Chemoprevention of Tobacco-related Oral Carcinogenesis

描述(由申请人提供) 该项目的目的是设计基于机制的化学预防策略，并开发烟草相关口腔癌发生的替代生物标志物。将使用7，12-二甲基苯并[a]菲(DMBA)诱导的仓鼠面颊囊后启动阶段的模型，该模型模仿以前吸烟者的口腔癌变。我们的初步结果表明，白三烯A4水解酶(LTA4H)、环氧合酶2(COX2)和表皮生长因子受体(EGFR)在口腔癌中过表达，在这一应用中，我们计划验证抑制异常的花生四烯酸(AA)代谢和EGFR/ErbB2将预防口腔癌发生的假设，具体目的如下： 1.确定LTA4H、COX2和EGFR/ErbB2的特异性抑制剂在短期和长期实验中作为口腔癌化学预防药物的有效性。VVE将Bestatin(LTA4H抑制剂)、Celecoxib(COX2抑制剂)或GW2974(EGFR/ErbB2双重抑制剂)局部应用于DMBA处理的金黄地鼠颊囊，以确定它们对白三烯B4(LTB4)、前列腺素E2(PGE2)和EGFR/ErbB2自动磷酸化的形成、LTA4H、COX2和EGFR/ErbB2的表达、增殖、凋亡、炎症和癌症形成的抑制作用。这些参数将与开发潜在的化学预防替代生物标记物相关。 2.用20-三氟-LTB_4或16，16-二甲基前列腺素E_2对单剂量DMBA处理的金黄地鼠进行局部应用，以确定LTB_4和PGE_2在促进口腔癌发生中的作用。在短期和长期实验中，将检测它们对细胞信号转导、AA代谢、细胞增殖、细胞凋亡、炎症以及异型增生和癌症发展的影响。潜在的替代生物标志物将进一步研究。 3.研究上述抑制剂组合的化学预防作用，并验证目标1中确定的替代生物标记物的有用性。 这些研究有望为预防戒烟者口腔癌的发生做出重大贡献。本文研究的一些试剂和生物标志物可用于白斑和红斑患者的化学预防。

DESCRIPTION (provided by applicant) The aim of this project is to design mechanism-based chemopreventive strategies and to develop surrogate biomarkers for tobacco-related oral carcinogenesis. The 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster cheek pouch model at the post-initiation stage, which mimics oral carcinogenesis in former smokers, will be used. Our preliminary results showed overexpression of leukotriene A4 hydrolase (LTA4H), cyclooxygenase 2 (Cox2) and epidermal growth factor receptor (EGFR) in oral cancer, in this application, we plan to test the hypothesis that inhibition of aberrant arachidonic acid (AA) metabolism and EGFR/ErbB2 will prevent oral carcinogenesis, with the following specific aims: 1. To determine the effectiveness of specific inhibitors of LTA4H, Cox2, and EGFR/ErbB2, as chemopreventive agents against oral carcinogenesis in short-term and long-term experiments. Vve will topically apply bestatin (LTA4H inhibitor), celecoxib (Cox2 inhibitor), or GW2974 (dual inhibitor of EGFR/ErbB2) to DMBA-treated hamster cheek pouches, to determine their efficacy against the, formation of leukotriene B4 (LTB4), prostaglandin E2 (PGE2) and EGFR/ErbB2 autophosphorylation, the expression of LTA4H, Cox2 and EGFR/ErbB2, proliferation, apoptosis, inflammation, and carcinoma formation. These parameters wilt be correlated to develop potential surrogate biomarkers for chemoprevention. 2. To determine the functional roles of LTB4 and PGE2 in promoting oral carcinogenesis by topically applying 20-tri-fluoro-LTB4 or 16,16-dimethyt-PGE2 to hamsters treated with one dose of DMBA. In short-term and long-term experiments, their effects on cell signaling kinases, AA metabolism, ceil proliferation, apoptosis, inflammation, and the development of dysplasia and carcinoma will be examined. The potential surrogate biomarkers will be further studied. 3. To investigate the chemopreventive effects of combinations of the above inhibitors, and to validate the usefulness of the surrogate biomarkers identified in Aim 1. These studies are expected to contribute significantly to the prevention of oral carcinogenesis in former smokers. Some of the agents and biomarkers studied herein may be used for chemoprevention in individuals with leukoplakia and erythroplakia.