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

Abstract

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.

Bioavailability and toxicity after oral administration of m-iodobenzylguanidine (MIBG)

“…Subsequently, [ 131 ]MIBG has been used at elevated radioactive doses for endo-irradiation of neuroadrenergic neoplasms such as phaeochromocytoma and neuroblastoma (Sisson and Wieland, 1986;Hoefnagel et al, 1987 a). The accumulation of MIBG in normal and neoplastic tissues of neuroadrenergic origin is based on its affinity for the specific uptake-1 mechanism of catecholamines (Jaques et al, 1987;Smets et al, 1991). Because of crossaffinity for the serotonin transporter (Rutgers et al, 1993), [ 131 l]MIBG is also applied for diagnosis and treatment of carcinoid tumours (Hoefnagel et al, 1987b;Taal et al, 1996a).…”

The effect of cisplatin pretreatment on the accumulation of MIBG by neuroblastoma cells in vitro

“…Treatments which enhance uptake of MIBG by neuroblastoma cells in culture include ionizing radiation, interferon-y and phorbol esters (Smets et al, 1991;Montaldo et al, 1992Montaldo et al, , 1996. In common with these agents, cisplatin causes perturbations of the DNA which in turn up-regulate p53 expression.…”

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“…The neuroblastoma cell line SK-N-SH and the rat pheochromocytoma cell line PC12 were chosen for this study because of their ability to actively accumulate MIBG [14] and because they represent cell lines with low (SK-N-SH) and high (PC12) granular content [15].…”