Pharmacokinetics and intracellular distribution of the tumor-targeted radiopharmaceutical m-iodo-benzylguanidine in SK-N-SH neuroblastoma and PC-12 pheochromocytoma cells.

Radiodinated meta-iodobenzylguandine (MIBG) is increasingly used for the diagnosis and targeted radiotherapy of neuro-adrenergic tumors. We have investigated various conditions for specific tumor loading and prolonged retention of this radiopharmaceutical in poorly differentiated SK-N-SH neuroblastoma and highly differentiated PC-12 pheochromocytoma cells. At a constant value of drug concentration x incubation time, short incubations were superior to protracted incubations for maximal cell loading. This effect was most pronounced in the SH-N-SH neuroblastoma cells. In highly differentiated pheochromocytoma cells, the levels of MIBG storage remained high and unchanged during incubations up to 46 hr in label-free medium, while primitive SK-N-SH cells lost 40-50% of accumulated drug by diffusion. In PC-12 cells, susceptibility of stored MIBG to exocytotic release induced by acetylcholine or K+ was similar to that of natural norepinephrine (NE) and prevented by the Ca(++)-channel blockers verapamil and nifedipine. Conversely, granule-poor SK-N-SH cells were insensitive to exocytotic release of MIBG. Uptake and retention capacities were minimally impaired by an externally delivered radiation dose of 5 Gy to mimic the radiobiological effect of 131I-MIBG in tumors. In pre-irradiated cultures, drug uptake was even stimulated, probably due to enrichment in non-proliferating cells. An autoradiographic comparison of the (sub)cellular distributions of 3H-norepinephrine and 125I-MIBG showed that routine conditions of cell fixation and sample processing do not yield reliable results regarding localization of MIBG.