Nitroxides as Protectors Against Oxidative Stress

氮氧化物作为氧化应激的保护剂

• 批准号: 7292012
• 负责人: JAMES B MITCHELL
• 金额: --
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7292012
• 关键词: Nitroxides; Protectors; Against; Oxidative; Stress

Nitroxides as Protectors against Oxidative StressExtensive studies in our laboratory have demonstrated that nitroxides (such as Tempol) are effective antioxidants and protectors against ionizing radiation damage. We have previously demonstrated that the potential mechanism(s) for nitroxide-mediated protection against oxidative stress include superoxide dismutase- and catalase-like activity and radical-radical reactions. However, more recent studies have focused on whether nitroxide treatment impacts gene expression. Cells treated with non-toxic concentrations of several different nitroxide analogues; including a nitroxide incapable of cellular entry (and protection) all exhibit similar patterns of gene expression. Prominent genes up-regulated by nitroxide treatment include the heat shock protein (HSP) family, reductive enzyme genes, and genes associated with the Wnt/beta-catenin pathway. We are currently comparing nitroxide-mediated gene expression profiles with other forms of oxidative stress including hydrogen peroxide, superoxide, and ionizing radiation. Additionally we are conducting gene expression studies of selected tissues taken from animals maintained on Tempol in the food. We have shown that long-term administration of Tempol (in the food or drinking water) results in dramatic weight reduction and a decrease in spontaneous tumor incidence in mice. Recently we have shown that Tempol administration delays the onset of tumors in Atm and p53 deficient mice. These studies will hopefully enable us to better understand the complex cellular/molecular mechanisms of nitroxides that trigger responses important in the antioxidant properties of nitroxides as well as those related to weight and the chemopreventive findings. Lastly, we are continuing our studies on the differential radioprotection of Tempol toward normal tissues as opposed to tumor. Recent studies indicate that Tempol administered 10 min prior to fractionated radiation treatment does not protect SCC and HT-29 tumor growth. We have recently shown that nitroxides administered prior to radiation protects against salivary gland damage and preliminary studies show protection against radiation-induced mucositis and damage to the rectum. We have also demonstrated that nitroxides can be followed non-invasively using MRI. We have shown that the disappearance of the nitroxide MRI signal represents reduction of the nitroxide to the hydroxylamine. A recent phase I clinical trial has shown that topically applied nitroxides protect against alopecia for patients receiving whole brain radiotherapy. Our pre-clinical studies support the concept that nitroxides such as Tempol will provide selective radioprotection of normal tissues. Since nitroxides readily penetrate cell membranes and are potent antioxidants, they may be of use in other areas of medical research such as ischemia/reperfusion injury studies, prevention of cataracts, inflammatory processes, and aging.

我们实验室的大量研究表明，氮氧化物（如Tempol）是有效的抗氧化剂和抗电离辐射损伤的保护剂。我们之前已经证明了氮氧化物介导的抗氧化应激保护的潜在机制包括超氧化物歧化酶和过氧化氢酶样活性以及自由基-自由基反应。然而，最近更多的研究集中在氮氧化物处理是否影响基因表达。用无毒浓度的几种不同的氮氧化物类似物处理细胞；包括不能进入（和保护）细胞的氮氧化物都表现出相似的基因表达模式。受氮氧化物处理上调的主要基因包括热休克蛋白（HSP）家族、还原酶基因以及与Wnt/ β -连环蛋白通路相关的基因。我们目前正在比较氮氧化物介导的基因表达谱与其他形式的氧化应激，包括过氧化氢、超氧化物和电离辐射。此外，我们正在对食物中Tempol饲养动物的特定组织进行基因表达研究。我们已经证明，长期服用Tempol（在食物或饮用水中）可以显著减轻小鼠的体重，并减少自发性肿瘤的发病率。最近，我们发现Tempol可以延缓Atm和p53缺陷小鼠的肿瘤发生。这些研究有望使我们更好地了解氮氧化物的复杂细胞/分子机制，这些机制触发了氮氧化物抗氧化性能的重要反应，以及与体重和化学预防相关的反应。最后，我们正在继续研究Tempol对正常组织和肿瘤的差异辐射防护。最近的研究表明，在分级放射治疗前10分钟给予Tempol并不能保护SCC和HT-29肿瘤的生长。我们最近表明，在辐射前施用氮氧化物可以防止唾液腺损伤，初步研究表明可以防止辐射引起的粘膜炎和直肠损伤。我们也证明了使用核磁共振成像可以无创地跟踪氮氧化物。我们已经证明，氮氧化物MRI信号的消失代表氮氧化物还原为羟胺。最近一期临床试验表明，局部应用氮氧化物对接受全脑放疗的患者预防脱发。我们的临床前研究支持氮氧化物（如Tempol）对正常组织提供选择性辐射防护的概念。由于氮氧化物很容易穿透细胞膜，是有效的抗氧化剂，它们可能用于其他医学研究领域，如缺血/再灌注损伤研究，预防白内障，炎症过程和衰老。