Tytgat Godelieve A M, van den Brug Marieke Dekker, Voûte P A, Smets Lou A, Rutgers Marja
Center of Microscopic Research, Academical Medical Center, Amsterdam, The Netherlands.
Exp Hematol. 2002 Jun;30(6):555-63. doi: 10.1016/s0301-472x(02)00804-4.
Thrombocytopenia is the major toxicity of radio-iodinated meta-iodobenzylguanidine (MIBG) therapy in patients with recurrent neuroblastoma. MIBG is taken up in platelets via the serotonin transporter. Given the delayed appearance and long duration of the thrombocytopenia, it seems likely that the precursor megakaryocytes are the primary targets of [131I]MIBG radiotoxicity.
We investigated MIBG and serotonin uptake in cultured human megakaryocytes grown in vitro from CD34(+) cells obtained from bone marrow.
With radio-iodinated MIBG, cell-associated radioactivity was negligible, even after prolonged incubations for up to 16 hours. In contrast, after 4 or 16 hours with 10(-8) M [3H]serotonin, 6% or 14% of the added substrate was accumulated in the megakaryocytes. This uptake approached saturation above 10(-7) M and was reduced greater than 90% by coincubation by imipramine. This indicates specific uptake, which was confirmed by fluvoxamine and citalopram. The serotonin reuptake inhibitors fluvoxamine (0.3 nM) and citalopram (1 nM) effectively reduced serotonin uptake to 44% +/- 3% and 30% +/- 9% of the controls, respectively.
Megakaryocytes efficiently retain serotonin in storage granules, as concluded from the consistent reductive effect of tetrabenazine on uptake, retention, and localization (micro-autoradiographic) of serotonin. Thus, serotonin, but not MIBG, is taken up by cultured megakaryocytes.
血小板减少是复发性神经母细胞瘤患者接受放射性碘化间碘苄胍（MIBG）治疗的主要毒性反应。MIBG通过5-羟色胺转运体被摄取到血小板中。鉴于血小板减少出现延迟且持续时间长，前体巨核细胞似乎很可能是[131I]MIBG放射毒性的主要靶点。
我们研究了从骨髓获得的CD34(+)细胞体外培养的人巨核细胞对MIBG和5-羟色胺的摄取。
使用放射性碘化MIBG时，即使长时间孵育长达16小时，细胞相关放射性也可忽略不计。相比之下，在10(-8) M [3H]5-羟色胺孵育4或16小时后，6%或14%的添加底物积聚在巨核细胞中。这种摄取在高于10(-7) M时接近饱和，并且通过与丙咪嗪共同孵育减少超过90%。这表明存在特异性摄取，氟伏沙明和西酞普兰证实了这一点。5-羟色胺再摄取抑制剂氟伏沙明（0.3 nM）和西酞普兰（1 nM）分别有效地将5-羟色胺摄取降低至对照的44%±3%和30%±9%。
从丁苯那嗪对5-羟色胺摄取、保留和定位（微放射自显影）的一致还原作用可以得出结论，巨核细胞有效地将5-羟色胺保留在储存颗粒中。因此，培养的巨核细胞摄取5-羟色胺而非MIBG。
