Improved survival after boron neutron capture therapy of brain tumors by Cereport-mediated blood-brain barrier modulation to enhance delivery of boronophenylalanine

W. Yang, R. F. Barth, R. T. Bartus, J. H. Rotaru, M. L. Moeschberger, A. K. Ferketich, M. M. Nawrocky, J. A. Coderre, J. H. Goodman, Edward Neuwelt

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

OBJECTIVE: Cereport (Alkermes, Inc., Cambridge, MA), or, as it has been previously called, RMP-7 (receptor-mediated permeabilizer-7), is a bradykinin analog that has been shown to produce a transient, pharmacologically mediated opening of the blood-brain barrier. The purpose of the present study was to determine whether the efficacy of boron neutron capture therapy (BNCT) could be enhanced by means of intracarotid (i.c.) infusion of Cereport, in combination with intravenous (i.v.) injection or i.c. infusion of boronophenylalanine (BPA) in the F98 rat glioma model. METHODS: For biodistribution studies, Fischer rats bearing intracerebral implants of the F98 glioma received i.v. or i.c. injections of 300 or 500 mg/kg body weight (b.w.) of BPA with or without i.c. infusion of 1.5 μg/kg b.w. of Cereport. For therapy studies, BNCT was initiated 14 days after intracerebral implantation of 103 F98 cells. The i.v. or i.c. injection of BPA (500 mg/kg b.w.) was given with or without Cereport, and the animals were irradiated 2.5 hours later at the Brookhaven Medical Research Reactor with a collimated beam of thermal neutrons delivered to the head. RESULTS: At a BPA dose of 500 mg/kg b.w., tumor boron concentrations (mean ± standard deviation) were 55.7 ± 9.6 μg/g with Cereport versus 33.6 ± 3.9 μg/g without Cereport at 2.5 hours after i.c. infusion of BPA, and concentrations were 29.4 ± 9.9 μg/g with Cereport versus 15.4 ± 3.5 μg/g without Cereport (P <0.05) after i.v. injection of BPA. After i.c. administration of BPA and Cereport, the tumor-to-blood ratio was 5.4 ± 0.6, and the tumor-to-brain ratio was 5.2 ± 2.4. After BNCT with BPA at a dose of 500 mg/kg, the survival time was 50 ± 16 days for i.c. administration of BPA with Cereport versus 40 ± 6 days without Cereport (P = 0.05), 38 ± 4 days for i.v. administration of BPA with Cereport versus 34 ± 3 days without Cereport (P = 0.02), 28 ± 5 days for irradiated controls, and 23 ± 3 days for untreated controls. Compared with untreated controls, there was a 117% increase in lifespan in rats that received an i.c. infusion of Cereport and then BPA, and an 86% increase in lifespan in rats that received i.c. administration of BPA without Cereport. CONCLUSION: These studies have established that i.c. administration of Cereport can not only increase tumor uptake of BPA, but also enhance the efficacy of BNCT.

Original languageEnglish (US)
Pages (from-to)189-198
Number of pages10
JournalNeurosurgery
Volume47
Issue number1
DOIs
StatePublished - 2000
Externally publishedYes

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Boron Neutron Capture Therapy
Blood-Brain Barrier
Brain Neoplasms
Body Weight
RMP 7
Glioma
Intravenous Injections
Neoplasms
Injections
Boron

Keywords

  • Boron neutron capture therapy
  • Boronophenylalanine
  • Cereport

ASJC Scopus subject areas

  • Clinical Neurology
  • Surgery

Cite this

Improved survival after boron neutron capture therapy of brain tumors by Cereport-mediated blood-brain barrier modulation to enhance delivery of boronophenylalanine. / Yang, W.; Barth, R. F.; Bartus, R. T.; Rotaru, J. H.; Moeschberger, M. L.; Ferketich, A. K.; Nawrocky, M. M.; Coderre, J. A.; Goodman, J. H.; Neuwelt, Edward.

In: Neurosurgery, Vol. 47, No. 1, 2000, p. 189-198.

Research output: Contribution to journalArticle

Yang, W. ; Barth, R. F. ; Bartus, R. T. ; Rotaru, J. H. ; Moeschberger, M. L. ; Ferketich, A. K. ; Nawrocky, M. M. ; Coderre, J. A. ; Goodman, J. H. ; Neuwelt, Edward. / Improved survival after boron neutron capture therapy of brain tumors by Cereport-mediated blood-brain barrier modulation to enhance delivery of boronophenylalanine. In: Neurosurgery. 2000 ; Vol. 47, No. 1. pp. 189-198.
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abstract = "OBJECTIVE: Cereport (Alkermes, Inc., Cambridge, MA), or, as it has been previously called, RMP-7 (receptor-mediated permeabilizer-7), is a bradykinin analog that has been shown to produce a transient, pharmacologically mediated opening of the blood-brain barrier. The purpose of the present study was to determine whether the efficacy of boron neutron capture therapy (BNCT) could be enhanced by means of intracarotid (i.c.) infusion of Cereport, in combination with intravenous (i.v.) injection or i.c. infusion of boronophenylalanine (BPA) in the F98 rat glioma model. METHODS: For biodistribution studies, Fischer rats bearing intracerebral implants of the F98 glioma received i.v. or i.c. injections of 300 or 500 mg/kg body weight (b.w.) of BPA with or without i.c. infusion of 1.5 μg/kg b.w. of Cereport. For therapy studies, BNCT was initiated 14 days after intracerebral implantation of 103 F98 cells. The i.v. or i.c. injection of BPA (500 mg/kg b.w.) was given with or without Cereport, and the animals were irradiated 2.5 hours later at the Brookhaven Medical Research Reactor with a collimated beam of thermal neutrons delivered to the head. RESULTS: At a BPA dose of 500 mg/kg b.w., tumor boron concentrations (mean ± standard deviation) were 55.7 ± 9.6 μg/g with Cereport versus 33.6 ± 3.9 μg/g without Cereport at 2.5 hours after i.c. infusion of BPA, and concentrations were 29.4 ± 9.9 μg/g with Cereport versus 15.4 ± 3.5 μg/g without Cereport (P <0.05) after i.v. injection of BPA. After i.c. administration of BPA and Cereport, the tumor-to-blood ratio was 5.4 ± 0.6, and the tumor-to-brain ratio was 5.2 ± 2.4. After BNCT with BPA at a dose of 500 mg/kg, the survival time was 50 ± 16 days for i.c. administration of BPA with Cereport versus 40 ± 6 days without Cereport (P = 0.05), 38 ± 4 days for i.v. administration of BPA with Cereport versus 34 ± 3 days without Cereport (P = 0.02), 28 ± 5 days for irradiated controls, and 23 ± 3 days for untreated controls. Compared with untreated controls, there was a 117{\%} increase in lifespan in rats that received an i.c. infusion of Cereport and then BPA, and an 86{\%} increase in lifespan in rats that received i.c. administration of BPA without Cereport. CONCLUSION: These studies have established that i.c. administration of Cereport can not only increase tumor uptake of BPA, but also enhance the efficacy of BNCT.",
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TY - JOUR

T1 - Improved survival after boron neutron capture therapy of brain tumors by Cereport-mediated blood-brain barrier modulation to enhance delivery of boronophenylalanine

AU - Yang, W.

AU - Barth, R. F.

AU - Bartus, R. T.

AU - Rotaru, J. H.

AU - Moeschberger, M. L.

AU - Ferketich, A. K.

AU - Nawrocky, M. M.

AU - Coderre, J. A.

AU - Goodman, J. H.

AU - Neuwelt, Edward

PY - 2000

Y1 - 2000

N2 - OBJECTIVE: Cereport (Alkermes, Inc., Cambridge, MA), or, as it has been previously called, RMP-7 (receptor-mediated permeabilizer-7), is a bradykinin analog that has been shown to produce a transient, pharmacologically mediated opening of the blood-brain barrier. The purpose of the present study was to determine whether the efficacy of boron neutron capture therapy (BNCT) could be enhanced by means of intracarotid (i.c.) infusion of Cereport, in combination with intravenous (i.v.) injection or i.c. infusion of boronophenylalanine (BPA) in the F98 rat glioma model. METHODS: For biodistribution studies, Fischer rats bearing intracerebral implants of the F98 glioma received i.v. or i.c. injections of 300 or 500 mg/kg body weight (b.w.) of BPA with or without i.c. infusion of 1.5 μg/kg b.w. of Cereport. For therapy studies, BNCT was initiated 14 days after intracerebral implantation of 103 F98 cells. The i.v. or i.c. injection of BPA (500 mg/kg b.w.) was given with or without Cereport, and the animals were irradiated 2.5 hours later at the Brookhaven Medical Research Reactor with a collimated beam of thermal neutrons delivered to the head. RESULTS: At a BPA dose of 500 mg/kg b.w., tumor boron concentrations (mean ± standard deviation) were 55.7 ± 9.6 μg/g with Cereport versus 33.6 ± 3.9 μg/g without Cereport at 2.5 hours after i.c. infusion of BPA, and concentrations were 29.4 ± 9.9 μg/g with Cereport versus 15.4 ± 3.5 μg/g without Cereport (P <0.05) after i.v. injection of BPA. After i.c. administration of BPA and Cereport, the tumor-to-blood ratio was 5.4 ± 0.6, and the tumor-to-brain ratio was 5.2 ± 2.4. After BNCT with BPA at a dose of 500 mg/kg, the survival time was 50 ± 16 days for i.c. administration of BPA with Cereport versus 40 ± 6 days without Cereport (P = 0.05), 38 ± 4 days for i.v. administration of BPA with Cereport versus 34 ± 3 days without Cereport (P = 0.02), 28 ± 5 days for irradiated controls, and 23 ± 3 days for untreated controls. Compared with untreated controls, there was a 117% increase in lifespan in rats that received an i.c. infusion of Cereport and then BPA, and an 86% increase in lifespan in rats that received i.c. administration of BPA without Cereport. CONCLUSION: These studies have established that i.c. administration of Cereport can not only increase tumor uptake of BPA, but also enhance the efficacy of BNCT.

AB - OBJECTIVE: Cereport (Alkermes, Inc., Cambridge, MA), or, as it has been previously called, RMP-7 (receptor-mediated permeabilizer-7), is a bradykinin analog that has been shown to produce a transient, pharmacologically mediated opening of the blood-brain barrier. The purpose of the present study was to determine whether the efficacy of boron neutron capture therapy (BNCT) could be enhanced by means of intracarotid (i.c.) infusion of Cereport, in combination with intravenous (i.v.) injection or i.c. infusion of boronophenylalanine (BPA) in the F98 rat glioma model. METHODS: For biodistribution studies, Fischer rats bearing intracerebral implants of the F98 glioma received i.v. or i.c. injections of 300 or 500 mg/kg body weight (b.w.) of BPA with or without i.c. infusion of 1.5 μg/kg b.w. of Cereport. For therapy studies, BNCT was initiated 14 days after intracerebral implantation of 103 F98 cells. The i.v. or i.c. injection of BPA (500 mg/kg b.w.) was given with or without Cereport, and the animals were irradiated 2.5 hours later at the Brookhaven Medical Research Reactor with a collimated beam of thermal neutrons delivered to the head. RESULTS: At a BPA dose of 500 mg/kg b.w., tumor boron concentrations (mean ± standard deviation) were 55.7 ± 9.6 μg/g with Cereport versus 33.6 ± 3.9 μg/g without Cereport at 2.5 hours after i.c. infusion of BPA, and concentrations were 29.4 ± 9.9 μg/g with Cereport versus 15.4 ± 3.5 μg/g without Cereport (P <0.05) after i.v. injection of BPA. After i.c. administration of BPA and Cereport, the tumor-to-blood ratio was 5.4 ± 0.6, and the tumor-to-brain ratio was 5.2 ± 2.4. After BNCT with BPA at a dose of 500 mg/kg, the survival time was 50 ± 16 days for i.c. administration of BPA with Cereport versus 40 ± 6 days without Cereport (P = 0.05), 38 ± 4 days for i.v. administration of BPA with Cereport versus 34 ± 3 days without Cereport (P = 0.02), 28 ± 5 days for irradiated controls, and 23 ± 3 days for untreated controls. Compared with untreated controls, there was a 117% increase in lifespan in rats that received an i.c. infusion of Cereport and then BPA, and an 86% increase in lifespan in rats that received i.c. administration of BPA without Cereport. CONCLUSION: These studies have established that i.c. administration of Cereport can not only increase tumor uptake of BPA, but also enhance the efficacy of BNCT.

KW - Boron neutron capture therapy

KW - Boronophenylalanine

KW - Cereport

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