title: Balance between somatostatin and D2 receptor expression drives TSH-secreting adenoma response to somatostatin analogues and dopastatins.
abstract: BACKGROUND
  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.
authors.affiliation: Department of Internal Medicine & Center of Excellence for Biomedical Research, University of Genoa, Viale Benedetto XV 2, Genoa, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Gatto
authors.forename: Federica
authors.initials: F
authors.lastname: Barbieri
authors.forename: Monica
authors.initials: M
authors.lastname: Gatti
authors.forename: Roberto
authors.initials: R
authors.lastname: Wurth
authors.forename: Stefan
authors.initials: S
authors.lastname: Schulz
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Ravetti
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Zona
authors.forename: Michael D
authors.initials: MD
authors.lastname: Culler
authors.forename: Alexandru
authors.initials: A
authors.lastname: Saveanu
authors.forename: Massimo
authors.initials: M
authors.lastname: Giusti
authors.forename: Francesco
authors.initials: F
authors.lastname: Minuto
authors.forename: Leo J
authors.initials: LJ
authors.lastname: Hofland
authors.forename: Diego
authors.initials: D
authors.lastname: Ferone
authors.forename: Tullio
authors.initials: T
authors.lastname: Florio
mesh_terms: D000236:Adenoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000077465:Cabergoline; D049109:Cell Proliferation / Q000187:drug effects; D004298:Dopamine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D018491:Dopamine Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D004357:Drug Synergism; D004873:Ergolines / Q000494:pharmacology / Q000627:therapeutic use; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D015282:Octreotide / Q000494:pharmacology / Q000627:therapeutic use; D010911:Pituitary Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000235:genetics* / Q000378:metabolism; D017481:Receptors, Somatostatin / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013004:Somatostatin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use*; D013972:Thyrotropin / Q000097:blood / Q000378:metabolism; D013974:Thyroxine / Q000097:blood; D016896:Treatment Outcome; D014284:Triiodothyronine / Q000097:blood; D014407:Tumor Cells, Cultured
chemical_list: C572905:BIM-23A387; D018491:Dopamine Agonists; D004873:Ergolines; D020033:Protein Isoforms; D017448:Receptors, Dopamine D2; D017481:Receptors, Somatostatin; D014284:Triiodothyronine; D013004:Somatostatin; D013972:Thyrotropin; C531242:TBR-760; D000077465:Cabergoline; D013974:Thyroxine; D015282:Octreotide; D004298:Dopamine