ENHANCED SURVIVAL OF GLIOMA BEARING RATS FOLLOWING BORON NEUTRON-CAPTURE THERAPY WITH BLOOD-BRAIN-BARRIER DISRUPTION AND INTRACAROTID INJECTION OF BORONOPHENYLALANINE

Boronophenylalanine (BPA) has been used for boron neutron capture ther apy (BNCT) of brain tumors in both experimental animals and humans. Th e purpose of the present study was to determine if the efficacy of BNC T could be enhanced by means of intracarotid (i.c.) injection of BPA w ith or without blood-brain barrier disruption (BBB-D) and neutron irra diation using a rat brain tumor model. For biodistribution studies, F9 8 glioma cells were implanted stereotactically into the brains of Fisc her rats, and 12 days later BBB-D was carried out by i.c. infusion of 25% mannitol (1.373 mOsmol/ml), followed immediately by i.c. administr ation of 300, 500 or 800 mg of BPA/kg body weight (b.w.). At the 500 m g dose a fourfold increase in tumor boron concentration (94.5 mu g/g) was seen at 2.5 hours after BBB-D, compared to 20.8 mu g/g in i.v. inj ected animals. The best composite tumor to normal tissue ratios were o bserved at 2.5 hours after BBB-D, at which time the tumor: blood (T: B l) ratio was 10.9, and the tumor: brain (T: Br) ratio was 7.5, compare d to 3.2 and 5.0 respectively for i.v. injected rats. In contrast, ani mals that had received i.c. BPA without BBB-D had T: Bl and T: Br rati os of 8.5 and 5.9, respectively, and the tumor boron concentration was 42.7 mu g/g. For therapy experiments, initiated 14 days after intrace rebral implantation of F98 glioma cells, 500mg/kg b.w. of BPA were adm inistered i.v. or i.c. with or without BBB-D, and the animals were irr adiated 2.5 hours later at the Brookhaven Medical Research Reactor wit h a collimated beam of thermal neutrons delivered to the head. The mea n survival time for untreated control rats was 24 +/- 3 days, 30 +/- 2 days for irradiated controls, 37 +/- 3 days for those receiving i.v. BPA, 52 +/- 15 days for rats receiving i.c. BPA without BBB-D, and 95 +/- 95 days for BBB-D followed by i.c. BPA and BNCT. The latter group had a 246% increase in life span (ILS) compared to untreated controls and a 124% ILS compared to that of i.v. injected animals. These surviv al data are the best ever obtained with the F98 glioma model and sugge st that i.c. administration of BPA with or without BBB-D may be useful as a means to increase the efficacy of BNCT.