CENTRAL-NERVOUS-SYSTEM TOLERANCE TO BORON NEUTRON-CAPTURE THERAPY WITH P-BORONOPHENYLALANINE

A rat spinal cord model was used to evaluate the effects of boron neut ron capture irradiation on the central nervous system (CNS), using a r ange of doses of the boron delivery agent p-boronophenylalanine (BPA). Three doses of BPA 700, 1000 and 1600 mg kg(-1) were used to establis h the biodistribution of boron-10 (B-10) in blood, spinal cord and bra in over a 3-h period after intraperitoneal (ip) administration. At the lowest dose of BPA used, blood B-10 levels remained relatively stable over the 3-h sampling period. With the two higher doses of BPA, blood B-10 concentrations were greatest at 1 h after BPA administration, an d thereafter exhibited a biphasic clearance profile. The largest decli ne in blood B-10 levels occurred between 1 and 2 h after ip injection and was most pronounced (approximately 45%) in the highest BPA dose gr oup. Considered overall, B-10 concentrations were marginally lower in the spinal cord than in the brain. Levels of B-10 in both of these org ans showed a slow but progressive increase with time after administrat ion of BPA. The B-10 concentration ratio for blood relative to CNS tis sue increased with BPA dosage and reached a peak value of approximatel y 10:1 in the highest BPA dose group, at 1 h after ip injection,Howeve r, at 3 h after injection the B-10 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 B-10 concentrat ions of approximately 42 and approximately 93 mu g g(-1), myelopathy d eveloped 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 2 5.0 +/- 0.6 Gy after irradiation with thermal neutrons at blood B-10 l evels of approximately 42 and approximately 93 mu g 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. T his compared with a previous estimate of 0.88 +/- 0.14 at a blood B-10 concentration of approximately 19 mu g g(-1). It was concluded that t he value of the CBE factor was not influenced by the level of log in t he blood, but by the blood:CNS B-10 concentration ratio. In effect, th e CBE factor decreases as the concentration ratio increases. Simulatio ns using boron neutron capture therapy (BNCT) treatment planning softw are indicate a significant therapeutic advantage could be obtained in moving to higher BPA doses than those in current clinical use.