Fike J R, Gobbel G T, Marton L J, Seilhan T M
Department of Neurological Surgery, School of Medicine, University of California, San Francisco 94143-0520.
Radiat Res. 1994 Apr;138(1):99-106.
Alpha-difluoromethylornithine (DFMO) was used to reduce 125I-induced brain injury in normal beagle dogs. Different DFMO doses and administration schedules were used to determine if the reduction in brain injury was dependent on dose and/or dependent upon when the drug was administered relative to the radiation treatment. Doses of DFMO of 75 mg/kg/day and 37.5 mg/kg/day given 2 days before, during and for 14 days after irradiation reduced levels of putrescine (PU) in the cerebrospinal fluid relative to controls. Volume of edema was significantly reduced by 75 mg/kg/day of DFMO before, during and after irradiation and by the same dose when the drug was started immediately after irradiation. A reduction in edema volume after 37.5 mg/kg/day before, during and after irradiation was very near significance. Ultrafast CT studies performed on dogs that received a DFMO dose of 75 mg/kg/day before, during and after irradiation suggested that the reduced edema volume was associated with reduced vascular permeability. Volume of necrosis and volume of contrast enhancement (breakdown of the blood-brain barrier) were significantly lower than controls only after a DFMO dose of 75 mg/kg/day before, during and after irradiation. These latter data, coupled with the findings relative to edema, suggest that different mechanisms may be involved with respect to the effects of DFMO on brain injury, or that the extents of edema, necrosis and breakdown of the blood-brain barrier may depend upon different levels of polyamine depletion. The precise mechanisms by which DFMO exerts the effects observed here need to be determined.
α-二氟甲基鸟氨酸（DFMO）被用于减轻正常比格犬中125I诱导的脑损伤。使用不同的DFMO剂量和给药方案来确定脑损伤的减轻是否依赖于剂量和/或依赖于相对于放射治疗而言药物给药的时间。在照射前2天、照射期间以及照射后14天给予75mg/kg/天和37.5mg/kg/天的DFMO剂量，相对于对照组降低了脑脊液中腐胺（PU）的水平。照射前、照射期间和照射后给予75mg/kg/天的DFMO可显著降低水肿体积，并且在照射后立即开始给药相同剂量时也有此效果。照射前、照射期间和照射后给予37.5mg/kg/天的DFMO后水肿体积的减少非常接近显著水平。对在照射前、照射期间和照射后接受75mg/kg/天DFMO剂量的犬进行的超快CT研究表明，水肿体积的减少与血管通透性降低有关。仅在照射前、照射期间和照射后给予75mg/kg/天的DFMO剂量后，坏死体积和对比增强体积（血脑屏障破坏）显著低于对照组。这些最新数据，再加上与水肿相关的发现，表明DFMO对脑损伤的影响可能涉及不同的机制，或者水肿、坏死和血脑屏障破坏的程度可能取决于不同水平的多胺消耗。需要确定DFMO发挥此处观察到的作用的确切机制。
