OXIDATIVE STRESS AND HEAT INDUCED RADIOSENTIZATION

氧化应激和热诱导辐射

• 批准号: 6269872
• 负责人: Douglas Robert Spitz
• 金额: $ 15.22万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6269872
• 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.

该提案的目的是确定氧化应激是否是否 有助于人类肿瘤细胞中的热诱导的放射敏化。 假设和目标是根据初步选择的 结果和已发表的工作建议：1）高温原因 氧化应激和2）抗氧化应激的机制 还赋予热诱导的放射敏化。这 假设是热诱导的二氧化剂产生增加 和/或细胞抗氧化能力的降低有助于热 诱导的放射敏化。 具体目的将：1）确定是否 热量（41度-43摄氏度） - 诱导的放射敏化相关 人类肿瘤细胞中的氧化剂产生增加。 2） 确定是否热（41度-43 degReec）诱导的放射敏化 与细胞抗氧化能力不人道的改变有关 肿瘤细胞，3）确定促氧化剂产生的变化还是 与高温相似的抗氧化能力是 能够在人类肿瘤细胞系中诱导放射敏 缺乏热疗，4）发展流式细胞仪方法 评估人类肿瘤细胞中的抗氧化剂/促氧化剂平衡 确定上述观察是否发生在人类中的工具 原位肿瘤。 在产生积极结果的实验​​中， 热诱导DNA损伤和/或DNA修复的氧化应激 在实验中也将在热量和辐射之后也确定 产生积极的结果，因果关系将通过抑制来确定 促氧化剂产生和/或抑制改变的改变 抗氧化能力并确定对热诱导的影响 放射敏化。 这些研究中收集的信息将 对机制的氧化应激进行严格评估 热诱导的人类肿瘤细胞的放射敏化。 如果氧化 表明应力有助于热诱导的放射敏化，然后 良好特征的修饰氧化应激的方法将 作为热诱导的修饰符可用于测试 放射敏化，并为理论框架提供 使用此组合的改进治疗方案的合理设计 方式。