MECHANISM OF NITROSAMINE ALKYALTION OF DNA AND RNA

目的是了解亚硝胺和亚硝胺的致癌作用。 它们的组织特异性效应的机制。具体地说，这 提案涉及BOP引发肿瘤的机制及相关 β-氧化亚硝胺导致胰腺管肿瘤和 叙利亚仓鼠体内的小管。这些肿瘤特别有趣，而且 重要的是因为它们与人类胰腺肿瘤相似，而 在性质上也主要是导管状。BOP对DNA甲基化的作用机制 将使用体外测试系统进行研究。在场的人 测定胰腺组织中的活化酶(S)。使用一种新的、 高灵敏的分析06-甲基鸟嘌呤、生成物和 在金黄地鼠分离的腺泡细胞和胰岛中修复这种修饰的碱基 老鼠将被测量。这项研究的结果将提供 关于防喷器目标单元的性质的信息，以及是否 敏感和不敏感(老鼠)物种在DNA方面有所不同 甲基化。为了直接评估肝脏是否在 BOP激活为胰腺的甲基化试剂，甲基化 BOP对胰腺DNA的影响将在接受了 肝脏部分切除，以及隔离的灌流胰腺。至 评估肝脏代谢的贡献，为胰腺灌流 将首先通过一个完整的仓鼠肝脏进行灌流。长期影响 将通过测量来评估培养的仓鼠胰岛的BOP和HPOP β细胞功能(胰岛素分泌)。对培养细胞有丝分裂的刺激 高葡萄糖浓度的胰岛将被用来优化机会 获得体外转化的可能性。此外，对有丝分裂的刺激 在体内通过静脉输注葡萄糖将被用来在仓鼠身上 确定胰岛前体细胞是否在胰腺癌的发生中起作用 波普。综合这些相互关联的目标的结果将提供 关于目标细胞的性质和机制的信息 BOP及相关亚硝胺对仓鼠胰腺的致瘤作用 以及大鼠胰腺对这些化合物具有抵抗力的原因。

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.