title: The multi-ligand somatostatin analogue SOM230 inhibits ACTH secretion by cultured human corticotroph adenomas via somatostatin receptor type 5.
abstract: OBJECTIVE
  Currently, there is no effective medical treatment for patients with pituitary-dependent Cushing's disease. A novel somatostatin (SS) analogue, named SOM230, with high binding affinity to SS receptor subtypes sst(1), sst(2), sst(3) and sst(5) was recently introduced. We compared the in vitro effects of the sst(2)-preferring SS analogue octreotide (OCT) and the multi-ligand SOM230 on ACTH release by human and mouse corticotroph tumour cells.
  
  
  METHODS
  By quantitative RT-PCR the sst subtype expression level was determined in human corticotroph adenomas. In vitro, the inhibitory effect of OCT and SOM230 on ACTH release by dispersed human corticotroph adenoma cells and mouse AtT20 corticotroph adenoma cells was determined. In addition, the influence of dexamethasone on the responsiveness to OCT and SOM230 was studied.
  
  
  RESULTS
  Corticotroph adenomas expressed predominantly sst(5) mRNA (six out of six adenomas), whereas sst(2) mRNA expression was detected at significantly lower levels. In a 72 h incubation with 10 nmol/l SOM230, ACTH release was inhibited in three out of five cultures (range -30 to -40%). Ten nmol/l OCT slightly inhibited ACTH release in only one of five cultures (- 28%). In AtT20 cells, expressing sst(2), sst(3) and sst(5), SOM230 inhibited ACTH secretion with high potency (IC(50) 0.2 nmol/l). Dexamethasone (10 nmol/l) pre-treatment did not influence the sensitivity of the cells to the inhibitory effect of SOM230, suggesting that sst(5) is relatively resistant to negative control by glucocorticoids.
  
  
  CONCLUSIONS
  The selective expression of sst(5) receptors in corticotroph adenomas and the preferential inhibition of ACTH release by human corticotroph adenoma cells by SOM230 in vitro, suggest that SOM230 may have potential in the treatment of patients with pituitary-dependent Cushing's disease.
authors.affiliation: Department of Internal Medicine, Section of Endocrinology, Erasmus Medical Centre, GD Rotterdam, The Netherlands. l.hofland@erasmusmc.nl
authors.forename: Leo J
authors.initials: LJ
authors.lastname: Hofland
authors.forename: Joost
authors.initials: J
authors.lastname: van der Hoek
authors.forename: Richard
authors.initials: R
authors.lastname: Feelders
authors.forename: Maarten O
authors.initials: MO
authors.lastname: van Aken
authors.forename: Peter M
authors.initials: PM
authors.lastname: van Koetsveld
authors.forename: Marlijn
authors.initials: M
authors.lastname: Waaijers
authors.forename: Diana
authors.initials: D
authors.lastname: Sprij-Mooij
authors.forename: Christian
authors.initials: C
authors.lastname: Bruns
authors.forename: Gisbert
authors.initials: G
authors.lastname: Weckbecker
authors.forename: Wouter W
authors.initials: WW
authors.lastname: de Herder
authors.forename: Albert
authors.initials: A
authors.lastname: Beckers
authors.forename: Steven W J
authors.initials: SW
authors.lastname: Lamberts
mesh_terms: D000236:Adenoma / Q000378:metabolism*; D000324:Adrenocorticotropic Hormone / Q000378:metabolism*; D000818:Animals; D015870:Gene Expression / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D051379:Mice; D015282:Octreotide / Q000494:pharmacology; D010911:Pituitary Neoplasms / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D017481:Receptors, Somatostatin / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D005938:Glucocorticoids; D012333:RNA, Messenger; D017481:Receptors, Somatostatin; D013004:Somatostatin; C094573:somatostatin receptor 5; D000324:Adrenocorticotropic Hormone; C517782:pasireotide; D015282:Octreotide