title: Demonstration of enhanced potency of a chimeric somatostatin-dopamine molecule, BIM-23A387, in suppressing growth hormone and prolactin secretion from human pituitary somatotroph adenoma cells.
abstract: In acromegaly, the combination of somatostatin (SS) and dopamine (DA) agonists has been shown to enhance suppression of GH secretion. In the present study, a new chimeric molecule, BIM-23A387, which selectively binds to the SS subtype 2 receptor (sst(2); K(i) = 0.10 nM) and to the DA D2 receptor (D2DR; K(i) = 22.1 nM) was tested in cultures prepared from 11 human GH-secreting tumors for its ability to suppress GH and prolactin (PRL) secretion. The chimeric compound was compared with individual sst(2) and D2DR agonists of comparable activity at the individual receptors. All tumors expressed both sst(2) and D2DR mRNAs (0.8 +/- 0.2 and 4.7 +/- 0.7 copy/copy beta-glucuronidase mRNA, respectively). In cell cultures from seven octreotide-sensitive tumors, the maximal inhibition of GH release induced by the individual sst(2) and D2DR analogs and by BIM-23A387 was similar. However, the mean EC(50) for GH suppression by BIM-23A387 (0.2 pM) was 50 times lower than that of the individual sst(2) and D2DR analogs, either used individually or combined. Similar data were obtained in four tumors that were only partially responsive to octreotide. The inhibition of GH release by BIM-23A387 was only partially reversed by the D2R2 antagonist, sulpiride, or by the sst(2) antagonist, BIM-23454. Only when both antagonists were combined was the GH suppressive effect of BIM-23A387 totally reversed. Finally, BIM-23A387 produced a mean 73 +/- 6% inhibition of PRL in six mixed GH plus PRL tumors. These data demonstrate an enhanced potency of the chimeric molecule, BIM-23A387, in suppressing GH and PRL secretion from acromegalic tumors, which cannot be explained merely on the basis of binding affinity for SS and/or DA receptors.
authors.affiliation: Interactions Cellulaires Neuroendocriniennes, Unité Mixte de Recherche 6544, Centre National de la Recherche Scientifique, Institut Fédératif Jean Roche, Faculté de Médecine Nord, 13916 Marseille Cedex 20, France.
authors.forename: A
authors.initials: A
authors.lastname: Saveanu
authors.forename: E
authors.initials: E
authors.lastname: Lavaque
authors.forename: G
authors.initials: G
authors.lastname: Gunz
authors.forename: A
authors.initials: A
authors.lastname: Barlier
authors.forename: S
authors.initials: S
authors.lastname: Kim
authors.forename: J E
authors.initials: JE
authors.lastname: Taylor
authors.forename: M D
authors.initials: MD
authors.lastname: Culler
authors.forename: A
authors.initials: A
authors.lastname: Enjalbert
authors.forename: P
authors.initials: P
authors.lastname: Jaquet
mesh_terms: D000236:Adenoma / Q000378:metabolism*; D000328:Adult; D000634:Aminoquinolines / Q000494:pharmacology; D002478:Cells, Cultured; D018491:Dopamine Agonists / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D004357:Drug Synergism; D005260:Female; D006728:Hormones / Q000494:pharmacology; D019382:Human Growth Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D008297:Male; D015282:Octreotide / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010911:Pituitary Neoplasms / Q000378:metabolism*; D011388:Prolactin / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000235:genetics; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors / Q000235:genetics; D013004:Somatostatin / Q000819:agonists / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000634:Aminoquinolines; C470245:BIM 23023; C572905:BIM-23A387; D018491:Dopamine Agonists; D065127:Dopamine D2 Receptor Antagonists; D006728:Hormones; D010456:Peptides, Cyclic; D020033:Protein Isoforms; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; D017481:Receptors, Somatostatin; D019382:Human Growth Hormone; D013004:Somatostatin; C046650:quinagolide; D011388:Prolactin; D015282:Octreotide