Tobacco Carcinogen Oral Cancer Model

描述（由申请人提供）： 在美国，每年约有30，000例新的口腔癌病例。口腔癌通常与烟草制品的使用有关，但目前减少新病例数量的预防方法无效。一个与人类暴露于烟草致癌物平行的口腔癌模型有望提高我们预防口腔癌的能力。验证口腔癌模型通常依赖于合成致癌物，最大限度地减少与人类暴露经验和口腔粘膜变化的相似性。其他环境因素，烟草特有的N-亚硝胺，或槟榔碱从甜菜坚果要么缺乏能力，启动口腔致癌或尚未进行广泛的细胞生物学机制的评估。很少有口腔致癌作用的研究，审查了细胞的事件，在口腔角化细胞暴露于烟草致癌物。本研究的目的是建立一种烟草致癌物诱导的口腔癌模型，为口腔癌的预防提供一种可复制的模型。该模型在相对较短的诱导期后将具有高肿瘤发病率和多样性。舌和口底的肿瘤诱导将与人类的部位平行。该模型还将扩展到其他模型，如豚鼠和基因敲除小鼠，以研究预防。环境和烟草致癌物，峡湾结构，二苯并[a，I]芘，二B [a，I]P将比较海湾地区的化学品，苯并[a]芘，B[a]P，一个既定的口腔仓鼠致癌物。在初步研究中，观察到二B [a，I]P是比B[a] P更有效的致癌物。diB[a，I]P/B[a]P评估肿瘤发生率和多重性的剂量反应效应。lb.口腔癌发生过程中DNA加合物类型、组织学部位和p53突变的检测lc.膜（芳基水解酶）和细胞质I相和II相酶的评估。LD.早期细胞启动和促进事件的确认对我们理解口腔癌的预防至关重要。

DESCRIPTION (provided by applicant): In the United States there are about 30,000 new oral cancer cases per year. Oral cancer is often associated with tobacco product use but current prevention methods to reduce numbers of new cases are ineffective. An oral cancer model paralleling human exposure to tobacco carcinogens is expected to enhance our ability to prevent oral cancer. Exisiting oral cancer models have generally relied upon synthetic carcinogens minimizing parallels to human exposure experience and changes in oral mucosa. Other environmental agents, tobacco specific N-nitrosamines, or arecoline derived from the betal nut either lack the ability to initiate oral carcinogenesis or have not been evaluated extensively for cell biology mechanisms. Few oral carcinogenesis studies have examined the cellular events in the oral keratincyte following exposure to tobacco carcinogen. Our goal is to establish a tobacco carcinogen induced oral carcinogenesis model, which can be replicated by others for prevention of oral cancer. This model will have a high tumor incidence and multiplicity after a relatively short period of induction. Tumor induction in tongue and floor of the mouth will parallel sites in humans. This model will also be extendable to other models such as the guinea pig and knock-out mouse to study prevention. Environmental and tobacco carcinogens, fjord structured, dibenzo[a,I]pyrene, diB[a,I]P will be compared to a bay region chemical, benzo[a]pyrene, B[a]P, an established oral carcinogen in the hamster. In a preliminary study, diB[a,I]P was observed to be a more potent carcinogen than B[a]P. This result requires confirmation which we will obtain from the following studies: Aim la. A dose response effect for diB[a,I]P/B[a]P assessing tumor incidence and multiplicity. lb. Detection of DNA adduct type and presence in histologic sites and p53 mutations during oral carcinogenesis. lc. Assessments of membrane (aryl hydrolase) and cytoplasmic phase I and II enzymes. ld. Confirmation of early cellular initiation and promotion events critical to our understanding for prevention of oral cancer.