Clinical Investigation
Boron neutron capture therapy of brain tumors: enhanced survival and cure following blood–brain barrier disruption and intracarotid injection of sodium borocaptate and boronophenylalanine

Presented in part at the 8th International Symposium on Neutron Capture Therapy, La Jolla, CA, Sept. 13–18, 1998; 11th International Congress on Radiation Research, Dublin, Ireland, July 19–23, 1999; 13th International Conference on Brain Tumor Research and Therapy, Hokkaido, Japan, Oct. 3–6, 1999; and 4th meeting of The Society for Neuro-Oncology, Scottsdale, AZ, Nov. 19–21, 1999.
https://doi.org/10.1016/S0360-3016(00)00421-1Get rights and content

Abstract

Purpose: Boronophenylalanine (BPA) and sodium borocaptate (Na2B12H11SH 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 and Materials: For biodistribution studies, 105 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, 103 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 μg/g with BBB-D compared to 20.8 ± 3.9 μg/g without BBB-D and 11.2 ± 1.8 μg/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.

Introduction

Boron neutron capture therapy (BNCT) is based on the nuclear capture reaction that occurs when boron-10, a nonradioactive constituent of natural elemental boron, is irradiated with low-energy thermal neutrons to yield high linear energy transfer (LET) α particles and recoiling 7Li nuclei. In order to be successful, a sufficiently large number of 10B atoms and thermal neutrons must be delivered to neoplastic cells in order to sustain a lethal 10B (n,α) 7Li reaction. These requirements are discussed in detail in several recent reviews 1, 2, 3 and monographs 4, 5. Two boron compounds currently are being used clinically for BNCT of high-grade gliomas. The first, sodium undecahydro-mercapto-closo-dodecaborate (Na2B12H11SH, sodium borocaptate or BSH) was used by Hatanaka (6), and more recently by Nakagawa (7), in Japan and Sauerwein in Europe (8). The second compound is 4-dihydroxyborylphenylalanine (boronophenylalanine [BPA]), which has been used in clinical trials in the United States at the Brookhaven National Laboratory, Upton, New York (9), and the New England Deaconess/Beth Israel Medical Center and the Massachusetts Institute of Technology in Boston (10).

Despite considerable effort on the part of boron chemists 2, 11, there currently are no other delivery agents for BNCT of brain tumors that have reached the stage of Phase I clinical evaluation. Until recently, relatively little attention had been paid to optimizing the delivery of BSH and BPA, although its importance has been recognized 12, 13. Using the well-characterized F98 rat glioma model (14), our own studies have shown that by using either hyperosmotic mannitol–induced blood–brain barrier disruption (BBB-D) 15, 16, 17, 18 or pharmacologically mediated modulation of the blood–brain barrier (BBB) by Cereport (receptor-mediated permeabilizer-7 [RMP-7]) 19, 20 and intracarotid (i.c.) injection of either BPA or BSH, it has been possible to increase tumor boron uptake up to fourfold compared to that attainable by intravenous (i.v.) injection. When followed by BNCT, this resulted in a 1.6–2.6 fold increase in survival time compared to irradiated control animals 16, 17, 18, 20. It has been our view for many years that combinations of various boron delivery agents would be required to target different subpopulations of tumor cells (21), and that a logical starting point for this approach would be the combined use of BPA and BSH. Based on this premise, we carried out a series of experiments in F98-glioma-bearing rats using BPA and BSH in combination, administered by intraperitoneal (i.p.) injection (22). These studies failed to show any improvement in survival times compared to those attained using an equivalent amount of boron in the chemical form of BPA. Based on our more recent studies with BPA, which showed enhanced delivery following BBB-D and i.c. administration (15), we suggested (22) that it would be of interest to carry out similar studies using the combination of BPA and BSH. In the present study, F98-glioma-bearing rats that had received BBB-D, followed by i.c. injection of both compounds, had a mean survival time (MST) in excess of 140 days with a 25% cure rate compared to a MST of 41 days for animals that received the compounds i.v. These are the best survival data that have ever been obtained with the F98 glioma model and suggest that further studies are warranted to determine if this approach can be used clinically to improve the efficacy of BNCT. A detailed description of our results follows.

Section snippets

Tumor model and biodistribution studies

The F98 rat glioma has been described in detail elsewhere (14), and its biologic behavior and lack of response to therapy closely simulates that of human high-grade brain tumors. Following intracerebral implantation, it forms a progressively growing tumor with islands of malignant cells at varying distances from the centrally growing mass (16), does not metastasize to extracranial sites, and until recently 16, 17, it has been invariably fatal with an inoculum containing as few as 100 tumor

Tissue biodistribution studies

Two studies were carried out. In the first, BPA and BSH were administered at doses of 250 mg and 30 mg/kg b.w., respectively, and in the second the compound doses were doubled to 500 mg and 60 mg/kg b.w., respectively. Based on previously reported pharmacokinetic data 15, 16, 17, 18, 2.5 hours following administration was selected as the time point for tissue sampling. The mean boron values ± SD for tumor, ipsilateral (tumor-bearing) and contralateral cerebral hemispheres and blood and T:Br and

Discussion

In the present study we have shown that BBB-D followed by i.c. injection of BPA and BSH resulted in a mean survival time in excess of 140 days (range 48–365+ days) with a 25% cure of F98-glioma-bearing rats. These are the best survival data that have been obtained with this heretofore incurable rat brain tumor model. Histopathologic examination of the brains of long-term surviving rats revealed no residual tumor cells. The changes that were seen within the brain itself most likely represented a

Acknowledgements

This work was supported by the U.S. Department of Energy Grants DE-AC02-76CH000016 and DE-FG02-98ERG2595. We thank Dr. Duane Smith for helpful suggestions, Amy Ferketich for computational assistance, and Mrs. Beth Kahl for excellent secretarial assistance in the preparation of this manuscript.

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