹和 将使用免疫组织化学方法。第二个目标将是定义 HNSCC中COX-2水平升高的机制。这项工作将 在人体组织和体外都可以进行。这一发现表明， COX-2在HNSCC中升高并不能保证抑制COX-2将 预防HNSCC。因此，第三个目标将是调查选择性的 COX-2抑制剂预防化学诱导的大鼠舌鳞状细胞癌 烟草前致癌物代谢产物与DNA加合物的形成 苯并(A)芘。最后，他们将阐明潜在的分子 维甲酸类化合物抑制化学预防作用的机制(S) 口腔鳞癌组织中环氧合酶-2转录和前列腺素合成的激活 细胞。这些研究的结果将为决策提供依据 关于选择性COX-2抑制剂是否应该被测试为化学预防 HNSCC高危患者的药物。

The overall goal of this proposal is to determine whether cyclooxygenase-2 (COX-2), the inducible form of COX, is a therapeutic target for preventing squamous cell carcinoma of the head and neck (HNSCC). Several lines of evidence suggest that COX-2 is important in carcinogenesis. COX-2 is up-regulated in transformed cells and in several malignancies including colon cancer. Moreover, COX-2 deficiency protects against tumorigenesis in experimental animals. The applicant has discovered that levels of COX-2 are elevated in HNSCC. This finding raises the possibility that selective COX-2 inhibitors will protect against HNSCC as was recently shown for colon cancer. One aim of this proposal is to define the stage at which COX-2 is up-regulated in the progression of normal squamous epithelium to HNSCC in humans. Several techniques including quantitative RT-PCR, immunoblotting and immunohistochemistry will be used. A second aim will be to define the mechanisms which account for increased levels of COX-2 in HNSCC. This work will be carried out both in human tissue and in vitro. The finding that levels of COX-2 are elevated in HNSCC does not assure that inhibition of COX-2 will prevent HNSCC. Hence, the third aim will be to investigate whether a selective COX-2 inhibitor prevents chemically-induced SCC of the tongue in rats or the formation of adducts between DNA and metabolites of the tobacco procarcinogen benzo(a)pyrene. Finally, they will elucidate the underlying molecular mechanism(s) by which retinoids, a class of chemopreventive agents, suppress the activation of COX-2 transcription and prostaglandin synthesis in oral SCC cells. The results of these studies will provide a basis for making a decision about whether selective COX-2 inhibitors should be tested as chemopreventive agents in patients at risk for HNSCC.