School of Biosciences, University of Kent, Canterbury, Kent, UK.
Eur J Nucl Med Mol Imaging. 2010 Feb;37(2):330-8. doi: 10.1007/s00259-009-1305-8. Epub 2009 Nov 14.
Hypoxia occurs frequently in cancers and can lead to therapeutic resistance due to poor perfusion and loss of the oxygen enhancement effect. (64)Cu-ATSM has shown promise as a hypoxia diagnostic agent due to its selective uptake and retention in hypoxic cells and its emission of positrons for PET imaging. (64)Cu also emits radiotoxic Auger electrons and beta(-) particles and may therefore exhibit therapeutic potential when concentrated in hypoxic tissue.
MCF-7 cells were treated with 0-10 MBq/ml (64)Cu-ATSM under differing oxygen conditions ranging from normoxia to severe hypoxia. Intracellular response to hypoxia was measured using Western blotting for expression of HIF-1alpha, while cellular accumulation of (64)Cu was measured by gamma counting. DNA damage and cytotoxicity were measured with, respectively, the Comet assay and clonogenic survival.
(64)Cu-ATSM uptake in MCF-7 cells increased as atmospheric oxygen decreased (up to 5.6 Bq/cell at 20.9% oxygen, 10.4 Bq/cell at 0.1% oxygen and 26.0 Bq/cell at anoxia). Toxicity of (64)Cu-ATSM in MCF-7 cells also increased as atmospheric oxygen decreased, with survival of 9.8, 1.5 and 0% in cells exposed to 10 MBq/ml at 20.9, 0.1 and 0% oxygen. The Comet assay revealed a statistically significant increase in (64)Cu-ATSM-induced DNA damage under hypoxic conditions.
The results support a model in which hypoxia-enhanced uptake of radiotoxic (64)Cu induces sufficient DNA damage and toxicity to overcome the documented radioresistance in hypoxic MCF-7 cells. This suggests that (64)Cu-ATSM and related complexes have potential for targeted radionuclide therapy of hypoxic tumours.
缺氧在癌症中经常发生，并由于灌注不良和丧失氧增强效应而导致治疗抵抗。（64）Cu-ATSM 作为缺氧诊断剂具有很大的应用前景，因为它可以选择性地摄取和保留在缺氧细胞中，并发射正电子用于 PET 成像。（64）Cu 还发射放射性毒的俄歇电子和β(-)粒子，因此当集中在缺氧组织中时，可能具有治疗潜力。
在从常氧到严重缺氧的不同氧条件下，用 0-10MBq/ml（64）Cu-ATSM 处理 MCF-7 细胞。通过 Western blot 检测缺氧诱导因子 1α（HIF-1α）的表达来测量细胞对缺氧的反应，同时通过伽马计数测量（64）Cu 的细胞内积累。分别用彗星试验和集落形成存活试验测量 DNA 损伤和细胞毒性。
在 MCF-7 细胞中，（64）Cu-ATSM 的摄取随大气氧的减少而增加（在 20.9%氧气下为 5.6 Bq/细胞，在 0.1%氧气下为 10.4 Bq/细胞，在缺氧下为 26.0 Bq/细胞）。（64）Cu-ATSM 在 MCF-7 细胞中的毒性也随大气氧的减少而增加，在暴露于 10MBq/ml 的细胞中，存活率分别为 20.9%、0.1%和 0%氧气。彗星试验显示，在缺氧条件下，（64）Cu-ATSM 诱导的 DNA 损伤明显增加。
这些结果支持这样一种模式，即缺氧增强放射性毒性（64）Cu 的摄取会引起足够的 DNA 损伤和毒性，以克服缺氧 MCF-7 细胞中已有的放射抗性。这表明（64）Cu-ATSM 和相关复合物具有针对缺氧肿瘤的靶向放射性核素治疗的潜力。
