AbstractOBJECTIVE:Using the well-characterized F98 rat glioma model, the purpose of the present study was to determine whether the delivery of boronophenylalanine (BPA) could be enhanced by prior administration of the bradykinin analog Cereport (Alkermes, Inc., Cambridge, MA) (previously known as Receptor-Mediated Permeabilizer-7), which produces a transient, pharmacologically mediated opening of the blood-brain barrier.METHODS:Two series of experiments were performed in F98 glioma-bearing rats that had received either intracarotid (i.e.) or intravenous infusions of Cereport (at doses ranging from 1.5 to 7.5 ftg/kg of body weight), followed by i.e. (or intravenous) injection of BPA (300 mg/kg of body weight). Animals were killed 0.5, 2.5, or 4 hours later, samples of blood, skin, muscle, and eye were obtained, brains were removed, and tumors were excised for boron determination by direct current plasma-atomic emission spectroscopy.RESULTS:Averaged over all time points, i.e. infusion of Cereport significantly enhanced tumor boron uptake (P = 0.0001), compared with the excipient (saline) control values. Tumor boron values were equivalent at 0.5 (36.0 g/g) and 2.5 hours (38.5/u.g/g) after i.e. administration of Cereport and BPA and then decreased by 33% (to 25.7/ug/g) at 4 hours. These tumor boron uptake values were significantly different (a = 0.05), compared with values measured at the corresponding times after i.e. administration of BPA without Cereport (22.6, 21.8, and 15.3 fxg/g, respectively). Although no time-related effects were observed, i.e. administration of Cereport followed by intravenous administrationof BPA also significantly enhanced (a = 0.05) tumor boron uptake at 0.5, 2.5, and 4 hours (27.4, 30.3, and 28-0/x.g/g, respectively), compared with values obtained without Cereport (11.3, 13.4, and 15.2 ng/g, respectively). Boron levels in normal brain tissue from tumor-bearing and non-tumor-bearing cerebral hemispheres and in blood were not significantly different from those measured in saline-treated control animals.CONCLUSION:This study established that i.e. infusion of Cereport significantly increased delivery of BPA to F98 rat gliomas, and this could enhance the efficacy of boron neutron capture therapy of this tumor.
Neurosurgery – Oxford University Press
Published: Feb 1, 1999
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