Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
Pediatr Blood Cancer. 2017 Apr;64(4). doi: 10.1002/pbc.26268. Epub 2016 Sep 22.
Neuroblastoma is a pediatric malignancy, and most tumor cells express the norepinephrine transporter (NET) enabling uptake of NET ligands. Meta-iodobenzylguanidine (MIBG) is a NET-specific ligand used as a highly specific imaging agent and targeted radiotherapeutic. Patients with neuroblastoma frequently require sedation during targeted radiotherapy. Dexmedetomidine has been increasingly used to achieve efficacious sedation. There are theoretical concerns that this highly selective alpha-2 adrenergic receptor agonist may interfere with active uptake of MIBG through the NET transporter. In this study, we analyzed the impact of [125-iodine]-labeled MIBG ([ I]MIBG) uptake in the presence of dexmedetomidine in human neuroblastoma-derived cellular models.
Carrier-free [ I]MIBG was synthesized using UltraTrace® resin (Molecular Insight Pharmaceuticals, Inc., Tarrytown, NY) through radioiododestannylation from a tin precursor bound by a solid-state polymer. NET (SLC6A2) protein expression was determined in human neuroblastoma cell lines (BE2C, SKNSH and IMR5). [ I]MIBG internalization studies were performed using [ I]MIBG alone or in combination with either desipramine or dexmedetomidine. Dexmedetomidine and desipramine competitive inhibition studies were performed and concentration at 50% maximal inhibition was calculated. Finally, NET inhibitor dissociation studies were performed in which after pre-incubation with either desipramine or dexmedetomidine, cells were washed and [ I]MIBG was added.
We show dose-dependent inhibition of [ I]MIBG uptake by dexmedetomidine, but at several logs lower potency than the known NET inhibitor desipramine. A review of pediatric dexmedetomidine pharmacokinetic data shows that the concentrations achieved in the serum are much lower than those required to block MIBG uptake.
We conclude that dexmedetomidine will not interfere with therapeutic [ I]MIBG efficacy.
神经母细胞瘤是一种儿科恶性肿瘤，大多数肿瘤细胞表达去甲肾上腺素转运体（NET），使其能够摄取 NET 配体。间碘苄胍（MIBG）是一种 NET 特异性配体，可用作高度特异性的成像剂和靶向放射性治疗药物。神经母细胞瘤患者在进行靶向放射治疗时常需镇静。右美托咪定已越来越多地用于实现有效的镇静。有人担心，这种高度选择性的α-2 肾上腺素能受体激动剂可能会通过 NET 转运体干扰 MIBG 的主动摄取。在这项研究中，我们分析了在人神经母细胞瘤衍生的细胞模型中，右美托咪定存在的情况下，[125-碘]-标记的 MIBG([I]MIBG)摄取的影响。
使用 UltraTrace®树脂（Molecular Insight Pharmaceuticals，Inc.，Tarrytown，NY）通过锡前体从锡前体进行放射性碘脱锡合成无载体[I]MIBG，锡前体由固态聚合物结合。用人神经母细胞瘤细胞系（BE2C、SKNSH 和 IMR5）测定 NET（SLC6A2）蛋白表达。单独或与去甲丙咪嗪或右美托咪定联合使用[I]MIBG 进行[I]MIBG 内化研究。进行右美托咪定和去甲丙咪嗪的竞争性抑制研究，并计算 50%最大抑制的浓度。最后，进行 NET 抑制剂解离研究，在预孵育去甲丙咪嗪或右美托咪定后，将细胞洗涤并用[I]MIBG 进行处理。
我们显示右美托咪定对[I]MIBG 摄取呈剂量依赖性抑制，但抑制效力比已知的 NET 抑制剂去甲丙咪嗪低几个对数级。对儿科右美托咪定药代动力学数据的回顾表明，血清中达到的浓度远低于阻断 MIBG 摄取所需的浓度。
我们的结论是，右美托咪定不会干扰治疗性[I]MIBG 的疗效。
