Download PDF
Horm Metab Res 2012; 44(05): 400-404
DOI: 10.1055/s-0032-1311603
Original Basic
© Georg Thieme Verlag KG Stuttgart · New York

Specific Binding and Uptake of 131I-MIBG and 111In-Octreotide in Metastatic Paraganglioma – Tools for Choice of Radionuclide Therapy

J. Spetz
1   Department of Radiation Physics, Sahlgrenska Cancer Center, University of Gothenburg, Göteborg, Sweden
,
J. Dalmo
1   Department of Radiation Physics, Sahlgrenska Cancer Center, University of Gothenburg, Göteborg, Sweden
,
O. Nilsson
2   Department of Pathology, Sahlgrenska Cancer Center, University of Gothenburg, Göteborg, Sweden
,
B. Wängberg
3   Department of Surgery, Sahlgrenska Cancer Center, University of Gothenburg, Göteborg, Sweden
,
H. Ahlman
3   Department of Surgery, Sahlgrenska Cancer Center, University of Gothenburg, Göteborg, Sweden
,
E. Forssell-Aronsson
1   Department of Radiation Physics, Sahlgrenska Cancer Center, University of Gothenburg, Göteborg, Sweden
› Author Affiliations
Further Information

Publication History

received 01 November 2011

accepted 27 March 2012

Publication Date:
07 May 2012 (online)

Also available at
    Permissions and Reprints

Abstract

Tumor-specific uptake of the radiolabeled nor­epinephrine analogue meta-iodobenzylguanidine via norepinephrine transporter or radiolabeled somatostatin analogues octreotide/octreotate via somatostatin receptors offers possibilities to diagnose and treat metastatic pheochromocytoma/paraganglioma. High uptake of 123I-meta-iodobenzylguanidine is dependent on high expression of vesicular monoamine transporters responsible for mediating uptake of biogenic amines into dense core granules. A patient with metastatic paraganglioma (liver and bone metastases) underwent surgical removal of the primary after injection of 131I-meta-iodobenzylguanidine and 111In-octreotide. Radioactivity was determined in biopsies from tumor and normal tissue biopsies. The tumor/blood concentration value was high: 180 for 131I-meta-iodobenzylguanidine 3 h after injection and 590 for 111In-octreotide 27 h after injection. Studies of primary tumor cell cultures demonstrated increased cell membrane binding and internalization over time for 131I-meta-iodobenzylguanidine. The vesicular monoamine transporter antagonist reserpine and the norepinephrine transporter inhibitor clomipramine reduced internalization by 90% and 70%, respectively, after 46 h of incubation. The results demonstrated increased cell membrane binding and internalization over time also for 111In-octreotide. Internalization was highest for a low concentration of 111In-octreotide. Excess of octreotide reduced internalization of 111In-octreotide with 75% after 46 h of incubation. In conclusion, uptake and tumor/blood concentration values of radiolabeled meta-iodobenzylguanidine and somatostatin analogues can be determined for metastatic pheochromocytoma/paraganglioma to evaluate the possibility to use one or both agents for therapy. For this patient, the high tumor/blood values clearly demonstrated that therapy using both radiopharmaceuticals would be most beneficial. In vitro studies verified specific cell-membrane binding and internalization in tumor cells of both radiopharmaceuticals.

Key words

norepinephrine transporter - VMAT - clomipramine - reserpine - somatostatin receptors - octreotate
 

  • References

  • 1 Ahlman H. Malignant Pheochromocytoma: state of the field with future projections. Ann NY Acad Sci 2005; 1073: 449-464
    PubMedGoogle Scholar
  • 2 Chrisoulidou A, Kaltsas G, Ilias I, Grossman A. The diagnosis of malignant pheochromocytoma and paraganglioma. Endocr Relat Cancer 2007; 14: 569-585
    CrossrefPubMedGoogle Scholar
  • 3 Amar L, Bertherat J, Baudin E, Ajzenberg C, Bressac-de Paillerets B, Chabre O, Chamontin B, Delemer B, Giraud S, Murat A, Niccoli-Sire P, Richard S, Rohmer V, Sadoul JL, Strompf L, Schlumberger M, Bertagna X, Plouin PF, Jeunemaitre X, Gimenez-Roqueplo AP. Genetic testing in pheochromocytoma or functional paraganglioma. J Clin Oncol 2005; 23: 8812-8818
    CrossrefPubMedGoogle Scholar
  • 4 Brouwers FM, Eisenhofer G, Tao JJ, Kant JA, Adams KT, Linehan WM, Pacak K. High frequency of SDHB germline mutations in patients with malignant catecholamine-producing paragangliomas: implications for genetic testing. J Clin Endocrinol Metab 2006; 91: 4505-4509
    CrossrefPubMedGoogle Scholar
  • 5 Wängberg B, Muth A, Khorram-Manesh A, Jansson S, Nilsson O, Forssell-Aronsson E, Tisell LE, Ahlman H. Malignant pheochromocytoma in a population-based study: survival and clinical results. Ann NY Acad Sci 2006; 1073: 512-516
    CrossrefPubMedGoogle Scholar
  • 6 Khoram-Manesh A, Ahlman H, Nilsson O, Friberg P, Odén A, Stenström G, Hansson G, Stenquist O, Wängberg B, Tisell LE, Jansson S. Long-term outcome of a large series of patients surgicallt treated for pheochromocytoma. J Inter Med 2005; 258: 55-66
    CrossrefPubMedGoogle Scholar
  • 7 Grogan RH, Mitmaker EJ, Duh QY. Changing paradigms in the treatment of malignant pheochromocytoma. Cancer Control 2011; 18: 104-112
    PubMedGoogle Scholar
  • 8 Forssell-Aronsson E, Schüler E, Ahlman H. Advances in the diagnostic imaging of pheochromocytomas. Reports in Medical Imaging 2011; 4: 1-19 available at http://www.dovepress.com/advances-in-the-diagnostic-imaging-of-pheochromocytomas-a7411
    PubMedGoogle Scholar
  • 9 Forssell-Aronsson E, Bernhardt P, Wängberg B, Kölby L, Nilsson O, Ahlman H. Aspects on radionuclide therapy in malignant pheochromocytomas. Ann NY Acad Sci 2006; 1073: 498-504
    CrossrefPubMedGoogle Scholar
  • 10 Shulkin BL, Ilias I, Sisson JC, Pacak K. Current trends in functional imaging of pheochromocytomas and paragangliomas. Ann NY Acad Sci 2006; 1073: 374-382
    CrossrefPubMedGoogle Scholar
  • 11 Bönisch H, Brüss M. The noradrenaline transporter of the neuronal plasma membrane. Ann N Y Acad Sci 1994; 733: 193-202
    CrossrefPubMedGoogle Scholar
  • 12 Erickson JD, Eiden LE, Hoffman BJ. Expression cloning of a reserpine-sensitive vesicular monoamine transporter. Proc Natl Acad Sci USA 1992; 89: 10993-10997
    CrossrefPubMedGoogle Scholar
  • 13 Liu Y, Peter D, Roghani A, Schuldiner S, Privé GG, Eisenberg D, Brecha N, Edwards RH. A cDNA that suppresses MPP+ toxicity encodes a vesicular amine transporter. Cell 1992; 70: 539-551
    CrossrefPubMedGoogle Scholar
  • 14 Henry JP, Botton D, Sagne C, Isambert MF, Desnos C, Blanchard V, Raisman-Vozari R, Krejci E, Massoulie J, Gasnier B. Biochemistry and molecular biology of the vesicular monoamine transporter from chromaffin granules. J Exp Biol 1994; 196: 251-262
    PubMedGoogle Scholar
  • 15 Jakobsen AM, Andersson P, Saglik G, Andersson E, Kölby L, Erickson JD, Forssell-Aronsson E, Wängberg B, Ahlman H, Nilsson O. Differential expression of vesicular monoamine transporter (VMAT) 1 and 2 in gastrointestinal endocrine tumours. J Pathol 2001; 195: 463-472
    CrossrefPubMedGoogle Scholar
  • 16 Kölby L, Bernhardt P, Johanson V, Wängberg B, Muth A, Jansson S, Forssell-Aronsson E, Nilsson O, Ahlman H. Can quantification of VMAT and sstr expression be helpful for planning radionuclide therapy of malignant pheochromocytomas?. Ann NY Acad Sci 2006; 1073: 491-497
    CrossrefPubMedGoogle Scholar
  • 17 Kölby L, Bernhardt P, Levin-Jakobsen AM, Wängberg B, Ahlman H, Forssell-Aronsson E, Nilsson O. Uptake of meta-iodobenzylguanidine in neuroendocrine tumours is mediated by vesicular monoamine transporters. Br J Cancer 2003; 89: 1383-1388
    CrossrefPubMedGoogle Scholar
  • 18 Muth A, Abel F, Jansson S, Nilsson O, Ahlman H, Wängberg B. Prevalence of germ-line mutations in patients with PC or abdominal PGL and sporadic presentation: A population-based study in western Sweden. World J Surg Jan 20 2012; [Epub ahead of print]
    PubMedGoogle Scholar
  • 19 Forssell Aronsson E, Fjälling M, Nilsson O, Wängberg B, Tisell LE, Ahlman H. 111In activity concentration in human tissue samples after i. v. injection of 111In-DTPA-Phe-1-Octreotide. J Nucl Med 1995; 36: 7-12
    PubMedGoogle Scholar
  • 20 Arvidsson Y, Bergström A, Arvidsson A, Kristiansson E, Ahlman H, Nilsson O. Hypoxia stimulates CXCR4 signalling in ileal carcinoids. Endocr Relat Cancer 2010; 17: 303-316
    CrossrefPubMedGoogle Scholar
  • 21 Mukherjee JJ, Kaltsas GA, Islam N, Plowman PN, Foley R, Hikmat J, Britton KE, Jenkins KJ, Chew SL, Monson JP, Besser GM, Grossman AB. Treatment of metastatic carcinoid tumours, phaeochromocytoma, paraganglioma and medullary carcinoma of the thyroid with 131I-meta-iodobenzylguanidine (131I-mIBG). Clin Endocrinol 2001; 55: 47-60
    CrossrefPubMedGoogle Scholar
  • 22 Safford SD, Coleman RE, Gockerman JP, Moore J, Feldman JM, Leight Jr GS, Tyler DS, Olson Jr JA. Iodine-131-metaiodobenzylguanidine is an effective treatment for malignant pheochromocytoma and paraganglioma. Surgery 2003; 134: 956-962
    CrossrefPubMedGoogle Scholar
  • 23 Loh KC, Fitzgerald PA, Matthay KK, Yeo PP, Price DC. The treatment of malignant pheochromocytoma with iodine-131 metaiodobenzylguanidine (131I-MIBG): a comprehensive review of 116 reported patients. J Endocrinol Invest 1997; 20: 648-658
    CrossrefPubMedGoogle Scholar
  • 24 Gonias S, Goldsby R, Matthay KK, Hawkins R, Price D, Huberty J, Damon L, Linker C, Sznewajs A, Shiboski S, Fitzgerald P. Phase II study of high-dose [131I]metaiodobenzylguanidine therapy for patients with metastatic pheochromocytoma and paraganglioma. J Clin Oncol 2009; 27: 4162-4168
    CrossrefPubMedGoogle Scholar
  • 25 Hashemi SH, Benjegård SA, Ahlman H, Wängberg B, Forssell-Aronsson E, Billig H, Nilsson O. 111In-labelled octreotide binding by the somatostatin receptor subtype 2 in neuroendocrine tumours. Br J Surg 2003; 90: 549-554
    CrossrefPubMedGoogle Scholar
  • 26 Forssell Aronsson E, Bernhardt P, Nilsson O, Tisell LE, Wängberg B, Ahlman H. Biodistribution data from 100 patients i. v. injected with 111in-DTPA-D-Phe1-Octreotide. Acta Oncol 2004; 43: 436-442
    CrossrefPubMedGoogle Scholar
  • 27 Cleary S, Brouwers FM, Eisenhofer G, Pacak K, Christie DL, Lipski J, McNeil AR, Phillips JK. Expression of the noradrenaline transporter and phenylethanolamine N-methyltransferase in normal human adrenal gland and phaeochromocytoma. Cell Tiss Res 2005; 322: 443-453
    CrossrefPubMedGoogle Scholar
  • 28 Meco D, Lasorella A, Riccardi A, Servidei T, Mastrangelo R, Riccardi R. Influence of cisplatin and doxorubicin on 125I-meta-iodobenzylguanidine uptake in human neuroblastoma cell lines. Eur J Cancer 1999; 35: 1227-1234
    CrossrefPubMedGoogle Scholar
  • 29 McCluskey A, Boyd M, Gaze MN, Mairs RJ. [131I]MIBG and topotecan: A rationale for combination therapy for neuroblastoma. Cancer Lett 2005; 228: 221-227
    CrossrefPubMedGoogle Scholar
  • 30 Zha Q, Wang Y, Fan Y, Zhu MY. Dexamethasone-induced up-regulation of the human norepinephrine transporter involves the glucocorticoid receptor and increased binding of C/EBP-β to the proximal promoter of norepinephrine transporter. J Neurochem 2011; 119: 654-663
    CrossrefPubMedGoogle Scholar
  • 31 Kippenberger AG, Palmer DJ, Comer AM, Lipski J, Burton LD, Christie DL. Localization of the noradrenaline transporter in rat adrenal medulla and PC12 cells: evidence for its association with secretory granules in PC12 cells. J Neurochem 1999; 73: 1024-1032
    PubMedGoogle Scholar
  • 32 Sung B, Lim G, Mao J. Altered expression and uptake activity of spinal glutamate transporters after nerve injury contribute to the pathogenesis of neuropathic pain in rats. J Neurosci 2003; 23: 2899-2910
    PubMedGoogle Scholar