RELEASE MECHANISMS OF [I-125] METAIODOBENZYLGUANIDINE IN NEUROBLASTOMA-CELLS - EVIDENCE OF A CARRIER-MEDIATED EFFLUX

[I-131]metaiodobenzylguanidine ([I-131]MIBG) is selectively taken up a nd stored by tumours derived from the neural crest, and is used for di agnosis and treatment of neuroblastoma (NB). The antitumoral effect of [I-131]MIBG is closely related to the intracellular level of the radi opharmaceutical compound, which is dependent on uptake and storage/rel ease mechanisms. While MIBG uptake is well characterised, storage and release mechanisms are still controversial. In order to better charact erise [I-125]MIBG release mechanisms, we studied the basal and stimula ted efflux of [I-125]MIBG in the human NE cell line, SH-SY5Y, preloade d with 0.1 mu M [I-125]MIBG for 1 h. We found that [I-125]MIBG basal e fflux is highly temperature-dependent, that [I-125]MIBG release, induc ed by cell depolarisatlon with high potassium, is mainly calcium-indep endent, and induced by exchange with cold MIBG or noradrenaline, inver sion of the sodium gradient across the cell membrane by veratridine or by substitution of sodium chloride with equimolar concentration of li thium chloride. The exposure of NE cells to imipramine, an Uptake-1 in hibitor, also produces a net stimulatory effect on [I-125]MIBG release . However, when used in association with other releasing stimuli, such as higher levels of intracellular sodium or external agonists, imipra mine abolishes the consequent increase of [I-125]MIBG release. Our fin dings suggest that stimulated [I-125]MIBG release is mediated by a car rier, most probably the uptake carrier working in a reverse mode, whil e a minimal fraction of[I-125]MIBG is released by an exocytotic mechan ism.