Radiolysis, Photolysis, Sonolysis and Sonoprotection of

辐射分解、光解、声波分解和声波防护

• 批准号: 7331390
• 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/7331390
• 关键词: Radiolysis; Photolysis; Sonolysis; Sonoprotection

Nitroxides as Protectors against Oxidative StressOur laboratory was first to demonstrate that nitroxides (such as Tempol) are effective antioxidants and protectors against ionizing radiation damage. The 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. A comparison was made of gene expression profiles for MCF7 cells exposed to nitroxides and various forms of oxidative stress (hydrogen peroxide, superoxide, nitric oxide, and ionizing radiation). Interestingly, a small subset of genes related to inflammatory responses was up regulated for all forms of oxidative stress; whereas, the same genes for nitroxide treatment were all down regulated. These studies will provide additional insight into the radio-protective properties of nitroxides, particularly with respect to the differential radioprotection of Tempol toward normal tissues as opposed to tumor. Tempol administered 10 min prior to fractionated radiation treatment does not protect SCC and HT-29 tumor growth; whereas, Tempol administered in the same fashion protects against radiation-induced salivary gland damage. Our lab has made a recent major advancement that can be used to explain this difference. Nitroxides can be used as functional MRI contrast probes allowing for determination of tissue redox status. We have shown that Tempol is reduced in tumor tissue to the non-radioprotective hydroxylamine faster than in salivary gland tissue. Nitroxide based MRI studies thus have the potential to guide to appropriate timing of nitroxide administration to yield maximal radioprotection of normal tissues without protection of tumor. In collaboration with the Radiation Oncology Branch a Phase I clinical trail (first in humans) has been submitted to evaluate Tempol as a functional MRI contrast probe. 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. Additionally, nitroxide based MRI evaluation may clinical utility in defining the above-mentioned conditions. Lastly, we continue to seek the mechanism of how 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. Tempol administration also delays the onset of tumors in Atm and p53 deficient mice. We have recently found that systemic levels of IGF-1 are decreased in Tempol treated animals, similar to that observed in caloric restricted animals. 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.

氮氧化物作为抗氧化应激的保护剂我们的实验室首次证明氮氧化物（如Tempol）是有效的抗氧化剂和电离辐射损伤的保护剂。氮氧自由基介导的抗氧化应激保护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的细胞;包括不能进入细胞（和保护）的氮氧化物，都表现出类似的基因表达模式。比较了MCF 7细胞暴露于氮氧化物和各种形式的氧化应激（过氧化氢，超氧化物，一氧化氮和电离辐射）的基因表达谱。有趣的是，与炎症反应相关的一小部分基因在所有形式的氧化应激中上调;而氮氧化物处理的相同基因都下调。这些研究将为氮氧自由基的辐射保护特性提供更多的见解，特别是关于Tempol对正常组织而不是肿瘤的差异辐射保护。分次放射治疗前10分钟给予Tempol不能保护SCC和HT-29肿瘤生长;而以相同方式给予Tempol可保护免受放射诱导的唾液腺损伤。我们的实验室最近取得了一项重大进展，可以用来解释这种差异。氮氧自由基可用作功能性MRI造影剂探针，用于确定组织的氧化还原状态。我们已经表明，Tempol在肿瘤组织中比在唾液腺组织中更快地还原为非放射保护性羟胺。因此，基于氮氧化物的MRI研究有可能指导氮氧化物给药的适当时机，以在不保护肿瘤的情况下对正常组织产生最大的辐射保护。与放射肿瘤学分支合作，已提交了一项I期临床试验（首次用于人体），以评价Tempol作为功能性MRI造影剂探头。由于氮氧自由基很容易穿透细胞膜，是有效的抗氧化剂，它们可以用于医学研究的其他领域，如缺血/再灌注损伤研究，预防白内障，炎症过程和衰老。此外，基于氮氧化物的MRI评价在定义上述病症方面可能具有临床实用性。最后，我们继续寻找长期施用Tempol（在食物或饮用水中）如何导致小鼠体重显著减轻和自发性肿瘤发病率降低的机制。Tempol给药还延迟了Atm和p53缺陷小鼠中肿瘤的发作。我们最近发现，全身水平的IGF-1降低Tempol治疗的动物，类似于热量限制的动物中观察到的。这些研究将使我们能够更好地了解复杂的细胞/分子机制的氮氧化物，触发反应的重要的抗氧化性能的氮氧化物，以及那些相关的重量和化学预防的结果。