Balance between somatostatin and D2 receptor expression drives TSH-secreting adenoma response to somatostatin analogues and dopastatins

Federico Gatto, Federica Barbieri, Monica Gatti, Roberto Wurth, Stefan Schulz, Jean Louis Ravetti, Gianluigi Zona, Michael D. Culler, Alexandru Saveanu, Massimo Giusti, Francesco Minuto, Leo J. Hofland, Diego Ferone, Tullio Florio

Research output: Contribution to journalArticle

Abstract

Context First-line therapy for thyrotropin-secreting pituitary adenomas (TSHomas) is neurosurgery, while medical treatment rests mainly on somatostatin analogues. Clinically available sst 2-preferring analogues, octreotide and lanreotide, induce normalization of hormone levels in approximately 90% of patients and tumour shrinkage in 45%. Objective We evaluated somatostatin 1, 2, 3 and 5 and dopamine D2 receptor expression in tumour samples from three TSHomas, and the relationships between receptor expression, in vitro antiproliferative response and clinical data, including octreotide test and three months of therapy with octreotide long-acting repeatable (LAR). TSHoma cell proliferation was tested in vitro using octreotide, cabergoline and two chimeric compounds, BIM-23A760 and BIM-23A387. Results All patients showed significant TSH lowering to acute octreotide test, but a hormonal response to long-term treatment was observed in only two patients, showing a high sst 5/sst 2 ratio. Patient 2, characterized by high expression of sst 2 and sst 1 and a relative lower expression of sst 5, experienced tachyphylaxis after prolonged octreotide treatment. In vitro, the somatostatin/dopamine receptor agonist BIM-23A760 caused the highest antiproliferative effect among those tested. Combined treatment with octreotide and cabergoline displayed an additive effect of magnitude comparable to that of the other chimeric compound (BIM-23A387). Octreotide resistance was confirmed in cells isolated from the nonresponder patient, although it could be overcome by treatment with the chimeric compounds. Conclusions A high sst 5/sst 2 ratio might be predictive of a positive outcome to long-term treatment with somatostatin analogues in TSHomas. Moreover, combined somatostatin and D 2 receptor targeting might be considered as a potential tool to improve the response rate in octreotide-resistant tumours.

Original languageEnglish
Pages (from-to)407-414
Number of pages8
JournalClinical Endocrinology
Volume76
Issue number3
DOIs
Publication statusPublished - Mar 2012

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Somatostatin Receptors
Octreotide
Somatostatin
Adenoma
Therapeutics
Tachyphylaxis
BIM 23A760
Neoplasms
Dopamine D2 Receptors
Dopamine Agonists
Neurosurgery
Pituitary Neoplasms
Thyrotropin
Cell Proliferation
Hormones

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism

Cite this

Balance between somatostatin and D2 receptor expression drives TSH-secreting adenoma response to somatostatin analogues and dopastatins. / Gatto, Federico; Barbieri, Federica; Gatti, Monica; Wurth, Roberto; Schulz, Stefan; Ravetti, Jean Louis; Zona, Gianluigi; Culler, Michael D.; Saveanu, Alexandru; Giusti, Massimo; Minuto, Francesco; Hofland, Leo J.; Ferone, Diego; Florio, Tullio.

In: Clinical Endocrinology, Vol. 76, No. 3, 03.2012, p. 407-414.

Research output: Contribution to journalArticle

Gatto, F, Barbieri, F, Gatti, M, Wurth, R, Schulz, S, Ravetti, JL, Zona, G, Culler, MD, Saveanu, A, Giusti, M, Minuto, F, Hofland, LJ, Ferone, D & Florio, T 2012, 'Balance between somatostatin and D2 receptor expression drives TSH-secreting adenoma response to somatostatin analogues and dopastatins', Clinical Endocrinology, vol. 76, no. 3, pp. 407-414. https://doi.org/10.1111/j.1365-2265.2011.04200.x
Gatto, Federico ; Barbieri, Federica ; Gatti, Monica ; Wurth, Roberto ; Schulz, Stefan ; Ravetti, Jean Louis ; Zona, Gianluigi ; Culler, Michael D. ; Saveanu, Alexandru ; Giusti, Massimo ; Minuto, Francesco ; Hofland, Leo J. ; Ferone, Diego ; Florio, Tullio. / Balance between somatostatin and D2 receptor expression drives TSH-secreting adenoma response to somatostatin analogues and dopastatins. In: Clinical Endocrinology. 2012 ; Vol. 76, No. 3. pp. 407-414.
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abstract = "Context First-line therapy for thyrotropin-secreting pituitary adenomas (TSHomas) is neurosurgery, while medical treatment rests mainly on somatostatin analogues. Clinically available sst 2-preferring analogues, octreotide and lanreotide, induce normalization of hormone levels in approximately 90{\%} of patients and tumour shrinkage in 45{\%}. Objective We evaluated somatostatin 1, 2, 3 and 5 and dopamine D2 receptor expression in tumour samples from three TSHomas, and the relationships between receptor expression, in vitro antiproliferative response and clinical data, including octreotide test and three months of therapy with octreotide long-acting repeatable (LAR). TSHoma cell proliferation was tested in vitro using octreotide, cabergoline and two chimeric compounds, BIM-23A760 and BIM-23A387. Results All patients showed significant TSH lowering to acute octreotide test, but a hormonal response to long-term treatment was observed in only two patients, showing a high sst 5/sst 2 ratio. Patient 2, characterized by high expression of sst 2 and sst 1 and a relative lower expression of sst 5, experienced tachyphylaxis after prolonged octreotide treatment. In vitro, the somatostatin/dopamine receptor agonist BIM-23A760 caused the highest antiproliferative effect among those tested. Combined treatment with octreotide and cabergoline displayed an additive effect of magnitude comparable to that of the other chimeric compound (BIM-23A387). Octreotide resistance was confirmed in cells isolated from the nonresponder patient, although it could be overcome by treatment with the chimeric compounds. Conclusions A high sst 5/sst 2 ratio might be predictive of a positive outcome to long-term treatment with somatostatin analogues in TSHomas. Moreover, combined somatostatin and D 2 receptor targeting might be considered as a potential tool to improve the response rate in octreotide-resistant tumours.",
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T1 - Balance between somatostatin and D2 receptor expression drives TSH-secreting adenoma response to somatostatin analogues and dopastatins

AU - Gatto, Federico

AU - Barbieri, Federica

AU - Gatti, Monica

AU - Wurth, Roberto

AU - Schulz, Stefan

AU - Ravetti, Jean Louis

AU - Zona, Gianluigi

AU - Culler, Michael D.

AU - Saveanu, Alexandru

AU - Giusti, Massimo

AU - Minuto, Francesco

AU - Hofland, Leo J.

AU - Ferone, Diego

AU - Florio, Tullio

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N2 - Context First-line therapy for thyrotropin-secreting pituitary adenomas (TSHomas) is neurosurgery, while medical treatment rests mainly on somatostatin analogues. Clinically available sst 2-preferring analogues, octreotide and lanreotide, induce normalization of hormone levels in approximately 90% of patients and tumour shrinkage in 45%. Objective We evaluated somatostatin 1, 2, 3 and 5 and dopamine D2 receptor expression in tumour samples from three TSHomas, and the relationships between receptor expression, in vitro antiproliferative response and clinical data, including octreotide test and three months of therapy with octreotide long-acting repeatable (LAR). TSHoma cell proliferation was tested in vitro using octreotide, cabergoline and two chimeric compounds, BIM-23A760 and BIM-23A387. Results All patients showed significant TSH lowering to acute octreotide test, but a hormonal response to long-term treatment was observed in only two patients, showing a high sst 5/sst 2 ratio. Patient 2, characterized by high expression of sst 2 and sst 1 and a relative lower expression of sst 5, experienced tachyphylaxis after prolonged octreotide treatment. In vitro, the somatostatin/dopamine receptor agonist BIM-23A760 caused the highest antiproliferative effect among those tested. Combined treatment with octreotide and cabergoline displayed an additive effect of magnitude comparable to that of the other chimeric compound (BIM-23A387). Octreotide resistance was confirmed in cells isolated from the nonresponder patient, although it could be overcome by treatment with the chimeric compounds. Conclusions A high sst 5/sst 2 ratio might be predictive of a positive outcome to long-term treatment with somatostatin analogues in TSHomas. Moreover, combined somatostatin and D 2 receptor targeting might be considered as a potential tool to improve the response rate in octreotide-resistant tumours.

AB - Context First-line therapy for thyrotropin-secreting pituitary adenomas (TSHomas) is neurosurgery, while medical treatment rests mainly on somatostatin analogues. Clinically available sst 2-preferring analogues, octreotide and lanreotide, induce normalization of hormone levels in approximately 90% of patients and tumour shrinkage in 45%. Objective We evaluated somatostatin 1, 2, 3 and 5 and dopamine D2 receptor expression in tumour samples from three TSHomas, and the relationships between receptor expression, in vitro antiproliferative response and clinical data, including octreotide test and three months of therapy with octreotide long-acting repeatable (LAR). TSHoma cell proliferation was tested in vitro using octreotide, cabergoline and two chimeric compounds, BIM-23A760 and BIM-23A387. Results All patients showed significant TSH lowering to acute octreotide test, but a hormonal response to long-term treatment was observed in only two patients, showing a high sst 5/sst 2 ratio. Patient 2, characterized by high expression of sst 2 and sst 1 and a relative lower expression of sst 5, experienced tachyphylaxis after prolonged octreotide treatment. In vitro, the somatostatin/dopamine receptor agonist BIM-23A760 caused the highest antiproliferative effect among those tested. Combined treatment with octreotide and cabergoline displayed an additive effect of magnitude comparable to that of the other chimeric compound (BIM-23A387). Octreotide resistance was confirmed in cells isolated from the nonresponder patient, although it could be overcome by treatment with the chimeric compounds. Conclusions A high sst 5/sst 2 ratio might be predictive of a positive outcome to long-term treatment with somatostatin analogues in TSHomas. Moreover, combined somatostatin and D 2 receptor targeting might be considered as a potential tool to improve the response rate in octreotide-resistant tumours.

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