Hahn S M, DeLuca A M, Coffin D, Krishna C M, Mitchell J B
Department of Radiation Oncology, University of Pennsylvania, Philadelphia, USA.
Int J Radiat Oncol Biol Phys. 1998 Nov 1;42(4):839-42. doi: 10.1016/s0360-3016(98)00317-4.
The purpose of this study was to screen several water soluble nitroxides for in vivo radioprotection, to evaluate their pharmacology, and to measure the effect of nitroxides on systemic blood pressure as a means of exploring the mechanism of in vivo radioprotection.
A number of water soluble nitroxides were screened for in vivo radioprotection in C3H mice at a single radiation dose. Selected nitroxides were administered by the intraperitoneal route 10 minutes prior to a whole body radiation dose of 9 Gy. Electron paramagnetic resonance spectroscopy (EPR) was used to measure whole blood levels of nitroxides. The nitroxides were evaluated for effects on systemic blood pressure in C3H mice.
All of the nitroxides studied demonstrated radioprotection compared to saline-treated controls. The 6-membered piperidine ring nitroxides including Tempol were reduced to the inactive hydroxylamine rapidly over 10-20 minutes. The 5-membered ring nitroxides were reduced more slowly over time. The 5-membered ring 3-carbamoyl-PROXYL did not produce a substantial decrease in systemic blood pressure after intraperitoneal administration compared to the other nitroxides studied. 3-carbamoyl-PROXYL was further evaluated over a range of whole body radiation doses and was found to provide radioprotection.
All of the nitroxides studied provided radioprotection. In vivo radioprotection for all of the compounds except 3-carbamoyl-PROXYL may be at least partially explained by the induction of hypotension and bone marrow hypoxia. 3-carbamoyl-PROXYL provided in vivo radioprotection similar in magnitude to Tempol and had little effect on blood pressure compared to the other nitroxides. Other mechanisms for radioprotection, including scavenging of free radicals are likely. 3-carbamoyl-PROXYL should be evaluated further as a systemic radioprotector.
本研究旨在筛选几种水溶性氮氧化物用于体内辐射防护，评估其药理学特性，并测量氮氧化物对全身血压的影响，以此探索体内辐射防护机制。
在单次辐射剂量下，对多种水溶性氮氧化物在C3H小鼠体内的辐射防护作用进行筛选。选定的氮氧化物在全身接受9 Gy辐射剂量前10分钟经腹腔注射给药。采用电子顺磁共振波谱（EPR）测量全血中氮氧化物的水平。评估这些氮氧化物对C3H小鼠全身血压的影响。
与生理盐水处理的对照组相比，所有研究的氮氧化物均表现出辐射防护作用。包括Tempol在内的六元哌啶环氮氧化物在10 - 20分钟内迅速还原为无活性的羟胺。五元环氮氧化物随时间推移还原得更慢。与其他研究的氮氧化物相比，腹腔注射五元环3 - 氨基甲酰基 - PROXYL后全身血压未出现显著下降。在一系列全身辐射剂量范围内对3 - 氨基甲酰基 - PROXYL进行了进一步评估，发现其具有辐射防护作用。
所有研究的氮氧化物均具有辐射防护作用。除3 - 氨基甲酰基 - PROXYL外，所有化合物的体内辐射防护作用可能至少部分归因于低血压和骨髓缺氧的诱导。3 - 氨基甲酰基 - PROXYL提供的体内辐射防护作用在程度上与Tempol相似，与其他氮氧化物相比对血压影响较小。可能还存在其他辐射防护机制，包括自由基清除。3 - 氨基甲酰基 - PROXYL作为一种全身辐射防护剂应进一步评估。
