Abstract
BackgroundThe therapeutic use of [131I]meta-iodobenzylguanidine ([131I]MIBG) is often accompanied by hematological toxicity, mainly consisting of persistent and severe thrombocytopenia. While MIBG accumulates in neuroblastoma cells via selective uptake by the norepinephrine transporter (NET), the serotonin transporter (SERT) is responsible for cellular uptake of MIBG in platelets. In this study, we have investigated whether pharmacological intervention with selective serotonin reuptake inhibitors (SSRIs) may prevent radiotoxic MIBG uptake in platelets without affecting neuroblastoma tumor uptake.MethodsTo determine the transport kinetics of SERT for [125I]MIBG, HEK293 cells were transfected with SERT and uptake assays were conducted. Next, a panel of seven SSRIs was tested in vitro for their inhibitory potency on the uptake of [125I]MIBG in isolated human platelets and in cultured neuroblastoma cells. We investigated in vivo the efficacy of the four best performing SSRIs on the accumulation of [125I]MIBG in nude mice bearing subcutaneous neuroblastoma xenografts. In ex vivo experiments, the diluted plasma of mice treated with SSRIs was added to isolated human platelets to assess the effect on [125I]MIBG uptake.ResultsSERT performed as a low-affinity transporter of [125I]MIBG in comparison with NET (Km = 9.7 μM and 0.49 μM, respectively). Paroxetine was the most potent uptake inhibitor of both serotonin (IC50 = 0.6 nM) and MIBG (IC50 = 0.2 nM) in platelets. Citalopram was the most selective SERT inhibitor of [125I]MIBG uptake, with high SERT affinity in platelets (IC50 = 7.8 nM) and low NET affinity in neuroblastoma cells (IC50 = 11.940 nM). The in vivo tested SSRIs (citalopram, fluvoxamine, sertraline, and paroxetine) had no effect on [125I]MIBG uptake levels in neuroblastoma xenografts. In contrast, treatment with desipramine, a NET selective inhibitor, resulted in profoundly decreased xenograft [125I]MIBG levels (p < 0.0001). In ex vivo [125I]MIBG uptake experiments, 100- and 34-fold diluted murine plasma of mice treated with citalopram added to isolated human platelets led to a decrease in MIBG uptake of 54–76%, respectively.ConclusionOur study demonstrates for the first time that SSRIs selectively inhibit MIBG uptake in platelets without affecting MIBG accumulation in an in vivo neuroblastoma model. The concomitant application of citalopram during [131I]MIBG therapy seems a promising strategy to prevent thrombocytopenia in neuroblastoma patients.
Highlights
The therapeutic use of [131I]meta-iodobenzylguanidine ([131I]MIBG) is often accompanied by hematological toxicity, mainly consisting of persistent and severe thrombocytopenia
Uptake and inhibition in serotonin transporter (SERT)- and norepinephrine transporter (NET)-transfected HEK293 cells To determine the affinity of SERT for MIBG and its natural substrate serotonin, HEK293 cells were transfected with cDNA coding for SERT (HEK-SERT)
HEK293 cells were transfected with cDNA coding for NET (HEK-NET) to investigate the affinity of NET for MIBG
Summary
The therapeutic use of [131I]meta-iodobenzylguanidine ([131I]MIBG) is often accompanied by hematological toxicity, mainly consisting of persistent and severe thrombocytopenia. Whereas the iodine-123 radiolabeled form is used as a highly selective radioactive imaging agent [5], radioactive iodine-131 MIBG is being used since 1984 in patients with relapsed or refractory neuroblastoma to achieve a tumor response [6] This treatment in these patients has been accompanied by hematological toxicity, mainly consisting of persistent and severe thrombocytopenia [7,8,9]. Thrombocytopenia after [125I]MIBG treatment, a radiopharmaceutical with negligible radiation exposure to nontargeted neighboring cells [12], was unforeseen and far more severe than expected from calculated wholebody radiation doses in neuroblastoma patients [13, 14]. It appears that it is not the iodine-125 in itself that leads to hematological toxicity but the combination of the radioiodine with MIBG, since in patients with advanced colon cancer, high doses of iodine-125-labeled monoclonal antibody did not cause bone marrow toxicity, while the iodine131-labeled antibody caused severe hematological toxicity in 26% of patients [15, 16]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have