OXIDATIVE STRESS AND HEAT INDUCED RADIOSENTIZATION

氧化应激和热诱导辐射

• 批准号: 6320824
• 负责人: Douglas Robert Spitz
• 金额: $ 15.32万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6320824
• 关键词: DNA damage; DNA repair; antioxidants; cell line; disease /disorder etiology; flow cytometry; heat; human tissue; hyperthermia; oxidative stress; pathologic process; radiation sensitivity; tissue /cell culture

The goal of this proposal is to determine if oxidative stress contributes to heat-induced radiosensitization in human tumor cells. The hypothesis and aims were chosen on the basis of preliminary results and published work which suggests: 1) hyperthermia causes oxidative stress, and 2) mechanisms of resistance to oxidative stress also confer resistance to heat-induced radiosensitization. The hypothesis is that heat-induced increases in prooxidant production and/or reductions in cellular antioxidant capacity contribute to heat- induced radiosensitization. The Specific Aims will: 1) determine if heat (41 degree - 43 degreeC)- induced radiosensitization correlates with increased prooxidant production in human tumor cells. 2) determine if heat (41 degree - 43 degreeC)-induced radiosensitization correlates with alterations in cellular antioxidant capacity inhuman tumor cells, 3) determine if changes in prooxidant production or antioxidant capacity similar to those produces by hyperthermia, are capable of inducing radiosensitization in human tumor cell lines in the absence of hyperthermia, and 4) develop flow cytometric methods for assessing antioxidant/prooxidant balance in human tumor cells as a tool for determining if the above observations occur in human tumors in situ. In experiments yielding positive results, the effects of heat-induced oxidative stress on DNA damage and/or DNA repair following heat and radiation will also determined also in experiments yielding positive results, causality will be determined by inhibiting increases in prooxidant production and/or inhibiting alterations in antioxidant capacity and determining the effects on heat-induced radiosensitization. The information gathered in these studies will provide a rigorous evaluation of oxidative stress in mechanisms of heat-induced radiosensitization in human tumor cells. If oxidative stress is shown to contribute to heat-induced radiosensitization, then well characterized methods of modifying oxidative stress would become available for testing as modifiers of heat-induced radiosensitization, and provide a theoretical framework for the rational design of improved treatment protocols using this combined modality.

该提案的目标是确定氧化应激是否 有助于人类肿瘤细胞的热诱导放射增敏。 假设和目标是在初步的基础上选择的 结果和已发表的作品表明：1）高热原因 氧化应激，2) 抗氧化应激的机制 还赋予对热诱导放射增敏的抵抗力。这 假设是热诱导促氧化剂产生增加 和/或细胞抗氧化能力的降低导致热 诱导放射增敏。 具体目标将： 1) 确定是否 热（41°C - 43°C）-引起的放射增敏相关 增加人类肿瘤细胞中促氧化剂的产生。 2） 确定热（41°C - 43°C）是否引起放射增敏 与人类细胞抗氧化能力的改变相关 肿瘤细胞，3) 确定促氧化剂产生或变化是否发生变化 抗氧化能力类似于热疗产生的抗氧化能力 能够在人类肿瘤细胞系中诱导放射增敏 无需高温，4) 开发流式细胞术方法 用于评估人类肿瘤细胞中的抗氧化剂/促氧化剂平衡 用于确定上述观察结果是否发生在人类身上的工具 原位肿瘤。 在产生积极结果的实验​​中， 热诱导的氧化应激对 DNA 损伤和/或 DNA 修复 以下热量和辐射也将在实验中确定 产生积极的结果，因果关系将通过抑制来确定 增加促氧化剂的产生和/或抑制 抗氧化能力并确定对热诱导的影响 放射增敏。 这些研究中收集的信息将 对氧化应激机制进行严格评估 人类肿瘤细胞的热诱导放射增敏作用。 如果氧化 应力被证明有助于热诱导的放射增敏，然后 明确描述的改变氧化应激的方法将 可作为热诱导的改性剂进行测试 放射增敏作用，并为放射增敏提供理论框架 使用这种组合合理设计改进的治疗方案 情态。