I-131-mIBG therapy in neuroblastoma: established role and prospective applications

Schmidt, Matthias; Hero, Barbara; Simon, Thorsten

doi:10.1007/s40336-016-0173-z

Cited by 11 publications

(3 citation statements)

References 79 publications

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“…The success of iodide-131 in targeting and treating thyroid disorders and carcinomas encouraged the expansion of its use in a variety of cancers through its incorporation into targeting vectors. For example, iobenguane I-131 is the radioiodinated small-molecule meta -iodobenzylguanidine ([ 131 I]mIBG), an analogue of the adrenergic neutrotransmitter noradrenaline that is used to treat patients with neuroblastomas 140 – 142 . Iodide-131 can be introduced to targeting vectors as a highly reactive electrophilic iodine compound, allowing rapid iodination of molecules containing activated aromatic groups, or through displacement by nucleophilic attack of the radioiodide 143 .…”

Section: Rpt Agents In Use and In Clinical Developmentmentioning

confidence: 99%

Radiopharmaceutical therapy in cancer: clinical advances and challenges

Sgouros

Bodei

McDevitt

et al. 2020

Nat Rev Drug Discov

546

430

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Radiopharmaceutical therapy (RPT) is emerging as a safe and effective targeted approach to treating many types of cancer. In RPT, radiation is systemically or locally delivered using pharmaceuticals that either bind preferentially to cancer cells or accumulate by physiological mechanisms. Almost all radionuclides used in RPT emit photons that can be imaged, enabling non-invasive visualization of the biodistribution of the therapeutic agent. Compared with almost all other systemic cancer treatment options, RPT has shown efficacy with minimal toxicity. With the recent FDA approval of several RPT agents, the remarkable potential of this treatment is now being recognized. This Review covers the fundamental properties, clinical development and associated challenges of RPT.

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Section: Rpt Agents In Use and In Clinical Developmentmentioning

confidence: 99%

Radiopharmaceutical therapy in cancer: clinical advances and challenges

Sgouros

Bodei

McDevitt

et al. 2020

Nat Rev Drug Discov

546

430

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“…Besides catecholamines, a few other compounds can be taken up by the NAT, among them ( meta -iodobenzyl)guanidine (mIBG) [ 5 ]. From the 1980s until now [ 6 ], radio-iodine-labelled mIBG {first [ 131 I]mIBG [ 7 , 8 ], ( Figure 1 , line 1), soon replaced by [ 123 I]mIBG}, has been used for scintigraphic diagnosis [ 9 ], and [ 131 I]mIBG for therapy [ 10 ] of neuroblastoma. It is noteworthy that the benzylguanidine (BG) with 131 iodine bound in the meta -position {[ 131 I]mIBG, Figure 1 , line 1)} is taken up by NAT-expressing cells equally well as its para -isomer [ 131 I]pIBG.…”

Section: Introductionmentioning

confidence: 99%

Hybrid Molecules of Benzylguanidine and the Alkylating Group of Melphalan: Synthesis and Effects on Neuroblastoma Cells

Bruchelt

Klose

Lischka

et al. 2023

JCM

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The therapy of neuroblastoma relies, amongst other things, on administering chemotherapeutics and radioactive compounds, e.g., the (meta-iodobenzyl)guanidine [131I]mIBG. For special applications (conditioning before stem cell transplantation), busulfan and melphalan (M) proved to be effective. However, both drugs are not used for normal chemotherapy in neuroblastoma because of their side effects. The alkylating drug melphalan contains a (Cl-CH2-CH2-)2N- group in the para-position of the phenyl moiety of the essential amino acid phenylalanine (Phe) and can, therefore, be taken up by virtually all kinds of cells by amino acid transporters. In contrast, mIBG isotopologs are taken up more selectively by neuroblastoma cells via the noradrenaline transporter (NAT). The present study aimed at synthesising and studying hybrid molecules of benzylguanidine (BG) and the alkylating motif of M. Such hybrids should combine the preferential uptake of BGs into neuroblastoma cells with the cytotoxicity of M. Besides the hybrid of BG with the dialkylating group (Cl-CH2-CH2-)2N- bound in the para-position as in M (pMBG), we also synthesised mMBG, which is BG meta-substituted by a (Cl-CH2-CH2-)2N- group. Furthermore, two monoalkylating hybrid molecules were synthesised: the BG para-substituted by a (Cl-CH2-CH2-)NH- group (pM*BG) and the BG meta-substituted by a (Cl-CH2-CH2-)NH- group (mM*BG). The effects of the four new compounds were studied with human neuroblastoma cell lines (SK-N-SH, Kelly, and LS) with regard to uptake, viability, and proliferation by standard test systems. The dialkylating hybrid molecules pMBG and mMBG were at least as effective as M, whereas the monoalkylating hybrid molecules pM*BG and mM*BG were more effective than M. Considering the preferred uptake via the noradrenaline transporter by neuroblastoma cells, we conclude that they might be well suited for therapy.

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“…Over the years, different strategies have been studied to optimize the application of [ 131 I]MIBG therapy in neuroblastoma patients [ 5 ]. In the majority of these studies, [ 131 I]MIBG was used as salvage therapy for refractory or relapsed disease [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Thrombocytopenia after meta-iodobenzylguanidine (MIBG) therapy in neuroblastoma patients may be caused by selective MIBG uptake via the serotonin transporter located on megakaryocytes

et al. 2021

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Background The therapeutic use of [131I]meta-iodobenzylguanidine ([131I]MIBG) is often accompanied by hematological toxicity, primarily consisting of severe and persistent thrombocytopenia. We hypothesize that this is caused by selective uptake of MIBG via the serotonin transporter (SERT) located on platelets and megakaryocytes. In this study, we have investigated whether in vitro cultured human megakaryocytes are capable of selective plasma membrane transport of MIBG and whether pharmacological intervention with selective serotonin reuptake inhibitors (SSRIs) may prevent this radiotoxic MIBG uptake. Methods Peripheral blood CD34+ cells were differentiated to human megakaryocytic cells using a standardized culture protocol. Prior to [3H]serotonin and [125I]MIBG uptake experiments, the differentiation status of megakaryocyte cultures was assessed by flow cytometry. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to assess SERT and NET (norepinephrine transporter) mRNA expression. On day 10 of differentiation, [3H]serotonin and [125I]MIBG uptake assays were conducted. Part of the samples were co-incubated with the SSRI citalopram to assess SERT-specific uptake. HEK293 cells transfected with SERT, NET, and empty vector served as controls. Results In vitro cultured human megakaryocytes are capable of selective plasma membrane transport of MIBG. After 10 days of differentiation, megakaryocytic cell culture batches from three different hematopoietic stem and progenitor cell donors showed on average 9.2 ± 2.4 nmol of MIBG uptake per milligram protein per hour after incubation with 10–7 M MIBG (range: 6.6 ± 1.0 to 11.2 ± 1.0 nmol/mg/h). Co-incubation with the SSRI citalopram led to a significant reduction (30.1%—41.5%) in MIBG uptake, implying SERT-specific uptake of MIBG. A strong correlation between the number of mature megakaryocytes and SERT-specific MIBG uptake was observed. Conclusion Our study demonstrates that human megakaryocytes cultured in vitro are capable of MIBG uptake. Moreover, the SSRI citalopram selectively inhibits MIBG uptake via the serotonin transporter. The concomitant administration of citalopram to neuroblastoma patients during [131I]MIBG therapy might be a promising strategy to prevent the onset of thrombocytopenia.

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I-131-mIBG therapy in neuroblastoma: established role and prospective applications

Cited by 11 publications

References 79 publications

Radiopharmaceutical therapy in cancer: clinical advances and challenges

Radiopharmaceutical therapy in cancer: clinical advances and challenges

Hybrid Molecules of Benzylguanidine and the Alkylating Group of Melphalan: Synthesis and Effects on Neuroblastoma Cells

Thrombocytopenia after meta-iodobenzylguanidine (MIBG) therapy in neuroblastoma patients may be caused by selective MIBG uptake via the serotonin transporter located on megakaryocytes

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