MEMBRANE FREE RADICALS IN PHOTODYNAMIC CANCER THERAPY

光动力癌症治疗中的膜自由基

• 批准号: 6103026
• 负责人: Garry R Buettner
• 金额: --
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-02-06 至 1999-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6103026
• 关键词: MCF7 cell; ascorbate; butylated hydroxytoluene; cytotoxicity; drug interactions; hydrogen peroxide; iron; leukemia; lipid peroxides; membrane lipids; neoplasm /cancer pharmacology; neoplasm /cancer photoradiation therapy; oxidative stress; oxidizing agents; peroxidation; porphyrins; singlet oxygen; tocopherols; unsaturated fatty acids; vascular endothelium

Photodynamic therapy (PDT) is a new and promising cancer treatment modality that is being investigated worldwide. The long term objective of this research is to investigate the fundamental mechanisms of its mode of action at the biochemical and cellular level and hence find ways to enhance the efficacy of PDT. We hypothesize that an environment that enhances free radical lipid peroxidation processes will lead to increased effectiveness of PDT. The working hypothesis of this proposal is that photodynamic therapy with a hematoporphyrin derivative preparation such as Photofrin (PDT/HPD) produces singlet oxygen in cell membranes, both tumor cell membranes and endothelial cell membranes of the tumor vascular system. This singlet oxygen reacts with unsaturated lipids and cholesterol, yielding hydroperoxides, which can serve as initiators of free radical lipid peroxidation chain reactions, disrupting membrane function. We believe that the microvascular endothelial cell is a key target for these peroxidative processes. We further hypothesize that an environment that will enhance the 'dark' free radical lipid peroxidation reactions after the delivery of light will result in enhanced endothelial cell damage and death. The endothelial cell appears to be particularly sensitive to free radical-mediated oxidative stress. Therefore, in all experiments we will compare results obtained with microvascular endothelial cells to those from vascular epithelial cells and two tumor cell lines. L1210 murine leukemia and MCF-7 human breast carcinoma. The working hypothesis of this project will be tested with the following Specific Aims: I. Determine if pro-oxidants, such as iron, or ascorbate, or iron with ascorbate, will enhance the phototoxicity of PDT/HPD to cells, and conversely, determine if small-molecule antioxidants such as vitamin E, lazaroids, and BHT will provide protection against peroxidative phototoxicity. II. Determine if membrane-derived free radicals are produced in intact, functioning cells by PDT/HPD, and if pro-oxidants will enhance the free radical peroxidation processes, then determine if radical production correlates with phototoxicity. III. Determine if making cell membranes more oxidizable by increasing the proportion of polyunsaturated fatty acids will increase the phototoxicity of PDT/HPD. IV. We will use molecular biology techniques to modify the antioxidant enzyme profile of cells and determine if this will alter their sensitivity to PDT/HPD. V. Study in detail the fundamental chemical reactions that may be key to PDT/HPD phototoxicity.

光动力疗法（PDT）是一种新的、有前途的癌症治疗方法 全世界正在研究的模式。 长期目标 本研究的目的是探讨其模式的基本机制 在生化和细胞水平上发挥作用，从而找到方法 增强PDT的疗效。 我们假设一个环境 增强自由基脂质过氧化过程将导致增加 PDT 的有效性。 该提案的工作假设是 使用血卟啉衍生物制剂进行光动力疗法，例如 由于 Photofrin (PDT/HPD) 在细胞膜中产生单线态氧，因此 肿瘤细胞膜和肿瘤血管内皮细胞膜 系统。 这种单线态氧与不饱和脂质发生反应， 胆固醇，产生氢过氧化物，它可以作为引发剂 自由基脂质过氧化链反应，破坏膜 功能。 我们认为微血管内皮细胞是关键 这些过氧化过程的目标。 我们进一步假设 会增强“暗”自由基脂质过氧化作用的环境 光传递后的反应将导致内皮细胞增强 细胞损伤和死亡。 内皮细胞似乎特别 对自由基介导的氧化应激敏感。 因此，在所有 实验我们将比较微血管获得的结果 内皮细胞、血管上皮细胞和两种肿瘤细胞 细胞系。 L1210 小鼠白血病和 MCF-7 人类乳腺癌。 该项目的工作假设将通过以下内容进行测试 具体目标： I. 确定促氧化剂（例如铁、抗坏血酸或铁）是否与 抗坏血酸，将增强 PDT/HPD 对细胞的光毒性，并且 相反，确定小分子抗氧化剂（例如维生素 E）是否 lazaroids 和 BHT 将提供针对过氧化反应的保护 光毒性。 二. 确定膜衍生的自由基是否完整地产生， 通过 PDT/HPD 使细胞发挥功能，并且促氧化剂是否会增强游离 自由基过氧化过程，然后确定自由基是否产生 与光毒性相关。 三．确定是否通过增加 多不饱和脂肪酸比例会增加光毒性 PDT/HPD。 四． 我们将利用分子生物学技术来修饰抗氧化剂 细胞的酶谱并确定这是否会改变它们 对 PDT/HPD 的敏感性。 五、详细研究可能是关键的基本化学反应 PDT/HPD 光毒性。