Can quantification of VMAT and SSTR expression be helpful for planning radionuclide therapy of malignant pheochromocytomas?
Tumor-specific uptake of the radio-iodinated norepinephrine analogue meta-iodobenzylguanidine (MIBG) or uptake of radiolabeled somatostatin analogues via somatostatin receptors (SSTRs) are possibilities to diagnose and treat malignant pheochromocytomas/paragangliomas (PCs/PGs). The aims of this study were to investigate the quantitative expression of vesicular monoamine transporters (VMAT 1, 2) and all five SSTRs in malignant pheochromocytoma/paraganglioma (PC/PG) to evaluate the possibilities for tumor-specific radionuclide therapy. High scintigraphic 123I-MIBG uptake was found in two malignant PGs with high VMAT expression (500-730 copies of VMAT 1, 1,500-1,700 copies of VMAT 2 per 1,000 beta-actin), while no 123I-MIBG uptake was found in the malignant PG with low VMAT expression (330 copies of VMAT 1, 350 copies of VMAT 2 per 1,000 beta-actin). The two patients with high VMAT expression and high 123I-MIBG uptake were treated with 131I-MIBG (2-3x8 GBq). In vitro, the VMAT antagonist, reserpine, and the membrane pump inhibitor, clomipramine, inhibited the uptake of 123I-MIBG into tumor cells equally well (48% and 53% reduction respectively, P<0.001). SSTR2 was the most abundant receptor subtype, but in the two malignant PGs its expression was only 110-260 copies/1,000 beta-actin. The transporters at the cell membrane and in the vesicular membrane both appear to be of importance for the uptake of 123I-MIBG into malignant PC/PG. Quantitative determination of VMAT expression may be helpful in selecting patients suitable for radionuclide therapy with 131I-MIBG. The present data indicate that SSTR-mediated radionuclide therapy will not be effective treatment of malignant PC/PG.
Kölby
Lars
L
Lundberg Laboratory for Cancer Research, Institute for Surgical Sciences, Department of Surgery, Göteborg University, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden. lars.kolby@surgery.gu.se
Bernhardt
Peter
P
Johanson
Viktor
V
Wängberg
Bo
B
Muth
Andreas
A
Jansson
Svante
S
Forssell-Aronsson
Eva
E
Nilsson
Ola
O
Ahlman
Håkan
H
D019797:3-Iodobenzylguanidine / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D006801:Humans; D007457:Iodine Radioisotopes / Q000627:therapeutic use*; D017481:Receptors, Somatostatin / Q000378:metabolism*; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism*
D007457:Iodine Radioisotopes; D017481:Receptors, Somatostatin; C493452:SLC18A2 protein, human; D050493:Vesicular Monoamine Transport Proteins; D019797:3-Iodobenzylguanidine