Basic characterization of 64Cu-ATSM as a radiotherapy agent
Basic characterization of 64Cu-ATSM as a radiotherapy agent
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DOI：
10.1016/j.nucmedbio.2004.08.012
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发表时间：
2005-01-01
影响因子：
3.1
通讯作者：
Fujibayashi, Y
中科院分区：
文献类型：
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作者：
Obata, A;Kasamatsu, S;Fujibayashi, Y
cu -64-二乙酰-双（n -4-甲基硫代氨基脲）（Cu-64-ATSM）是一种治疗缺氧肿瘤的有前途的放射治疗药物。为了阐明Cu-64-ATSM放射治疗的放射生物学基础，我们在体外细胞系模型中研究了细胞反应模式。用Cu-64-ATSM孵育细胞，通过克隆生存实验获得剂量-反应曲线。碱彗星法检测辐射诱导的DNA损伤，Annexin V-FITC法和碘化丙啶染色法检测凋亡细胞。研究细胞中(CU)-C-64的洗脱率和亚细胞分布，进一步从分子层面评估CU -64- atsm治疗的有效性。将Cu-ATSM的亚细胞定位与流动示踪剂类似物cu -丙酮-双（n -4-甲基硫代氨基脲）进行了直接比较。在本研究中，Cu-64-ATSM显示出以剂量依赖的方式降低肿瘤细胞的克隆存活率。在缺氧条件下，细胞吸收CU -64- atsm，放射性(CU)-C-64在细胞内大量积累。在CU -64- atsm处理的细胞中，检测到(CU)-C-64辐射对DNA的损伤，并在处理后24和36 h观察到细胞增殖抑制和凋亡诱导。观察了Cu-64-ATSM处理后放射诱导的细胞分裂后凋亡的典型特征。进入细胞的(CU)- c -64大部分留在线粒体后的上清液（去除细胞核和线粒体后的细胞残留物）中，这表明(CU)- c -64发射的β(-)粒子在CU -64- atsm治疗中可能与俄格电子一样有效。这些数据允许我们假设CU -64- atsm将能够直接攻击缺氧肿瘤细胞，并可能通过(CU)- c -64的β(-)粒子衰变间接影响外周非缺氧区域。(C) 2005爱思唯尔公司版权所有。
Cu-64-diacetyl-bis(N-4-methylthiosemicarbazone) (Cu-64-ATSM) is a promising radiotherapy agent for the treatment of hypoxic tumors. In an attempt to elucidate the radiobiological basis of Cu-64-ATSM radiotherapy, we have investigated the cellular response patterns in vitro cell line models. Cells were incubated with Cu-64-ATSM, and the dose-response curves were obtained by performing a clonogenic survival assay. Radiation-induced damage in DNA was evaluated using the alkali comet assay and apoptotic cells were detected using Annexin V-FITC and propidium iodide staining methods. Washout rate and subcellular distribution of (CU)-C-64 in cells were investigated to further assess the effectiveness of Cu-64-ATSM therapy on a molecular basis. A direct comparison of subcellular localization of Cu-ATSM was made with the flow tracer analog Cu-pyruvladehyde-bis(N-4-Methylthiosemicarbazone). In this study, Cu-64-ATSM was shown to reduce the clonogenic survival rate of tumor cells in a dose-dependent manner. Under hypoxic conditions, cells took up Cu-64-ATSM and radioactive (CU)-C-64 was highly accumulated in the cells. In the Cu-64-ATSM-treated cells, DNA damage by the radiation emitted from (CU)-C-64 was detected, and inhibition of cell proliferation and induction of apoptosis was observed at 24 and 36 h after the treatment. The typical features of postmitotic apoptosis induced by radiation were observed following Cu-64-ATSM treatment. The majority of the (CU)-C-64 taken up into the cells remained in the postmitochondrial supernatant (the cellular residue after removal of the nuclei and mitochondria), which indicates that the beta(-) particle emitted from (CU)-C-64 may be as effective as the Auger electrons in Cu-64-ATSM therapy. These data allow us to postulate that Cu-64-ATSM will be able to attack the hypoxic tumor cells directly, as well as potentially affecting the peripheral nonhypoxic regions indirectly by the beta(-) particle decay of (CU)-C-64. (C) 2005 Elsevier Inc. All rights reserved.