OXYGEN EFFECT MECHAMISMS STUDIED USING TRANSFORMING DNA

使用转化 DNA 研究氧效应机制

• 批准号: 3183034
• 负责人: Kathryn Dale Held
• 金额: $ 8.14万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-08-01 至 1988-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3183034
• 关键词: gene mutation; hypoxia; ionizing radiation; radiation carcinogenesis; radiation genetics; radiation sensitivity; respiratory oxygen; transfer RNA

Hypoxic cells are generally three-fold more resistant to ionizing radiation-induced cell kill than are fully oxygenated cells. Since there is evidence that human tumors contain hypoxic cells, it is possible that those cells limit the curability of some human tumors by radiotherapy. Improvement of radiotherapy treatments of cancer might be realized if the problem of hypoxic cells could be eliminated. Therefore, it is critical that the mechanisms by which hypoxic cells are made radioresistant or, conversely, the mechanisms by which oxic cells become sensitized (the oxygen effect) be understood. The oxygen effect has been the topic of many previous studies; a great deal of information has been obtained regarding oxygen's modes of action, but many questions remain. In order to understand the mechanisms of the oxygen effect, a radiation chemical approach to the question should be taken. In this project bacterial transforming DNA and plasmid DNA systems will be used. Purified DNA will be irradiated under carefully controlled conditions, such that the radiation chemical reactions occurring in the solutions are known or can be predicted, yet the DNA damage will be assessed by studying the biological functioning and single-stranded integrity of the DNA. This approach makes it possible to elucidate the chemical reactions involved in radiation-induced DNA damage and modification of that damage by oxygen. This information will aid in the design of methods to effectively overcome the problem of hypoxic cells in human tumors. The proposed project will address five specific questions: (1) How does the high local concentration of DNA in cells alter radiosensitivity and modification of that sensitivity by oxygen? (2) Do membrane components, lipids and proteins, radiochemically interact with DNA in such a manner that oxygen modification of damage is seen, and does this support the hypothesis that the DNA-membrane attachment site is the target for the oxygen effect? (3) Does the close association of cellular DNA with polyamines and histones alter DNA radiosensitivity and modification thereof by oxygen? (4) Is the oxygen effect dependent upon interactions with sulfhydryl-containing compounds? (5) Are radiation-induced DNA strand breaks involved in or critical for the loss of biological function of DNA, and how does the presence of oxygen modify that contribution?

低分化细胞对电离辐射的抵抗力通常是正常细胞的三倍。 辐射诱导的细胞死亡比完全氧化的细胞。 由于 是人类肿瘤含有缺氧细胞的证据， 这些细胞限制了某些人类肿瘤通过放射疗法的治愈能力。 如果能提高癌症的放射治疗水平， 可以消除缺氧细胞的问题。 因此， 低氧细胞产生抗辐射性的机制， 相反，氧化细胞变得敏感的机制（ 氧的影响）。 氧气效应一直是许多人关注的话题 以前的研究;获得了大量关于 氧气的作用方式，但仍有许多问题。 为了了解氧效应的机制， 对这个问题应该采取化学方法。 在这个项目中 将使用细菌转化DNA和质粒DNA系统。 纯化 DNA将在严格控制的条件下进行辐照， 在溶液中发生的辐射化学反应是已知的或可以 预测，但DNA损伤将通过研究生物 DNA的单链完整性。 这种方法使得 它可以阐明参与的化学反应 辐射诱导的DNA损伤和氧对该损伤的修饰。 这些信息将有助于设计有效克服 人类肿瘤中缺氧细胞的问题。 拟议的项目将解决五个具体问题：（1）如何 细胞中局部高浓度的DNA会改变辐射敏感性， 通过氧气改变这种敏感性 (2)做膜组件， 脂质和蛋白质与DNA发生放射化学反应， 损伤的氧修饰被看到，这是否支持 假设DNA-膜附着位点是 氧气效应？ (3)细胞DNA的紧密结合 多胺和组蛋白改变DNA辐射敏感性及其修饰 通过氧气？ (4)氧效应是否取决于与 含巯基化合物 (5)是辐射诱导的DNA链 涉及DNA生物学功能丧失或对DNA生物学功能丧失至关重要的断裂， 氧气的存在又是如何改变这种贡献的呢