NITROXIDES AS PROTECTORS AGAINST OXIDATIVE STRESS

已被用作EPR自旋标记的氮氧化物已被证明， 具有超氧化物歧化酶（SOD）活性，是非常有效的药剂 保护细胞免受各种氧化应激，包括 过氧化氢，超氧化物，有机过氧化氢，氧化还原循环 化疗药物和电离辐射。 我们已经证明 Tempol保护体外细胞和小鼠免受电离辐射。 因此，氮氧化物代表了一类新的辐射保护剂， 可能在保护人类免受辐射方面有广泛的用途。 使用啮齿动物肿瘤模型的初步研究表明，Tempol确实 不能保护肿瘤组织 这一发现的机制可能涉及 正常与肿瘤的不同代谢还原特性。 此外，工作已经开始确定最有效的氮氧化合物， 保护目的。我们目前正在评估大约75个 氮氧自由基的结构-活性关系研究。 这些氮氧化物 来自匈牙利的国际专家Hideg博士 氮氧化合物的合成 我们目前正在体外筛选化合物 并且当识别出合适的候选物时，体内测试将开始。 初步研究已经确定了至少3种药物， 在体外辐射防护比Tempol（氮氧化物用于所有 上述研究）。 出乎意料的是，我们还发现了一种新的非- 有毒的辐射敏化剂，进一步的工作正在进行中。 进行了研究，以确定这一有趣发现的机制。 以来 这些试剂容易穿透细胞膜，它们可用于其它用途。 医学研究领域，如缺血/再灌注损伤研究。 此外，这些研究开启了相互关联的可能性， 氮氧化物的生物化学和代谢， 内皮舒张因子、一氧化氮。

Nitroxides which have been used as EPR spin labels have been shown to exhibit superoxide dismutase (SOD) activity and are quite effective agents in protecting cells against a wide variety of oxidative stresses including hydrogen peroxide, superoxide, organic hydroperoxides, redox-cycling chemotherapy drugs, and ionizing radiation. We have demonstrated that Tempol protects both cells in vitro and mice against ionizing radiation. Thus, the nitroxides represent a new class of radiation protectors that may have widespread use in protecting humans against radiation. Preliminary studies using a rodent tumor model have shown that Tempol does not protect tumor tissue. The mechanism of this finding may involve differential metabolic reduction properties of normal versus tumor. Additionally, work has begun to identify the most efficient nitroxide for protection purposes. We are currently evaluating approximately 75 nitroxides in a structure-activity relationship study. These nitroxides were kindly given to us from Dr. Hideg of Hungary, an international expert on nitroxide synthesis. We are presently screening the compounds in vitro and when appropriate candidates are identified in vivo testing will begin. Preliminary studies have identified at least 3 agents which provide more in vitro radioprotection than Tempol (the nitroxide used for all the studies noted above). Unexpectedly, we have also identified a novel non- toxic radiation sensitizer in this screen and further work is being conducted to determine the mechanism for this interesting finding. Since these agents readily penetrate cell membranes, they may be of use in other areas of medical research such as ischemia/reperfusion injury studies. Furthermore, these studies have opened the possibility of inter-relating the biochemistry and metabolism of nitroxides to endogenously produced endothelial relaxation factor, nitric oxide.