CELLULAR PROLIFERATION AND INFILTRATION FOLLOWING INTERSTITIAL IRRADIATION OF NORMAL DOG BRAIN IS ALTERED BY AN INHIBITOR OF POLYAMINE SYNTHESIS

Purpose: The objectives of this study were to quantitatively define pr oliferative and infiltrative cell responses after focal I-125 irradiat ion of normal brain, and to determine the effects of an intravenous in fusion of alpha-difluoromethylornithine (DFMO) on those responses. Met hods and Materials: Adult beagle dogs were irradiated using high activ ity I-125 sources. Saline (control) or DFMO (150 mg/kg/day) was infuse d for 18 days starting 2 days before irradiation. At varying times up to 8 weeks after irradiation, brain tissues were collected and the cel l responses in and around the focal lesion were quantified. Immunohist ochemical stains were used to label astrocytes (GFAP), vascular endoth elial cells (Factor VIII), polymorphonuclear leukocytes (PMNs; MAC 387 ) and cells synthesizing deoxyribonucleic acid (DNA) (BrdU). Cellular responses were quantified using a histomorphometric analysis.Results: After radiation alone, cellular events included a substantial acute in flammatory response followed by increased BrdU labeling and progressiv e increases in numbers of capillaries and astrocytes. alpha-Difluorome thylornithine treatment significantly affected the measured cell respo nses. As in controls, an early inflammatory response was measured, but after 2 weeks there were more PMNs/unit area than in controls. The on set of measurable BrdU labeling was delayed in DFMO-treated animals, a nd the magnitude of labeling was significantly reduced. Increases in a strocyte and vessel numbers/mm(2) were observed after a 2-week delay. At the site of implant, astrocytes from DFMO-treated dogs were signifi cantly smaller than those from controls. Conclusions: There is substan tial cell proliferation and infiltration in response to interstitial i rradiation of normal brain, and these responses are significantly alte red by DFMO treatment. Although the precise mechanisms by which DPMO e xerts its effects in this model are not known, the results from this s tudy suggest that modification of radiation injury may be possible by manipulating the response of normal cells to injury.