Boron neutron capture therapy of brain tumors: enhanced survival and cure following blood-brain barrier disruption and intracarotid injection of sodium borocaptate and boronophenylalanine.
OBJECTIVE
Boronophenylalanine (BPA) and sodium borocaptate (Na(2)B(12)H(11)SH or BSH) have been used clinically for boron neutron capture therapy (BNCT) of high-grade gliomas. These drugs appear to concentrate in tumors by different mechanisms and may target different subpopulations of glioma cells. The purpose of the present study was to determine if the efficacy of BNCT could be further improved in F98-glioma-bearing rats by administering both boron compounds together and by improving their delivery by means of intracarotid (i.c.) injection with or without blood-brain barrier disruption (BBB-D).


METHODS
For biodistribution studies, 10(5) F98 glioma cells were implanted stereotactically into the brains of syngeneic Fischer rats. Eleven to 13 days later animals were injected intravenously (i.v.) with BPA at doses of either 250 or 500 mg/kg body weight (b.w.) in combination with BSH at doses of either 30 or 60 mg/kg b.w. or i.c. with or without BBB-D, which was accomplished by i.c. infusion of a hyperosmotic (25%) solution of mannitol. For BNCT studies, 10(3) F98 glioma cells were implanted intracerebrally, and 14 days later animals were transported to the Brookhaven National Laboratory (BNL). They received BPA (250 mg/kg b.w.) in combination with BSH (30 mg/kg b.w. ) by i.v. or i.c. injection with or without BBB-D, and 2.5 hours later they were irradiated with a collimated beam of thermal neutrons at the BNL Medical Research Reactor.


RESULTS
The mean tumor boron concentration +/- standard deviation (SD) at 2.5 hours after i. c. injection of BPA (250 mg/kg b.w.) and BSH (30 mg/kg b.w.) was 56. 3 +/- 37.8 microgram/g with BBB-D compared to 20.8 +/- 3.9 microgram/g without BBB-D and 11.2 +/- 1.8 microgram/g after i.v. injection. Doubling the dose of BPA and BSH produced a twofold increase in tumor boron concentrations, but also concomitant increases in normal brain and blood levels, which could have adverse effects. For this reason, the lower boron dose was selected for BNCT studies. The median survival time was 25 days for untreated control rats, 29 days for irradiated controls, 42 days for rats that received BPA and BSH i.v., 53 days following i.c. injection, and 72 days following i.c. injection + BBB-D with subsets of long-term survivors and/or cured animals in the latter two groups. No histopathologic evidence of residual tumor was seen in the brains of cured animals.


CONCLUSIONS
The combination of BPA and BSH, administered i.c. with BBB-D, yielded a 25% cure rate for the heretofore incurable F98 rat glioma with minimal late radiation-induced brain damage. These results demonstrate that using a combination of boron agents and optimizing their delivery can dramatically improve the efficacy of BNCT in glioma-bearing rats.
Barth
R F
RF
Department of Pathology, The Ohio State University, Columbus, OH, USA. barth.1@osu.edu
Yang
W
W
Rotaru
J H
JH
Moeschberger
M L
ML
Boesel
C P
CP
Soloway
A H
AH
Joel
D D
DD
Nawrocky
M M
MM
Ono
K
K
Goodman
J H
JH
D000818:Animals; D001812:Blood-Brain Barrier; D001894:Borohydrides / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001896:Boron Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016754:Boron Neutron Capture Therapy / Q000379:methods*; D001921:Brain / Q000098:blood supply / Q000378:metabolism; D001932:Brain Neoplasms / Q000378:metabolism / Q000401:mortality / Q000532:radiotherapy*; D004354:Drug Screening Assays, Antitumor; D004359:Drug Therapy, Combination; D005910:Glioma / Q000378:metabolism / Q000401:mortality / Q000532:radiotherapy*; D007269:Injections, Intra-Arterial; D010649:Phenylalanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011853:Radiobiology; D011879:Radiotherapy Dosage; D051381:Rats; D011916:Rats, Inbred F344; D013438:Sulfhydryl Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics; D013997:Time Factors
D001894:Borohydrides; D001896:Boron Compounds; D011838:Radiation-Sensitizing Agents; D013438:Sulfhydryl Compounds; C014651:mercaptoundecahydrododecaborate; D010649:Phenylalanine; C033685:4-boronophenylalanine