FREE RADICALS IN HYPERTHERMIA

热疗中的自由基

• 批准号: 6174167
• 负责人: Garry R Buettner
• 金额: $ 21.78万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6174167
• 关键词: antioxidants; antisense nucleic acid; chelating agents; complementary DNA; electron spin resonance spectroscopy; enzyme activity; enzyme inhibitors; ferritin; free radicals; glutathione peroxidase; hyperthermia; intracellular transport; neoplastic cell; nitric oxide; nitric oxide synthase; northern blottings; oxidative stress; southern blotting; stress proteins; superoxide dismutase; temperature; tissue /cell culture; transfection; vascular endothelium; western blottings

Therapeutic hyperthermia is the production of super-physiological temperatures for treatment of disease. Hyperthermia is currently being investigated as an adjuvant for many cancer therapies, (e.g. prostate cancer) including radiation and photodynamic therapy. The oxidative stress theory of heat shock has the following components: heat shock can produce free radicals and related oxidants; these species can cause part of the cellular injury produced by heat; and cellular injury can be tolerated if protective proteins are induced. The research proposed in this application is designed to test the oxidative stress theory of heat shock. We hypothesize that cells subjected to hyperthermia (e.g., 41-45 C) will produce an increased flux of free radicals. Thus, using cultured cells we will: detect and identify these free radicals using electron paramagnetic resonance; examine the overall flux or oxidants in cells; and examine the response of cells to these oxidants. We hypothesize that elevated levels of the antioxidant enzymes superoxide dismutase (SOD) and/or glutathione peroxidase (GPx) will lead to thermotolerance, whereas depressed levels of SOD and/or GPx will lead to heat sensitivity. We will test this hypothesis by using molecular biology techniques to alter the antioxidant enzyme level in cells and then test their thermotolerance. For those cells capable of generating nitric oxide, we hypothesize that heat will result in increased production of nitric oxide, which under certain circumstances, can be cytotoxic. We will examine the ability of cultured endothelial (and other appropriate) cells to generate nitric oxide in response to hyperthermia and determine if this nitric oxide is detrimental. If ROS are important, then we would predict that catalytic iron would increase in heat-stressed cells, thereby amplifying the oxidations initiated by heat treatment. We will examine the role of this iron in producing cell toxicity during hyperthermia and determine if modulation of catalytic iron levels will alter the thermotolerance of cells. This proposed research program is designed to test the hypothesis that production of free radicals and related oxidants is an important aspect of the detrimental effects of hyperthermia.

热疗是产生超生理温度以治疗疾病。 目前正在研究热疗作为许多癌症治疗（例如前列腺癌）的辅助治疗，包括放射和光动力治疗。 热休克的氧化应激理论有以下组成部分：热休克可产生自由基和相关氧化剂;这些物质可引起热产生的部分细胞损伤;如果诱导保护性蛋白，细胞损伤是可以耐受的。 本申请中提出的研究旨在测试热休克的氧化应激理论。 我们假设经受高温的细胞（例如，41-45 C）将产生增加的自由基通量。因此，使用培养的细胞，我们将：检测和识别这些自由基使用电子顺磁共振;检查细胞中的总流量或氧化剂;并检查细胞对这些氧化剂的反应。 我们推测，抗氧化酶超氧化物歧化酶（SOD）和/或谷胱甘肽过氧化物酶（GPx）的水平升高将导致耐热性，而SOD和/或GPx的水平降低将导致热敏感性。 我们将利用分子生物学技术改变细胞中的抗氧化酶水平，然后测试它们的耐热性来验证这一假设。 对于那些能够产生一氧化氮的细胞，我们假设热会导致一氧化氮的产生增加，在某些情况下，一氧化氮可能具有细胞毒性。 我们将研究培养的内皮细胞（和其他适当的）产生一氧化氮的能力，以应对高温，并确定这种一氧化氮是有害的。 如果活性氧是重要的，那么我们可以预测，催化铁将增加热应激细胞，从而放大由热处理引发的氧化。 我们将研究这种铁在高热过程中产生细胞毒性的作用，并确定催化铁水平的调节是否会改变细胞的耐热性。这项拟议的研究计划的目的是测试的假设，生产的自由基和相关的氧化剂是一个重要方面的有害影响的高温。