CYCLOOXYGENASE 2 ABD PREVENTION OF HEAD AND NECK CANCER

本提案的总体目标是确定 环氧合酶-2（考克斯-2）是考克斯的诱导型，是治疗的靶点 用于预防头颈部鳞状细胞癌（HNSCC）。几 一系列证据表明考克斯-2在癌发生中是重要的。考克斯-2是 在转化细胞和包括结肠癌在内的几种恶性肿瘤中上调 癌此外，考克斯-2缺陷可保护肿瘤的发生。 实验动物本申请人已经发现，考克斯-2的水平是 在HNSCC中升高。这一发现增加了选择性考克斯-2 抑制剂将保护免受HNSCC，如最近显示的结肠癌。 该建议的一个目的是确定考克斯-2上调的阶段 在人类正常鳞状上皮向HNSCC的进展中。几 包括定量RT-PCR、免疫印迹和 将使用免疫组织化学。第二个目标是确定 HNSCC中考克斯-2水平升高的机制。这项工作将 可以在人体组织和体外进行。研究发现， 考克斯-2在HNSCC中升高并不保证考克斯-2的抑制将 预防HNSCC。因此，第三个目标将是调查是否有选择性的 考克斯-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 类维生素A（一类化学预防剂）抑制 口腔鳞癌中考克斯-2转录激活和前列腺素合成 细胞这些研究的结果将为作出决定提供依据 关于选择性考克斯-2抑制剂是否应该作为化学预防剂进行测试， 药物治疗有HNSCC风险的患者。

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.