In vitro therapeutic targeting of neuroblastomas using ¹²⁵I‐labelled meta‐iodobenzylguanidine

Abstract

The use of labelled radiopharmaceuticals such as metaiodobenzylguanidine (m-IBG) enables neuroblastomas and other malignant cells from neural crests to be visualized. In vitro study of cellular incorporation into human neuroblastoma lines (SK-N-SH, SK-N-MC, LAN I) showed that only the SK-N-SH line retained iodine-125 m-IBG (125I-m-IBG) significantly. Fifty-five percent of the initial activity was retained after 1 hr incubation at a concentration of 10(-7) M of m-IBG (specific activity: 1,480 MBq/mg). Beyond this value, m-IBG uptake mechanisms were saturated. Study of release kinetics showed a rapid first phase (50% released after 4 hr) and a slower second phase (30% of the value retained at the equilibrium point was present after 48 hr), indicating the existence of a storage compartment. Autoradiography studies confirmed the intracytoplasmic localization of m-IBG and showed that a low percentage (3 to 5%) of SK-N-SH cells strongly retained m-IBG. Cytotoxicity tests showed that SK-N-SH cell growth was significantly reduced during the first days of culture, following 2 hr incubation with 1,500 KBq of 125I-m-IBG, whereas no toxic effect on SK-N-MC cells was found at the same activity. Moreover, the toxic effect observed in the SK-N-SH line was clearly related to the use of 125I-m-IBG since the same activity of 1,500 KBq of non-coupled 125I was without effect. For the latter line, colony-forming capacity was reduced for activities of 150 and 1,500 KBq of 125I-m-IBG, with respectively 32% and 38% lower survival rates. The cytotoxic effect of labelled m-IBG was, however, limited in non-saturating concentrations because the specific activity used was too low. Moreover, the low number of cells reconcentrating m-IBG is indicative of the heterogeneous cellular composition of the SK-N-SH line.

Intracellular localization of metaiodobenzyl guanidine in human neuroblastoma cells by electron spectroscopic imaging

“…There is, however, no reason to assume that intracellular localization of mIBG depends on the mode of uptake, and it is reasonable to suppose that our findings are likely to be representative of mIBG distribution in vivo also. Our identification of the mitochondrion as the principal site of mIBG accumulation is a valuable finding, since, although Smets et al (1989) and Guerreau et al (1990) have demonstrated that mIBG accumulation in neuroblastoma is predominantly extra-vesicular, the actual subcellular compartmentalization has not previously been described. The precise intracellular localization is of more than purely academic interest: it is of critical importance for the success of targeted radiotherapy with radionuclides emitting short-range radiation.…”

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

“…However, subsequent storage of the radiopharmaceutical by poorly differentiated SK-N-SH cells, containing few specialized storage granules (Smets et al, 1989;Guerreau et al, 1990), occurs mainly by rapid re-uptake of diffusing drug . In contrast, MIBG storage in PC-12 cells and bovine chromaffin cells is strongly dependent on these organelles and thus sensitive to depletion by drugs such as reserpine (Guilloteau et al, 1984;Smets et al, 1990).…”

Toxicity to neuroblastoma cells and spheroids of benzylguanidine conjugated to radionuclides with short-range emissions

“…Firstly, the efficacy of Auger electronemitters will be unaffected by the same size constraints as 1311, with the result that the energy they deposit will be more fully absorbed in small tumour volumes. In addition, crossfire to adjacent non-target sites will be negligible, resulting in the sparing of surrounding normal tissues.['251I]MIBG has been shown to be toxic to neuroblastoma cells in vitro (Bruchelt et al, 1988;Guerreau et al, 1990;Senekowitsch et al, 1992). In contrast, in vivo data from mice bearing microscopic disease demonstrated no difference in tumour survival between control and ['25I]MIBG-treated animals (Rutgers et al, 1994).…”

“…['251I]MIBG has been shown to be toxic to neuroblastoma cells in vitro (Bruchelt et al, 1988;Guerreau et al, 1990;Senekowitsch et al, 1992). In contrast, in vivo data from mice bearing microscopic disease demonstrated no difference in tumour survival between control and ['25I]MIBG-treated animals (Rutgers et al, 1994).…”