Barth R F, Yang W, Rotaru J H, Moeschberger M L, Joel D D, Nawrocky M M, Goodman J H, Soloway A H
Department of Pathology, The Ohio State University, Columbus 43210, USA.
Cancer Res. 1997 Mar 15;57(6):1129-36.
The purpose of the present study was to determine whether the efficacy of boron neutron capture therapy could be enhanced by means of intracarotid (i.c.) injection of sodium borocaptate (BSH) or boronophenylalanine (BPA) with or without blood-brain barrier disruption (BBB-D). For biodistribution studies, F98 glioma-bearing rats were injected i.v. or i.c. with either BSH (30 mg of boron/kg of body weight) or BPA (24 mg of boron/kg of body weight) with or without mannitol-induced, hyperosmotic BBB-D and killed 2.5 h later. The highest tumor boron concentrations for BSH and BPA were attained following i.c. injection with BBB-D (48.6 and 94.0 microg/g, respectively) compared to i.c. (30.8 and 42.7 microg/g) and i.v. injection (12.9 and 20.8 microg). Using the same doses of BSH and BPA, therapy experiments were initiated 14 days after intracerebral implantation of F98 glioma cells. Animals were irradiated 2.5 h after i.v. or i.c. administration of the capture agent with or without BBB-D using a collimated beam of thermal neutrons at the Brookhaven Medical Research Reactor. The median survival times of rats given BSH or BPA i.c. were 52 and 69 days, respectively, for rats with BBB-D; 39 and 48 days for rats without BBB-D; 33 and 37 days for i.v. injected rats; 29 days for irradiated controls; and 24 days for untreated controls. i.c. injection of either BSH or BPA resulted in highly significant enhancement (P = 0.01 and P = 0.0002, respectively) of survival times compared to i.v. injection, and this was further augmented by BBB-D (P = 0.02 and P = 0.04, respectively) compared to i.c. injection. Normal brain tissue tolerance studies were carried out with non-tumor-bearing rats, which were treated in the same way as tumor-bearing animals. One year after irradiation, the brains of these animals showed only minimal radiation-induced changes in the choroid plexus, but no differences were discernible between irradiated controls and those that had BBB-D followed by i.c. injection of either BSH or BPA. Our data clearly show that the route of administration, as well as BBB-D, can enhance the uptake of BSH and BPA, and, subsequently, the efficacy of boron neutron capture therapy.
本研究的目的是确定通过颈内动脉（i.c.）注射硼酸钠捕获剂（BSH）或硼苯丙氨酸（BPA），无论有无血脑屏障破坏（BBB-D），是否能够提高硼中子俘获疗法的疗效。对于生物分布研究，将携带F98胶质瘤的大鼠通过静脉注射（i.v.）或颈内动脉注射给予BSH（30毫克硼/千克体重）或BPA（24毫克硼/千克体重），同时或不伴有甘露醇诱导的高渗血脑屏障破坏，2.5小时后处死。与颈内动脉注射（分别为30.8和42.7微克/克）和静脉注射（12.9和20.8微克）相比，颈内动脉注射并伴有血脑屏障破坏后，BSH和BPA的肿瘤硼浓度最高（分别为48.6和94.0微克/克）。使用相同剂量的BSH和BPA，在F98胶质瘤细胞脑内植入14天后开始治疗实验。在静脉注射或颈内动脉注射捕获剂后2.5小时，使用布鲁克海文医学研究反应堆的准直热中子束对动物进行照射，同时或不伴有血脑屏障破坏。对于伴有血脑屏障破坏的大鼠，颈内动脉注射BSH或BPA后的中位生存时间分别为52天和69天；无血脑屏障破坏的大鼠分别为39天和48天；静脉注射的大鼠分别为33天和37天；照射对照组为29天；未治疗对照组为24天。与静脉注射相比，颈内动脉注射BSH或BPA均导致生存时间显著延长（P分别为0.01和0.0002），与颈内动脉注射相比，血脑屏障破坏进一步增强了这种延长效果（P分别为0.02和0.04）。对无肿瘤的大鼠进行正常脑组织耐受性研究，其治疗方式与携带肿瘤的动物相同。照射一年后，这些动物的大脑在脉络丛中仅显示出最小程度的辐射诱导变化，但照射对照组与伴有血脑屏障破坏并随后颈内动脉注射BSH或BPA的组之间没有明显差异。我们的数据清楚地表明，给药途径以及血脑屏障破坏能够提高BSH和BPA的摄取，进而提高硼中子俘获疗法的疗效。
