MECHANISM OF NITROSAMINE ALKYALTION OF DNA AND RNA

目的是了解亚硝胺的致癌作用， 其组织特异性作用的机制。 具体来说， 该提案阐述了BOP引发肿瘤的机制和相关的 β-氧化亚硝胺，可诱发胰腺导管肿瘤， 叙利亚仓鼠的小管。 这些肿瘤特别有趣， 重要是因为它们与人类胰腺肿瘤相似， 本质上也主要是导管。 BOP诱导DNA甲基化的机制 将使用体外测定系统进行研究。 存在 将测定胰腺组织中的活化酶。 使用新的， 用于分析06-甲基鸟嘌呤、形成和 在仓鼠的离体腺泡细胞和胰岛中修复这种修饰的碱基 并测量大鼠。 这项研究的结果将提供 关于BOP的目标小区的性质的信息，以及是否 易感和非易感物种（大鼠）在DNA方面不同 甲基化 为了直接评估肝脏是否在 BOP活化为胰腺的甲基化试剂，甲基化 胰腺DNA的BOP将在已经接受了 部分肝切除术和离体灌注胰腺。 到 评估肝脏代谢、灌注液对胰腺的贡献 将首先通过一个完整的仓鼠肝脏进行灌注。 长期影响 将通过测量BOP和HPOP在培养的仓鼠胰岛上的浓度来评估BOP和HPOP在培养的仓鼠胰岛上的浓度。 β细胞功能（胰岛素分泌）。 刺激培养的有丝分裂 将使用高葡萄糖浓度的胰岛来优化 获得体外转化。 此外，刺激有丝分裂 通过仓鼠的静脉内葡萄糖输注进行体内试验， 确定胰岛前体细胞是否在肿瘤发生中起作用， BOP。 将这些相互关联的目标的结果结合起来， 关于靶细胞的性质和靶细胞的作用机制的信息。 BOP和相关亚硝胺在仓鼠胰腺中引发肿瘤， 以及大鼠胰腺对这些化合物产生耐药性的原因。

The objective is to understand the carcinogenic action of nitrosamines and the mechanism of their tissue specific effects. Specifically, this proposal addresses the mechanism of tumor initiation by BOP and related Beta-oxidized nitrosamines which induce tumors of the pancreatic ducts and ductules in Syrian hamsters. These tumors are particularly interesting and important because of their similarity to pancreatic tumors in man which are also principally ductal in nature. The mechanism of DNA methylation by BOP will be investigated using an in vitro assay system. Presence of the activating enzyme(s) in pancreatic tissue will be determined. Using a new, highly sensitive method for analysis of 06-methylguanine, formation and repair of this modified base in isolated acinar cells and islets of hamster and rat will be measured. The results of this study will provide information regarding the nature of the target cell for BOP, and whether susceptible and non-susceptible (rat) species differ with respect to DNA methylation. In order to assess directly whether the liver plays a role in the activation of BOP to a methylating agent for the pancreas, methylation of pancreatic DNA by BOP will be determined in hamsters that have received a partial hepatectomy and also in the isolated perfused pancrease. To assess the contribution of hepatic metabolism, perfusate for the pancreas will be first perfused through an intact hamster liver. Long-term effects of BOP and HPOP on cultured hamster islets will be evaluated by measuring Beta-cell function (insulin secretion). Stimulation of mitosis in cultured islets by high glucose concentrations will be used to optimize the chances of obtaining in vitro transformation. Furthermore, stimulation of mitosis in vivo by intravenous glucose infusion in hamsters will be used to determine whether islet precursor cells play a role in the tumorigenesis of BOP. Integration of the results from these interrelated aims will provide information concerning the nature of the target cell and the mechanism of tumor initiation by BOP and related nitrosamines in the hamster pancreas, and reasons why the rat pancreas is resistant to these compunds.