Radiation quality-dependent bystander effects elicited by targeted radionuclides
Radiation quality-dependent bystander effects elicited by targeted radionuclides
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DOI：
10.1211/jpp.60.8.0002
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发表时间：
2008-08-01
影响因子：
3.3
通讯作者：
Mairs, Robert J.
中科院分区：
文献类型：
--
作者：
Boyd, Marie;Sorensen, Annette;Mairs, Robert J.
放射治疗的疗效可能部分依赖于间接效应，间接效应可以杀死未直接照射的恶性细胞。然而，人们对这些效应在癌症靶向放射性核素治疗中的影响知之甚少。我们确定了去甲肾上腺素转运蛋白（NAT）基因转染的肿瘤细胞摄取放射性碘化碘脱氧尿苷（[*I]IUdR）和间碘苄基胍（[I-星]MIBG）放射性卤代类似物所产生的旁观者反应。 NAT专门积累MIBG。由 5% 表达 NAT 的细胞组成的多细胞球体，能够主动摄取放射性药物，通过用 20 kBq mL(-1) 的 α 发射体间位[At-211]astatobenzylguanidine ([At-211]MABG) 处理进行灭菌。类似地，在裸鼠中，用[I-131]MIBG治疗后观察到含有5% NAT阳性的肿瘤异种移植物的生长延迟。为了确定放射性标记药物亚细胞定位的效果，我们比较了[I-131]MIBG和[I-131]UdR（低线性能量转移（LET）β发射体）以及[I-123]MIBG和[I-123]IUdR（高LET俄歇电子发射体）的细胞内浓度引起的旁观者效应。 [*I]IUdR 掺入 DNA 中，而 [*I]MIBG 积聚在核外位点。暴露于[I-131]MIBG或[I-131]IUdR处理细胞的培养基的细胞表现出与克隆细胞死亡更密切的反应关系。相反，接受来自用[I-123]MIBG或[I-123]IUdR处理的培养物的培养基的细胞在低剂量下表现出剂量依赖性毒性，但随着辐射剂量的增加而消除细胞毒性（即U形生存曲线）。因此，发射高 LET 辐射的放射性核素可能分别在低剂量和高剂量下对邻近的非靶细胞产生毒性或保护作用。结论是，放射性药物引起的旁观者效应可能取决于衰变粒子的 LET，但与细胞内放射性核素浓度的位置无关。
The efficacy of radiotherapy may be partly dependent on indirect effects, which can sterilise malignant cells that are not directly irradiated. However, little is known of the influence of these effects in targeted radionuclide treatment of cancer. We determined bystander responses generated by the uptake of radioiodinated iododeoxyuridine ([*I]IUdR) and radiohaloanalogues of meta-iodobenzylguanidine ([I-star]MIBG) by noradrenaline transporter (NAT) gene-transfected tumour cells. NAT specifically accumulates MIBG. Multicellular spheroids that consisted of 5% of NAT-expressing cells, capable of the active uptake of radiopharmaceutical, were sterilised by treatment with 20 kBq mL(-1) of the alpha-emitter meta-[At-211]astatobenzylguanidine ([At-211]MABG). Similarly, in nude mice, retardation of the growth of tumour xenografts containing 5% NAT-positivity was observed after treatment with [I-131]MIBG. To determine the effect of subcellular localisation of radiolabelled drugs, we compared the bystander effects resulting from the intracellular concentration of [I-131]MIBG and [I-131]UdR (low linear energy transfer (LET) beta-emitters) as well as [I-123]MIBG and [I-123]IUdR (high LET Auger electron emitters). [*I]IUdR is incorporated in DNA whereas [*I]MIBG accumulates in extranuclear sites. Cells exposed to media from [I-131]MIBG- or [I-131]IUdR-treated cells demonstrated a closeresponse relationship with respect to clonogenic cell death. In contrast, cells receiving media from cultures treated with [I-123]MIBG or [I-123]IUdR exhibited dose-dependent toxicity at low dose but elimination of cytotoxicity with increasing radiation dose (i.e. U-shaped survival curves). Therefore radionuclides emitting high LET radiation may elicit toxic or protective effects on neighbouring untargeted cells at low and high dose respectively. It is concluded that radiopharmaceutical-induced bystander effects may depend on LET of the decay particles but are independent of site of intracellular concentration of radionuclide.