Overexpression of 5-lipoxygenase and cyclooxygenase 2 in hamster and human oral cancer and chemopreventive effects of zileuton and celecoxib
Overexpression of 5-lipoxygenase and cyclooxygenase 2 in hamster and human oral cancer and chemopreventive effects of zileuton and celecoxib
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DOI：
10.1158/1078-0432.ccr-04-1684
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发表时间：
2005-03-01
影响因子：
11.5
通讯作者：
Chen, XX
中科院分区：
文献类型：
--
作者：
Li, N;Sood, S;Chen, XX
目的：以往的研究表明，花生四烯酸代谢异常，尤其是环氧合酶（考克斯）途径，在口腔癌的发生中起重要作用。然而，目前尚不清楚5-脂氧合酶（5-Lox）通路是否有助于口腔癌的发生，以及两种通路的抑制剂的组合是否可能具有化学预防的协同或累加效应。用免疫组织化学方法检测了7，12-二甲基苯并[a]蒽（DMBA）诱导的仓鼠和人口腔癌组织中5-Lox的表达，用原位杂交法检测仓鼠口腔组织中Cox2的表达。门顿（一个特定的5-Lox抑制剂）和塞来昔布（一个特定的Cox2抑制剂），无论是单独或组合，进行了研究，其化学预防作用的DMBA诱导的仓鼠模型在启动后阶段，通过局部application.Results：5-Lox过表达在仓鼠和人类的口腔癌发生过程中，以及在仓鼠组织中的Cox2。在一项使用启动后DMBA模型的化学预防研究中，仓鼠口腔鳞状细胞癌的发生率从76.9%降低（20/26）至45.8%（11/24，P <0.05）和32.1% 3%和6%局部齐留通组分别为57.6%（15/26，P> 0.05）和50%（12/24，P <0.05）。塞来昔布和门顿（各3%）联合使用时，对鳞状细胞癌的发病率具有相加抑制作用（36%，9/25，P <0.01）。其他病理变量和水平的白三烯B4和前列腺素E2的仓鼠tissues.Conclusions的减少，以及：结果清楚地表明，5-Lox和Cox2在口腔癌的发生发挥了重要作用。齐留通和塞来昔布通过其对花生四烯酸代谢的抑制作用在起始后阶段预防口腔癌的发生。
Purpose: Previous studies have suggested an important role of aberrant arachidonic acid metabolism, especially the cyclooxygenase (Cox) pathway, in oral carcinogenesis. However, it is unknown whether the 5-lipoxygenase (5-Lox) pathway contributes to oral carcinogenesis, and whether combination of inhibitors of both pathways may have synergistic or additive effects of chemoprevention.Experimental Design: 5-Lox expression was examined in 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster and human oral cancer tissues by immunohistochemistry, and Cox2 expression was investigated in hamster oral tissues using in situ hybridization. Menton (a specific 5-Lox inhibitor) and celecoxib (a specific Cox2 inhibitor), either alone or in combination, were investigated for their chemopreventive effects on the DMBA-induced hamster model at the post-initiation stage through topical application.Results: 5-Lox was overexpressed during oral carcinogenesis in hamsters and humans, as well as Cox2 in the hamster tissues. In a chemoprevention study using the postinitiation DMBA model, incidence of hamster oral squamous cell carcinoma was reduced from 76.9% (20 of 26) to 45.8% (11 of 24, P < 0.05) and 32.1% (9 of 28, P < 0.01) by 3% and 6% topical zileuton, respectively; and to 57.6% (15 of 26, P > 0.05) and 50% (12 of 24, P < 0.05) by 3% and 6% topical celecoxib, respectively. When used in combination, celecoxib and Menton (3% of each) had an additive inhibitory effect on the incidence of squamous cell carcinoma (36%, 9 of 25, P < 0.01). Other pathologic variables and the levels of leukotriene B4 and prostaglandin E2 of the hamster tissues were reduced as well.Conclusions: The results clearly showed that both 5-Lox and Cox2 played important roles in oral carcinogenesis. Zileuton and celecoxib prevented oral carcinogenesis at the post-initiation stage through their inhibitory effects on arachidonic acid metabolism.