Increase of metaiodobenzylguanidine uptake and intracellular half-life during differentiation of human neuroblastoma cells

Abstract

iodine-labelled metaiodobenrylguanidine (MIBG) is a radiopharmaceutical used for diagnostic imaging and targeted radiotherapy of neuroendocrine tumors. We previously reported that the ability of a neuroblastoma (NB) cell line, LAN-5, to accumulate MIBG was powerfully stimulated by interferon-γ (lFN-γ), a well-known NB differentiation-promoting agent. To extend the above findings, we have investigated 5 NB cell lines for their ability to accumulate 125I-MIBG in basal conditions or after various combinations of differentiative stimuli. Our results show that association of lFN-γ and tumor necrosis factor-a boosts MIBG uptake in the early times of incubation in LAN-5 and GI-LI-N cells, while both SK-N-SH and SK-N-BE(2)c cells are strongly stimulated by co-treatment with lFN-γ and alltrans retinoic acid. Moreover, although only LAN-5 and GI-LI-N cells are sensitive to IFN-γ atone, the combination of lFN-γ and IFN-α causes a synergistic increase in MIBG uptake in all the NB cell lines tested. From experiments on MIBG release we conclude that no intracellular storage within specialized structures took place during differentiation. The observed enhancement in MIBG accumulation results from an increased uptake of the drug only. This conclusion was confirmed by analyzing MIBG-transporter gene expression, which was increased in cells subjected to differentiative regimens. According to these findings, inducing differentiation of NB cells in vitro appears to improve their MIBG incorporation ability powerfully.