Central nervous system tolerance to boron neutron capture therapy with p-boronophenylalanine.

Abstract

A rat spinal cord model was used to evaluate the effects of boron neutron capture irradiation on the central nervous system (CNS), using a range of doses of the boron delivery agent p-boronophenylalanine (BPA). Three doses of BPA 700, 1000 and 1600 mg kg(-1) were used to establish the biodistribution of boron-10 (10B) in blood, spinal cord and brain over a 3-h period after intraperitoneal (i.p.) administration. At the lowest dose of BPA used, blood 10B levels remained relatively stable over the 3-h sampling period. With the two higher doses of BPA, blood 10B concentrations were greatest at 1 h after BPA administration, and thereafter exhibited a biphasic clearance profile. The largest decline in blood 10B levels occurred between 1 and 2 h after i.p. injection and was most pronounced (approximately 45%) in the highest BPA dose group. Considered overall, 10B concentrations were marginally lower in the spinal cord than in the brain. Levels of 10B in both of these organs showed a slow but progressive increase with time after administration of BPA. The 10B concentration ratio for blood relative to CNS tissue increased with BPA dosage and reached a peak value of approximately 10:1 in the highest BPA dose group, at 1 h after i.p. injection. However, at 3 h after injection the 10B concentration ratios had decreased to approximately 3:1 in all of the BPA dose groups. After irradiation with thermal neutrons in combination with BPA at blood 10B concentrations of approximately 42 and approximately 93 microg g(-1), myelopathy developed after latent intervals of 20.0 +/- 0.6 and 20.0 +/- 1.2 weeks respectively. ED50 values (+/- s.e.) for the incidence of myelopathy were calculated from probit-fitted curves, and were 17.5 +/- 0.7 and 25.0 +/- 0.6 Gy after irradiation with thermal neutrons at blood 10B levels of approximately 42 and approximately 93 microg g(-1) respectively. The compound biological effectiveness (CBE) factor values, estimated from these data, were 0.67 +/- 0.23 and 0.48 +/- 0.18 respectively. This compared with a previous estimate of 0.88 +/- 0.14 at a blood 10B concentration of approximately 19 microg g(-1). It was concluded that the value of the CBE factor was not influenced by the level of 10B in the blood, but by the blood:CNS 10B concentration ratio. In effect, the CBE factor decreases as the concentration ratio increases. Simulations using boron neutron capture therapy (BNCT) treatment planning software indicate a significant therapeutic advantage could be obtained in moving to higher BPA doses than those in current clinical use.