OXYGEN EFFECT MECHAMISMS STUDIED USING TRANSFORMING DNA

低氧细胞对电离的抵抗力一般高三倍。 辐射诱导的细胞比完全充氧的细胞更能杀死细胞。因为在那里 是人类肿瘤含有缺氧细胞的证据，有可能 这些细胞限制了一些人类肿瘤通过放射治疗的治愈能力。 如果癌症放射治疗的改善是可能实现的 低氧细胞的问题可以消除。因此，它是至关重要的 低氧细胞抵抗辐射的机制， 相反，氧化细胞变得敏感的机制( 氧气效应)是可以理解的。氧气效应一直是许多人讨论的话题 以前的研究；已经获得了大量关于 氧气的作用模式，但仍有许多问题。 为了了解氧气效应的机制，一种辐射 应该用化学方法来解决这个问题。在这个项目中 将使用细菌转化DNA和质粒DNA系统。纯净的 DNA将在严格控制的条件下进行照射，以便 溶液中发生的辐射化学反应是已知的或可以是 然而，DNA损伤将通过研究生物 DNA的功能和单链完整性。这种方法使 有可能阐明涉及到的化学反应 辐射诱导的DNA损伤和氧气对这种损伤的修正。 这些信息将有助于设计有效地克服 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 细胞内DNA的高局部浓度改变了辐射敏感性和 氧对这种敏感度的影响？(2)膜组件， 脂类和蛋白质以放射化学的方式与DNA相互作用 可以看到氧气对损伤的修饰，这是否支持 假设DNA-膜附着位置是 氧效应？(3)细胞DNA与 多胺和组蛋白改变DNA辐射敏感性及其修饰 氧的作用？(4)氧的作用依赖于 含硫羟基化合物？(5)是辐射诱导的DNA链 与DNA生物功能丧失有关的或对其至关重要的断裂， 氧气的存在是如何改变这种贡献的呢？

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?