Evaluation of hypoxia-specific cytotoxic bioreductive agent-sodium borocaptate-10B conjugates as 10B-carriers in boron neutron capture therapy.
Evaluation of hypoxia-specific cytotoxic bioreductive agent-sodium borocaptate-10B conjugates as 10B-carriers in boron neutron capture therapy.
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DOI：
10.1007/bf02493275
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发表时间：
2006-02-01
影响因子：
--
通讯作者：
Ono, Koji
中科院分区：
文献类型：
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作者：
Masunaga, Shin-Ichiro;Nagasawa, Hideko;Ono, Koji
目得：评价5种新的10 B-化合物（TX-2091、TX-2095、TX-2097、TX-2100和TX-2110）作为10 B-载体在硼中子俘获治疗（BNCT）中的有效性。它们是由缺氧特异性细胞毒性生物还原剂氧化喹喔啉TX-402和临床上使用的10 B-载体硼癸酸钠-10B（BSH）合成的缀合物。材料和方法：这5个新化合物是具有缺氧细胞毒素单元和热中子敏化单元BSH的杂化化合物。将这些新化合物和BSH腹膜内给予SCC VII荷瘤小鼠。然后，通过γ射线光谱法测量肿瘤和正常组织中的10 B浓度。随后，连续给予SCC VII荷瘤小鼠5-溴-2 '-脱氧尿苷（BrdU）以标记肿瘤中的所有增殖（P）细胞，然后用TX-2100（其基于上述生物分布分析的结果选择）或BSH（以与生物分布研究中相同的方式）处理。照射后，肿瘤内10 B浓度保持在彼此相似的水平，立即切除肿瘤，切碎，并胰蛋白酶消化。将由此获得的肿瘤细胞悬液与细胞松弛素-B（胞质分裂阻滞剂）一起孵育，并使用BrdU免疫荧光染色法测定未标记BrdU的细胞[=静止（Q）细胞]中的微核（MN）频率。同时，从未用BrdU预处理的肿瘤确定总（P+Q）肿瘤细胞群中的MN频率。克隆形成细胞的存活率也确定在小鼠给予没有BrdU.Results：10 B在肿瘤，脑，皮肤，肌肉，血液和肝脏中的生物分布分析表明，TX-2100具有最有利的特点，集中了足够量的10 B在肿瘤中，并保持足够高的10 B浓度在照射过程中。此外，TX-2100与反应堆热中子束相比，对实体瘤中的总细胞和Q细胞具有显著更强的放射增敏作用。此外，TX-2100不仅对总细胞，而且对Q和缺氧肿瘤细胞都清楚地表现出对γ射线的放射增敏作用，这是BSH所不能实现的。一种10 B-载体，其作为肿瘤细胞上的缺氧细胞毒素，并且具有将10 B保持在肿瘤中的潜力，并且比常规10 B-载体如TX-2100更显著地使肿瘤细胞敏化，是用于BNCT的有希望的候选者。
PURPOSE: To evaluate the usefulness of 5 new 10B-compounds (TX-2091, TX-2095, TX-2097, TX-2100, and TX-2110) as 10B-carriers in boron neutron capture therpy (BNCT). They were conjugates that had been synthesized from a hypoxia-specific cytotoxic bioreductive agent, quinoxaline oxide TX-402, and a clinically used 10B-carrier, sodium borocaptate-10B (BSH).MATERIALS AND METHODS: The 5 new compounds were hybrid compounds that have both a hypoxic cytotoxin unit and a thermal neutron-sensitizing unit, BSH. These new compounds and BSH were administered intraperitoneally to SCC VII tumor-bearing mice. Then, the 10B concentrations in the tumors and normal tissues were measured by gamma-ray spectrometry. Subsequently, SCC VII tumor-bearing mice were continuously given 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating (P) cells in the tumors, then treated with TX-2100, which was chosen based on the results of the above-mentioned biodistribution analyses, or BSH in the same manner as in the biodistribution studies. Right after irradiation, during which intratumor 10B concentrations were kept at levels similar to each other, the tumors were excised, minced, and trypsinized. The tumor cell suspensions thus obtained were incubated with cytochalasin-B (a cytokinesis blocker), and the micronucleus (MN) frequency in cells without BrdU labeling [= quiescent (Q) cells] was determined using immunofluorescence staining for BrdU. Meanwhile, the MN frequency in the total (P+Q) tumor cell population was determined from the tumors that were not pretreated with BrdU. Clonogenic cell survival was also determined in mice given no BrdU.RESULTS: 10B biodistribution analyses in tumors, brain, skin, muscles, blood, and liver indicated that TX-2100 has the most favorable characteristics for concentrating a sufficient amount of 10B in tumors and maintaining a high enough 10B concentration during irradiation. In addition, TX-2100 had a significantly stronger radio-sensitizing effect with reactor thermal neutron beams than BSH on both total and Q cells in solid tumors. Further, TX-2100 clearly exhibited a radio-sensitizing effect with gamma-rays not only on total cells but also on Q and hypoxic tumor cells, which was not achieved by BSH.CONCLUSION: A 10B-carrier that acts as a hypoxic cytotoxin on tumor cells as well as having the potential to keep 10B in tumors and sensitize tumor cells more markedly than conventional 10B-carriers, such as TX-2100, is a promising candidate for use in BNCT.