title: 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.
authors.affiliation: Division of Experimental Therapy, The Netherlands Cancer Institute, Amsterdam.
authors.forename: L A
authors.initials: LA
authors.lastname: Smets
authors.forename: M
authors.initials: M
authors.lastname: Janssen
authors.forename: M
authors.initials: M
authors.lastname: Rutgers
authors.forename: K
authors.initials: K
authors.lastname: Ritzen
authors.forename: C
authors.initials: C
authors.lastname: Buttenhuis
mesh_terms: D019797:3-Iodobenzylguanidine; D000109:Acetylcholine / Q000494:pharmacology; D000310:Adrenal Gland Neoplasms / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D001345:Autoradiography; D001692:Biological Transport / Q000187:drug effects / Q000528:radiation effects; D002460:Cell Line; D005089:Exocytosis / Q000187:drug effects; D005720:Gamma Rays; D007457:Iodine Radioisotopes; D007462:Iodobenzenes / Q000378:metabolism* / Q000493:pharmacokinetics; D007700:Kinetics; D009447:Neuroblastoma / Q000378:metabolism*; D009543:Nifedipine / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism; D010673:Pheochromocytoma / Q000378:metabolism*; D051381:Rats; D014700:Verapamil / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D007457:Iodine Radioisotopes; D007462:Iodobenzenes; D019797:3-Iodobenzylguanidine; D014700:Verapamil; D009543:Nifedipine; D000109:Acetylcholine; D009638:Norepinephrine