Boron neutron capture therapy of brain tumors: functional and neuropathologic effects of blood-brain barrier disruption and intracarotid injection of sodium borocaptate and boronophenylalanine.
Sodium borocaptate (BSH) and boronophenylalanine (BPA) are two drugs that have been used clinically for boron neutron capture therapy (BNCT) of brain tumors. We previously have reported that hyperosmotic mannitol-induced disruption of the blood-brain barrier (BBB-D), followed by intracarotid (i.c.) administration of BPA or BSH, either individually or in combination, significantly enhanced tumor boron delivery and the efficacy of BNCT in F98 glioma bearing rats. The purpose of the present study was to determine the short-term neuropathologic consequences of this treatment and the long-term effects on motor and cognitive function, as well as the neuropathologic sequelae 1 year following neutron capture irradiation. BBB-D was carried out in non-tumor bearing Fischer rats by infusing a 25% solution of mannitol i.c. followed by i.c. injection of BPA or BSH, either individually or in combination, immediately thereafter. Animals were euthanized 2 days after compound administration, and their brains were processed for neuropathologic examination, which revealed sporadic, mild, focal neuronal degeneration, hemorrhage, and necrosis. To assess the long-term effects of such treatment followed by neutron capture irradiation, non-tumor bearing rats were subjected to BBB-D after which they were injected i.c. with BPA (25 mg B/kg body weight (b.w)) or BSH (30 mg B/kg b.w.) either individually or in combination (BPA 12.5 mg and BSH 14 mg B/kg b.w.). Two and a half hours later they were irradiated at the Medical Research Reactor, Brookhaven National Laboratory, Upton, NY, with the same physical radiation doses (5.79, 8.10 or 10.06 Gy), delivered to the brain, as those that previously had been used for our therapy experiments. The animals tolerated this procedure well, after which they were returned to Columbus, Ohio where their clinical status was monitored weekly. After 1 year, motor function was assessed using a sensitive and reliable locomotor rating scale for open field testing in rats and cognitive function was evaluated by their performance in the Morris water maze, the results of which were similar to those obtained with age matched controls. After functional evaluation, the rats were euthanized, their brains were removed, and then processed for neuropathologic examination. Subtle histopathologic changes were seen in the choroid plexuses of irradiated animals that had received BPA, BSH or saline. Radiation related ocular changes consisting of keratitis, blepharitis, conjunctivitis and cataract formation were seen with similar frequency in most rats in each treatment group. Based on these observations, and the previously reported significant therapeutic gain associated with BBB-D and i.c. injection of BSH and BPA, the present observations establish its safety in rats and suggest that further studies in large animals and humans are warranted.
Yang
W
W
Department of Pathology, The Ohio State University, Columbus 43210, USA.
Barth
R F
RF
Rotaru
J H
JH
Boesel
C P
CP
Wilkie
D A
DA
Bresnahan
J C
JC
Hadjiconstantinou
M
M
Goettl
V M
VM
Joel
D D
DD
Nawrocky
M M
MM
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000528:radiation effects*; D001894:Borohydrides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D001896:Boron Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D016754:Boron Neutron Capture Therapy; D001921:Brain / Q000187:drug effects / Q000473:pathology* / Q000528:radiation effects; D001932:Brain Neoplasms / Q000532:radiotherapy; D002343:Carotid Artery, Internal; D002543:Cerebral Hemorrhage / Q000473:pathology; D003071:Cognition / Q000187:drug effects*; D005123:Eye / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D005128:Eye Diseases / Q000209:etiology / Q000473:pathology; D007269:Injections, Intra-Arterial; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D009498:Neurotoxins; D009502:Neutrons; D010649:Phenylalanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D013438:Sulfhydryl Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D014018:Tissue Distribution
D001894:Borohydrides; D001896:Boron Compounds; D009498:Neurotoxins; D011838:Radiation-Sensitizing Agents; D013438:Sulfhydryl Compounds; C014651:mercaptoundecahydrododecaborate; D010649:Phenylalanine; C033685:4-boronophenylalanine