The radio-iodinated noradrenaline analogue meta-iodobenzylguanidine (MIBG) can be used for scintigraphy and radiation therapy of neuroendocrine (NE). The aim of the present study was to study the importance of vesicular monoamine transporters (VMATs) for the uptake of ¹²³I-MIBG in NE tumours. In nude mice, bearing the human transplantable midgut carcinoid GOT1, all organs and xenografted tumours accumulated ¹²³I after i.v. injection of ¹²³I-MIBG. A high concentration of ¹²³I was maintained in GOT1 tumours and adrenals, which expressed VMATs, but rapidly decreased in all other tissues. In the VMAT-expressing NE tumour cell lines GOT1 and BON and in VMAT-expressing primary NE tumour cell cultures (carcinoids, n=4 and pheochromocytomas, n=4), reserpine significantly reduced the uptake of ¹²³I-MIBG. The membrane pump inhibitor clomipramine had no effect on the uptake of ¹²³I-MIBG in GOT1 and BON cells, but inhibited the uptake in one out of four primary carcinoid cell cultures and three out of four primary pheochromocytoma cell cultures. In conclusion, VMATs and secretory granules are of importance for the uptake and retention of ¹²³I-MIBG in NE tumours. Information about the type and degree of expression of VMATs in NE tumours may be helpful in future to select patients suitable for radiation therapy with radio-iodinated MIBG.

Somatostatin receptor (sstr)-mediated radiation therapy is a new therapeutic modality for neuroendocrine (NE) tumours. High expression of sstr in NE tumours leads to tumour-specific uptake of radiolabelled somatostatin analogues and high absorbed doses. In this study, we present the first optimised radiation therapy via sstr using [¹⁷⁷Lu-DOTA⁰-Tyr³]-octreotate given to nude mice xenografted with the human midgut carcinoid GOT1. The tumours in 22 out of 23 animals given therapeutic amounts showed dose-dependent, rapid complete remission. The diagnostic amount (0.5 MBq [¹⁷⁷Lu-DOTA⁰-Tyr³]-octreotate) did not influence tumour growth and was rapidly excreted. In contrast, the therapeutic amount (30 MBq [¹⁷⁷Lu-DOTA⁰-Tyr³]-octreotate) induced rapid tumour regression and entrapment of ¹⁷⁷Lu so that the activity concentration of ¹⁷⁷Lu remained high, 7 and 13 days after injection. The entrapment phenomenon increased the absorbed dose to tumours from 1.6 to 4.0 Gy MBq⁻¹ and the tumours in animals treated with 30 MBq received 120 Gy. Therapeutic amounts of [¹⁷⁷Lu-DOTA⁰-Tyr³]-octreotate rapidly induced apoptosis and gradual development of fibrosis in grafted tumours. In conclusion, human midgut carcinoid xenografts can be cured by receptor-mediated radiation therapy by optimising the uptake of radioligand and taking advantage of the favourable change in biokinetics induced by entrapment of radionuclide in the tumours.