RADIATION BRAIN INJURY IS REDUCED BY THE POLYAMINE INHIBITOR ALPHA-DIFLUOROMETHYLORNITHINE

Alpha-difluoromethylomithine (DFMO) was used to reduce I-125-induced b rain injury in normal beagle dogs. Different DFMO doses and administra tion schedules were used to determine if the reduction in brain injury was dependent on dose and/or dependent upon when the drug was adminis tered relative to the radiation treatment. Doses of DMFO of 75 mg/kg/d ay and 37.5 mg/kg/day given 2 days before, during and for 14 days afte r irradiation reduced levels of putrescine (PU) in the cerebrospinal f luid relative to controls. Volume of edema was significantly reduced b y 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 afte r irradiation was very near significance. Ultrafast CT studies perform ed on dogs that received a DFMO dose of 75 mg/kg/day before, during an d after irradiation suggested that the reduced edema volume was associ ated with reduced vascular permeability. Volume of necrosis and volume of contrast enhancement (breakdown of the blood-brain barrier) were s ignificantly lower than controls only after a DFMO dose of 75 mg/kg/da y before, during and after irradiation. These latter data, coupled wit h the findings relative to edema, suggest that different mechanisms ma y 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 b arrier may depend upon different levels of polyamine depletion. The pr ecise mechanisms by which DFMO exerts the effects observed here need t o be determined.