Chemoprevention of Tobacco-related Oral Carcinogenesis

描述（由申请人提供） 本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]蒽（DMBA）诱导的仓鼠颊囊模型，该模型在启动后阶段模拟既往吸烟者的口腔致癌作用。我们的初步结果显示，在口腔癌中，白三烯A4水解酶（LTA 4 H）、环氧合酶2（Cox 2）和表皮生长因子受体（EGFR）过表达，在本申请中，我们计划检验抑制异常花生四烯酸（AA）代谢和EGFR/ErbB 2将预防口腔癌发生的假设，具体目标如下： 1.确定LTA 4 H、Cox 2和EGFR/ErbB 2的特异性抑制剂作为化学预防剂在短期和长期实验中对口腔癌发生的有效性。VVE将局部应用bestatin（LTA 4 H抑制剂），塞来昔布（Cox 2抑制剂）或GW 2974（EGFR/ErbB 2的双重抑制剂）对DMBA处理的仓鼠颊囊的作用，以确定它们对白三烯B4（LTB 4）、前列腺素E2（PGE 2）和EGFR/ErbB 2自磷酸化的形成，LTA 4 H、Cox 2和EGFR/ErbB 2的表达，增殖，凋亡，炎症，和癌形成。这些参数将被关联以开发用于化学预防的潜在替代生物标志物。 2.通过局部应用20-tri-fluoro-LTB_4或16，16-dimethyt-PGE_2，以确定LTB_4和PGE_2在促进口腔癌发生中的功能作用。在短期和长期实验中，将检查它们对细胞信号传导激酶、AA代谢、细胞增殖、凋亡、炎症以及发育异常和癌的发展的影响。将进一步研究潜在的替代生物标志物。 3.研究上述抑制剂组合的化学预防作用，并验证目标1中鉴定的替代生物标志物的有用性。 这些研究预计将有助于显著预防口腔癌的前吸烟者。本文研究的一些试剂和生物标志物可用于患有白斑病和红斑病的个体的化学预防。

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.