Origins of Spontaneous Mutagenesis

自发突变的起源

• 批准号: 6866482
• 负责人: JOSEPH B GUTTENPLAN
• 金额: $ 7.38万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6866482
• 关键词: acetylcysteine; age difference; age group; animal old age; antioxidants; ascorbate; bleomycin; cancer prevention; carcinogenesis; chemoprevention; colon neoplasms; drug discovery /isolation; enzyme induction /repression; free radical scavengers; free radicals; gene mutation; genetically modified animals; inhibitor /antagonist; laboratory mouse; neoplasm /cancer genetics; neoplasm /cancer pharmacology; nucleic acid sequence; nutrition related tag; oxidative stress; tocopherols; urinary tract neoplasms

DESCRIPTION (provided by applicant): Approximately half of human cancer has no documented origin. It is often postulated that endogenous agents, including reactive oxygen species, are responsible for a significant fraction of these cancers. A presumed mechanism by which such agents act is via mutations, which in turn, may arise from DNA damage. Modified or damaged DNA has been detected at significant levels in a number of organs from nonsmokers with no known environmental exposures, lending support to this hypothesis. Mutations in proto-oncogenes and tumor suppressor genes have been found in a majority of human tumors, indicating that mutagenesis plays an important role in carcinogenesis. The lacI and lacZ rodents represent the only whole animal multi-organ systems applicable to the investigation of mutagenesis in vivo. Using such a system it has become possible to determine rates of spontaneous mutagenesis in any organ in vivo. As mutations in this system are neutral, the tissues accumulate new mutations over time, but previous mutations remain. Thus, only in organs where there is a substantial increase in spontaneous mutagenesis over time, is it practical to attempt to modify spontaneous mutagenesis. Based on reports from the lab of the PI and others, several such organs have been identified. In this application the effects of potential inhibitors on levels of spontaneous mutagenesis in two such organs (colon and bladder) will be monitored over time. The inhibitors have been chosen from classes of agents believed to prevent or reduce DNA damage from endogenous sources. These sources include oxidative agents, electrophiles, and flee radicals. The inhibitors include the antioxidant vitamins, E and C; the free radical scavenger amifostine (a known radioprotector); N-acetylcysteine, a potential radical scavenger which also enhances levels of glutathione; and 1,2-dithiole-3-thionine, a phase II enzyme inducer. In addition, the spontaneous mutation profile in older and younger animals will be compared with that of the oxidative mutagen, bleomycin, to determine whether oxidative damage is a major contributor to spontaneous mutagenesis. As mechanisms have been proposed by which the above inhibitors act, the results of this study will provide the basis for future studies on the detailed mechanisms of inhibition, and the origins of spontaneous mutagenesis. In view of the large numbers of human cancers likely attributable to endogenous sources, an understanding of spontaneous mutagenesis and the identification of inhibitory agents could have important public health consequences.

描述（由申请人提供）： 大约一半的人类癌症没有记录的起源。人们通常认为内源性因素（包括活性氧）是造成这些癌症的很大一部分的原因。推测此类药物的作用机制是通过突变，而突变又可能由 DNA 损伤引起。在没有已知环境暴露的非吸烟者的许多器官中检测到了显着水平的修饰或损坏的 DNA，这为这一假设提供了支持。大多数人类肿瘤中都发现了原癌基因和抑癌基因的突变，表明突变在癌变过程中发挥着重要作用。 lacI 和 lacZ 啮齿动物代表了唯一适用于体内诱变研究的完整动物多器官系统。使用这样的系统，可以确定体内任何器官的自发突变率。由于该系统中的突变是中性的，随着时间的推移，组织会积累新的突变，但以前的突变仍然存在。因此，只有在自发诱变随时间显着增加的器官中，尝试改变自发诱变才可行。根据首席研究员和其他实验室的报告，已经确定了几个这样的器官。在该应用中，将随着时间的推移监测潜在抑制剂对两个这样的器官（结肠和膀胱）中自发诱变水平的影响。这些抑制剂选自被认为可以预防或减少内源性 DNA 损伤的药物类别。这些来源包括氧化剂、亲电子试剂和自由基。抑制剂包括抗氧化维生素 E 和 C；自由基清除剂氨磷汀（一种已知的辐射防护剂）； N-乙酰半胱氨酸，一种潜在的自由基清除剂，也能提高谷胱甘肽的水平；和 1,2-二硫醇-3-硫堇（II 相酶诱导剂）。此外，将年老和年轻动物的自发突变谱与氧化诱变剂博来霉素进行比较，以确定氧化损伤是否是自发诱变的主要因素。由于上述抑制剂的作用机制已被提出，本研究的结果将为未来研究抑制的详细机制和自发突变的起源提供基础。鉴于大量人类癌症可能归因于内源性来源，对自发突变的了解和抑制剂的鉴定可能会对公共卫生产生重要影响。