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

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.

Metabolism of methyl-branched iodo palmitic acids in cultured hepatocytes.

The metabolic fate of methyl-branched iodo fatty acids was studied in primary culture of rat hepatocytes. We compared 16-iodo-2-R,S-methyl palmitic acid (2-Me), which can be beta oxidized, with 16-iodo-3-R,S-methyl palmitic acid (3-Me) which can be beta oxidized only after an initial alpha oxydation and with 16-iodo-2,2-dimethyl palmitic acid (2,2-Me2) and 16-iodo-3,3-dimethyl palmitic acid (3,3-Me2) which cannot be beta oxidized at all. The normal fate of natural fatty acids was given by comparative experiments with [1-14C] palmitic acid. Monomethyl-branched iodo fatty acids were taken up in the same range as palmitic acid but more than dimethyl-branched iodo fatty acids. After a 15-h incubation, acido-soluble products (ASP) accounted for 75% of the radioactivity taken up as 16-iodo-2-methyl palmitic acid, 50% as other methyl-branched iodo fatty acids and only 30% as palmitic acid, which indicated that all the methyl-branched iodo fatty acids underwent a strong deiodination process. Fatty acids were esterified in the following order: palmitic acid greater than 16-iodo-3-R,S-methyl palmitic acid greater than 16-iodo-2-R,S-methyl palmitic acid greater than 16-iodo-2,2-dimethyl palmitic acid greater than 16-iodo-3,3-dimethyl palmitic acid. Cultured hepatocytes, labelled for 3 h with the various fatty acids and reincubated for 12 h without fatty acid, secreted large amounts of free dimethyl-branched iodo fatty acids as compared to the monomethyl ones and palmitic acid.(ABSTRACT TRUNCATED AT 250 WORDS)

Hepatic artery injection of I-131-labeled lipiodol. Part I. Biodistribution study results in patients with hepatocellular carcinoma and liver metastases.

Biodistribution of iodine-131-labeled Lipiodol Ultra-Fluide (I-131 LUF) injected into the hepatic artery was studied scintigraphically in 47 patients with hepatocellular carcinoma (n = 23), hepatic metastases (n = 14), or normal livers (n = 10). The investigation was extremely well tolerated. I-131 LUF concentrated mainly in the liver (L) and the lungs (l), with L/L + l activity ratios greater than 75% for all three groups of patients. I-131 LUF distribution was homogeneous in normal livers and heterogeneous in cirrhotic livers. I-131 LUF concentrated in the tumor with a tumorous (T) to nontumorous (NT) activity ratio (T/NT) of 4.3 +/- 3.6 for hepatocellular carcinoma and 2.4 +/- 0.7 for hepatic metastases. The effective half-life of I-131 LUF is more than 4.5 days for the three groups. It was eliminated mainly through the urine. Clearance from tumor is slower than from normal liver, as shown by the increase in T/NT at day 18. Biodistribution did not change in patients who had a second injection, which indicates that there is no saturation phenomenon. The results of this study suggest that LUF may be considered as a potential carrier vehicle for therapeutic agents.

[Sensitivity and specificity of meta-iodobenzylguanidine (mIBG) scintigraphy in the evaluation of neuroblastoma: analysis of 115 cases]. / Sensibilité et spécificité de la scintigraphie à la méta-iodobenzylguanidine (mIBG) dans l'exploration des neuroblastomes: analyse de 115 examens.

Seventy children (3.7 +/- 3.3 y) with definitely confirmed diagnosis of neuroblastoma had 115 whole body scans carried out 24 h after injection of 3.7 MBq/kg of I-123 mIBG (83 scans) or 0.7 MBq/kg of I-131 mIBG (17 scans) or 0.9 to 4.5 GBq of I-131 mIBG (15 post-therapeutic scans). The scans were interpreted as positive in the presence of any non-physiological uptake area or of any bone uptake of the tracer, even at the level of the metaphyseal complex. For the primary tumour, the sensitivity of mIBG scans was 73%. Ten false negative patients had an overlap of the tumour with the bladder or heart images (4 cases) or with positive metastatic images (6 cases: liver, spine). Three false negative patients had neuroblastomas which did not secrete catecholamines. The specificity of mIBG was 94%. In our opinion, mIBG scans have a complementary role to assess the activity of post-therapeutic remnants. For the detection of hepatic and lymph node metastases, the sensitivity was about 50% and the specificity was 100%. The standard used for the detection of bone marrow metastases was the cytological and histological examination of 10 bone marrow aspirations and one or more biopsies (CHBMS). The sensitivity of mIBG scans was 90% and the specificity 68%. However, reviewing the data from the 16 false positive scans, we found 11 definitely proven bone metastases, 3 biological relapses and 2 cases of delayed abnormal CHBMS supporting the positivity of the mIBG scans, raising the specificity to 100%. Tc-99m diphosphonate bone scans had a sensitivity of 78% and a specificity of 51%. We suggest that positive mIBG scans may save other procedures since our data do not support false positive detection of bone or bone marrow metastases. In contrast, patients with negative mIBG findings should be further explored.

[Lipiodolized angiography in hepatocellular carcinomas. Contribution of iodine-131-labelled lipiodol]. / L'angiographie lipiodolée au cours des carcinomes hépato-cellulaires. Apport du lipiodol marqué à l'iode 131.

Twelve patients with hepatocellular carcinoma and cirrhosis were investigated by Lipiodol injection into the hepatic artery. A CT scan was done 4-6 days later. Lipiodol was retained by hepatic tumors in each case. This method emphasized the extension of the carcinoma and allowed to discover daughter tumors. I131-lipiodol was also injected in 4 of the 12 patients and then its biodistribution was evaluated. At the 6th hour after injection, I131-lipiodol was detected by scintigraphy over the liver (74-91 percent) and over the lungs (9-16 percent) only. The tumor to normal liver pixel count ratio was about 5. These results indicate that there is a preferential arterial blood flow towards the hepatic tumors, and that we can consider a therapeutic use of I131-Lipiodol in hepatocellular-carcinoma.

Uptake of meta-iodobenzylguanidine by bovine chromaffin granule membranes.

meta-Iodobenzylguanidine, an adrenal imaging agent used for the scintigraphic detection of human pheochromocytoma, is a substrate for the monoamine uptake system of chromaffin granules. It is accumulated by bovine chromaffin granule membrane vesicles in the presence of ATP, and it can be released by an osmotic shock. The uptake is dependent upon the generation of an H+-electrochemical gradient by an ATP-dependent H+ pump since it is blocked by an H+ ionophore and since meta-iodobenzylguanidine uptake can be driven by imposing an artificial pH gradient (inside acidic) on the membrane vesicles. The transport is saturable and its Km value (2.0 microM at pH 8.0) is similar to that of noradrenaline (5.3 microM). Transport occurs through the monoamine transporter since it is blocked by the same inhibitors, tetrabenazine and reserpine, and also by the transporter substrates noradrenaline and serotonin. Noradrenaline inhibits meta-iodobenzylguanidine uptake competitively (Ki = 13 microM). In addition, meta-iodobenzylguanidine displaces dihydrotetrabenazine and reserpine from their binding sites on chromaffin granule membranes. It is thus likely that, after in vivo administration, [131I] meta-iodobenzylguanidine is ultimately stored in chromaffin granules and that it is translocated by the monoamine transporter.

[Localization of pheochromocytomas by scintigraphy with meta-iodobenzyl guanidine. Comparison with computed x-ray tomography]. / Localisation des phéochromocytomes par la scintigraphie à la méta-iodobenzylguanidine. Comparaison avec la tomodensitométrie.

Meta-iodobenzylguanidine was synthesized, radiolabelled with I 131 or I 123 and injected to 28 controls and 7 patients totalling 13 foci of pheochromocytoma. The tumour was located in one adrenal gland in 3 cases, in both adrenal glands in 1 case, and between the aorta and the vena cava in 1 case; 2 were malignant with metastases. Scintigraphy was negative in all controls, whereas all pheochromocytomas were clearly demonstrated 24 h after injection, except one regarded as non functional due to necrosis. By comparison, CT readily showed the tumour in 7 cases, showed it only thanks to scintigraphic guidance in 4 cases and failed in 2 cases. It is concluded that scintigraphy with meta-iodobenzylguanidine provides a safe and reliable means of locating a wide range of pheochromocytomas.

[Chemical and pharmacological aspects of cerebral cellular tracers]. / Aspects chimique et pharmacologique des traceurs cellulaires cérébraux.

Among the iodophenylalkylamines studied and labelled with iodine 125 or iodine 123, N-isopropyl-iodo-amphetamin (IAMP) was selected and proposed as tracer for blood flow, a "chemical embolus" having almost 100% extraction in the brain. A new way of obtaining N-isopropyl-p-iodo-amphetamin is proposed and the easily-applied exchange reaction with iodine 125 or 123 gives a product with a radiochemical purity of more than 96% and an unexchanged radioactive iodine content of less than 1%. The pharmacokinetic study of this product in the Wistar rat showed distribution in three compartments and the appearance of a steady state by the fourth minute. The target organs are the lungs, liver and brain. The latter receives 3% of the radioactivity and the autoradiographic study shows that the early distribution in the brain for IAMP closely equals the blood flow as found by a diffusible indicator. In the first hour, the redistribution is very low and at this time although IAMP is proposed for the study of regional blood flow, it does not exactly determine the flow but rather mirrors cell activity.