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.

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In the current study the authors have investigated whether human primary breast cancer specimens contain insulin-like growth factor-1 (IGF-1) receptors (IGF-1-R) or IGF-1-like activities. Simultaneously, epidermal growth factor (EGF) receptors (EGF-R) and cytosolic estrogen receptor (ER), progesterone receptor (PR), and EGF-like activity were determined. All tumors assayed contained a single class of specific iodine 125 (125I)-IGF-1 binding sites (Kd: median 106, range 48-755 pM; n = 32) with limited capacity (Bmax: median 147, range 19-11,900 fmol/mg membrane protein). Seventy percent of 44 tumors (50% ER+, PR+), displayed specific 125I-EGF binding with a wide range of values (median 13, range 2-215 fmol/mg protein, n = 31). A positive relationship was apparent between the amount of IGF-1-R with ER and PR (Spearman; 2P less than 0.02 and 2P less than 0.01, respectively; n = 32), whereas for EGF-R a negative relationship was observed (for both 2P less than 0.01; n = 44). All tumors contained endogeneous IGF-1-like and EGF-like activities as measured by radioreceptor assay on acid-ethanol extracted cytosols (median 15, range 3-131 ng/mg protein, n = 78 for IGF-1; and median 86, range 26-517 ng/mg protein, n = 142 for EGF). Tumor contents of IGF-1-like and EGF-like activities showed a negative relationship with ER (2P less than 0.1 for IGF-1, n = 78; and 2P less than 0.001 for EGF, n = 142), and with PR (2P less than 0.05, n = 78; and 2P less than 0.001, n = 142). No relationship was observed between the tumor contents of IGF-1-like and EGF-like activities. In conclusion, these data support the view that IGF-1 and EGF can act as autocrine or paracrine growth factors in human breast cancer.

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