title: Somatostatin and dopamine-somatostatin multiple ligands directed towards somatostatin and dopamine receptors in pituitary adenomas.
abstract: OBJECTIVE
  We report the comparative efficacy of octreotide, cabergoline and multiple ligands directed towards the different somatostatin subtypes (ssts), such as BIM-23A779 and SOM-230, and of chimeric analogs which bind both somatostatin and the dopamine D2 receptors (D2R), such as BIM-23A760 and BIM-23A781, in cell cultures from human growth hormone (GH)-secreting pituitary adenomas.
  
  
  METHODS
  RT-PCR analysis of the quantitative expression of the different ssts and D2R mRNAs was performed on tumor fragments of 22 GH-secreting adenomas collected after surgery. Pharmacological studies, using the different ligands, were performed on cell cultures of such tumors.
  
  
  RESULTS
  sst2, sst5 and D2R were constantly coexpressed in all tumors, in variable amounts. The levels of expression of sst2 and D2R mRNAs were significantly correlated with the maximal GH suppression by either octreotide or cabergoline (p < 0.001). In each tumor tested, 3 patterns of response, in terms of GH suppression, were observed. GH secretion was preferentially inhibited by the sst2 preferential compound octreotide in 61% of the tumors. In 19% of the tumors, the maximal inhibition of GH release was achieved with the sst5 preferential compound BIM-23268. The dopamine analog cabergoline was the most effective inhibitor of GH secretion in 21% of cases. Among the compounds tested, the most potent inhibitors of GH secretion were the sst2, sst5, D2R chimeric compound BIM-23A760, followed by the sst universal ligand SOM-230.
  
  
  CONCLUSIONS
  The variable patterns of response to sst2, sst5 and dopamine D2 analogs may explain the greater efficacy of drugs which bind to the 3 receptors in suppressing GH secretion. The biological potency (EC50) and efficacy of the chimeric compound BIM-23A760 on GH secretion can be partly explained by its high affinity for sst2. The effect of multiple receptor activation on the functions of other pituitary tumor types, such as prolactinomas and corticotropinomas, is not presently analyzed, and the efficacy of multireceptor ligands remains to be elucidated.
authors.affiliation: Interactions Cellulaires Neuroendocriniennes, UMR 6544, Centre National de la Recherche Scientifique, Institut Fédératif Jean Roche, Faculté de Médecine Nord, Marseille, France.
authors.forename: Alexandru
authors.initials: A
authors.lastname: Saveanu
authors.forename: Ginette
authors.initials: G
authors.lastname: Gunz
authors.forename: Severine
authors.initials: S
authors.lastname: Guillen
authors.forename: Henry
authors.initials: H
authors.lastname: Dufour
authors.forename: Michael D
authors.initials: MD
authors.lastname: Culler
authors.forename: Philippe
authors.initials: P
authors.lastname: Jaquet
mesh_terms: D000236:Adenoma / Q000188:drug therapy* / Q000378:metabolism / Q000601:surgery; D000328:Adult; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D000077465:Cabergoline; D004298:Dopamine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use; D004354:Drug Screening Assays, Antitumor; D004873:Ergolines / Q000627:therapeutic use; D005260:Female; D019382:Human Growth Hormone / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008297:Male; D015282:Octreotide / Q000627:therapeutic use; D010911:Pituitary Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000601:surgery; D012333:RNA, Messenger / Q000032:analysis; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D017481:Receptors, Somatostatin / Q000145:classification / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
chemical_list: D018931:Antineoplastic Agents, Hormonal; C121506:BIM 23268; D004873:Ergolines; D008024:Ligands; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; D017481:Receptors, Somatostatin; D011993:Recombinant Fusion Proteins; D019382:Human Growth Hormone; D013004:Somatostatin; D000077465:Cabergoline; D015282:Octreotide; D004298:Dopamine