Boron neutron capture therapy of brain tumors: Enhanced survival and cure following blood-brain barrier disruption and intracarotid injection of sodium borocaptate and boronophenylalanine
Boron neutron capture therapy of brain tumors: Enhanced survival and cure following blood-brain barrier disruption and intracarotid injection of sodium borocaptate and boronophenylalanine
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DOI：
10.1016/s0360-3016(00)00421-1
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发表时间：
2000-04-01
影响因子：
7
通讯作者：
Goodman, JH
中科院分区：
文献类型：
--
作者：
Barth, RF;Yang, WL;Goodman, JH
目的：硼苯丙氨酸（BPA）和硼卡酸钠（Na2B12H11SH或BSH）已被临床用于高级别胶质瘤的硼中子捕获治疗（BNCT）。这些药物似乎通过不同的机制集中在肿瘤中，并且可能靶向胶质瘤细胞的不同亚群。本研究的目的是确定BNCT的功效是否可以通过将两种硼化合物一起给药以及通过颈动脉内（i. c.）方法和材料：为了进行生物分布研究，将10（5）个F98神经胶质瘤细胞立体定向植入同系Fischer大鼠的脑中。11至13天后，将动物静脉内（i.v.）BPA剂量为250或500 mg/kg体重（b.w.）与剂量为30或60 mg/kg b.w.的BSH联合给药。或I.C.有或没有BBB-D，这是通过i.c.输注高渗（25%）甘露醇溶液。对于BNCT研究，将10（3）个F98神经胶质瘤细胞植入脑内，14天后将动物运送到Brookhaven国家实验室（BNL）。与BSH（30 mg/kg b.w.）通过i.v.或i.c.结果：在i.c.注射或不注射BBB-D后2.5小时，它们用准直的热中子束在BNL医学研究反应堆中照射。注射BPA（250 mg/kg b.w.）和BSH（30 mg/kg b.w.）在有BBB-D的情况下为56.3 +/-37.8 μ g/g，相比之下，在没有BBB-D的情况下为20.8 +/-3.9 μ g/g，静脉注射后为11.2 +/-1.8 μ g/g。BPA和BSH的剂量加倍会使肿瘤硼浓度增加两倍，但同时也会使正常脑和血液水平增加，这可能会产生不良影响。出于这个原因，BNCT研究选择了较低的硼剂量。未处理的对照组大鼠的中位生存时间为25天，辐照对照组为29天，静脉注射BPA和BSH的大鼠为42天，i.c.注射后53天和i.c.注射+BBB-D与后两组中的长期存活动物和/或治愈动物的子集。结论：BPA和BSH联合应用，i.c.与BBB-D，产生了25%的治愈率，迄今无法治愈的F98大鼠神经胶质瘤与最小的晚期辐射诱导的脑损伤。这些结果表明，使用硼剂的组合并优化其递送可以显著提高BNCT在荷胶质瘤大鼠中的功效。(C)2000 Elsevier Science Inc.
Purpose: Boronophenylalanine (BPA) and sodium borocaptate (Na2B12H11SH or BSH) have been used clinically for boron neutron capture therapy (BNCT) of high-grade gliomas. These drugs appear to concentrate in tumors by different mechanisms and may target different subpopulations of glioma cells. The purpose of the present study was to determine if the efficacy of BNCT could be further improved in F98-glioma-bearing rats by administering both boron compounds together and by improving their delivery by means of intracarotid (i.c.) injection with or without blood-brain barrier disruption (BBB-D),Methods and Materials: For biodistribution studies, 10(5) F98 glioma cells were implanted stereotactically into the brains of syngeneic Fischer rats. Eleven to 13 days later animals were injected intravenously (i.v.) with BPA at doses of either 250 or 500 mg/kg body weight (b.w.) in combination with BSH at doses of either 30 or 60 mg/kg b.w. or i.c. with or without BBB-D, which was accomplished by i.c. infusion of a hyperosmotic (25%) solution of mannitol. For BNCT studies, 10(3) F98 glioma cells were implanted intracerebrally, and 14 days later animals were transported to the Brookhaven National Laboratory (BNL), They received BPA (250 mg/kg b.w.) in combination with BSH (30 mg/kg b.w.) by i.v. or i.c. injection with or without BBB-D, and 2.5 hours later they were irradiated with a collimated beam of thermal neutrons at the BNL Medical Research Reactor.Results: The mean tumor boron concentration +/- standard deviation (SD) at 2.5 hours after i.c. injection of BPA (250 mg/kg b.w.) and BSH (30 mg/kg b.w.) was 56.3 +/- 37.8 mu g/g with BBB-D compared to 20.8 +/- 3.9 mu g/g without BBB-D and 11.2 +/- 1.8 mu g/g after i.v. injection. Doubling the dose of BPA and BSH produced a twofold increase in tumor boron concentrations, but also concomitant increases in normal brain and blood levels, which could have adverse effects, For this reason, the lower boron dose was selected for BNCT studies. The median survival time was 25 days for untreated control rats, 29 days for irradiated controls, 42 days for rats that received BPA and BSH i.v., 53 days following i.c, injection, and 72 days following i.c. injection + BBB-D with subsets of long-term survivors and/or cured animals in the latter two groups. No histopathologic evidence of residual tumor was seen in the brains of cured animals.Conclusions: The combination of BPA and BSH, administered i.c. with BBB-D, yielded a 25% cure rate for the heretofore incurable F98 rat glioma with minimal late radiation-induced brain damage. These results demonstrate that using a combination of boron agents and optimizing their delivery can dramatically improve the efficacy of BNCT in glioma-bearing rats. (C) 2000 Elsevier Science Inc.