Nitroxides as Protectors Against Oxidative Stress

氮氧化物作为氧化应激的保护剂我们实验室的大量研究表明，氮氧化物(如坦波尔)是有效的抗氧化剂和抗电离辐射损伤的保护剂。我们先前已经证明，氮氧化物介导的氧化应激保护的潜在机制(S)包括超氧化物歧化酶和过氧化氢酶样活性以及自由基反应。然而，最近的研究主要集中在氮氧化物治疗是否会影响基因表达。用几种不同氮氧化物类似物的无毒浓度处理的细胞，包括一种不能进入细胞(和保护细胞)的氮氧化物，都表现出相似的基因表达模式。氮氧化物处理上调的显著基因包括热休克蛋白(HSP)家族、还原酶基因以及与Wnt/β-连环蛋白途径相关的基因。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，我们正在对食物中使用坦波尔的动物的选定组织进行基因表达研究。我们已经证明，长期服用坦波尔(在食物或饮用水中)可以显著减轻小鼠的体重，并降低小鼠自发肿瘤的发生率。最近，我们发现坦普尔给药可以延缓ATM缺陷小鼠肿瘤的发生。这些研究有望使我们更好地了解氮氧化物触发反应的复杂细胞/分子机制，这些反应在氮氧化物的抗氧化性能以及与体重和化学预防发现有关的反应中非常重要。最后，我们正在继续研究坦波尔对正常组织的差异性辐射防护，而不是肿瘤。最近的研究表明，在分割放射治疗前10分钟给予Tempoll并不能保护SCC和HT-29肿瘤的生长。我们最近已经证明，在辐射前给予氮氧化物可以防止唾液腺损伤，初步研究表明，它对辐射诱导的唾液腺具有保护作用。粘膜炎和直肠损伤。最近的一项I期临床试验表明，局部应用氮氧化物可以预防接受全脑放射治疗的患者脱发。我们的临床前研究支持这样的概念，即氮氧化物，如坦波尔，将提供对正常组织的选择性辐射防护。由于氮氧化物很容易穿透细胞膜，是有效的抗氧化剂，它们可能在医学研究的其他领域中使用，如缺血/再灌注损伤研究、预防白内障、炎症过程和衰老。

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 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. 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.