title: BIM-23A760, a chimeric molecule directed towards somatostatin and dopamine receptors, vs universal somatostatin receptors ligands in GH-secreting pituitary adenomas partial responders to octreotide.
abstract: We report the comparative efficacy of a somatostatin receptor 1 and 5 subtypes (SSTR2 and SSTR5), and dopamine D2 (DAD2) compound, BIM-23A760, in suppressing GH secretion, in cell culture from human GH-secreting tumors, from patients partially responsive to long-term treatments with octreotide or lanreotide. In 18 tumors tested, the SSTR2, SSTR5, and DAD2 mRNAs were coexpressed. The SSTR2-selective analog, BIM-23197, the SSTR5-selective analog, BIM-23268, and the dopamine (DA) analog, BIM-53097, produced a mean maximal suppression of GH secretion (24 +/- 3, 20 +/- 3, and 20 +/- 3%, respectively) that was similar to that obtained with octreotide (23 +/- 3%). Nevertheless, based on individual responses, 60% of the tumors were mostly sensitive to the SSTR2 analog while 19 and 21% of the tumors were mainly responsive to the SSTR5 analog and to the DA analog, respectively. Among a series of new chimeric compounds that bind the SSTR2, SSTR5, and DAD2 receptors with variable affinities, BIM-23A760 produced greater maximal suppression of GH secretion than octreotide (38 +/- 2 vs 24 +/- 2%; p<0.03). The EC50 for BIM-23A760 was 2 pmol/l. In the presence of sulpride, the dose response inhibition of GH secretion by the trihybrid molecule, BIM-23A760, was partially reversed. The trihybrid produced also a maximal suppression of PRL greater than octreotide (74 +/- 5 vs 46 +/- 11%). When SSTRs pan inhibitors such as BIM-23A779 (binding affinity for SSTR1, SSTR2, SSTR3, SSTR5, respectively: 2.5, 0.3, 0.6, 0.6 nmol/l) or SOM230 were tested for their suppressive effects on GH secretion, they were less potent than the previous dopastatin hybrid molecule. After a brief exposure to a SSTR2-selective analog, BIM-23197, or to a DA analog, BIM-53097, the maximal GH suppression was achieved during 12 h. Under exposure to BIM-23A760, in the same conditions, maximal suppression of GH secretion lasted for 24 h. Such a longer biological effect, yet not explained, probably participates in the higher efficacy of BIM-23A760. The higher efficacy of BIM-23A760 is, at least partially, linked to its high affinity for the SSTR2 receptor subtype (IC50: 3 pmol/l). As compared to the dopastatin compound, the lower efficacy of the universal somatostatin ligands in the inhibition of GH secretion of GH-secreting tumors argues for the use of drugs targeted, according to specific receptors expression and functionality which may vary among the various classes of tumors.
authors.affiliation: Interactions Cellulaires Neuroendocriniennes, UMR6544, Centre National de la Recherche Scientifique, Institut Fédératif Jean Roche, Faculté de Médecine Nord, Marseille, France. jaquet.p@jean-roche.univ.mrs.fr
authors.forename: P
authors.initials: P
authors.lastname: Jaquet
authors.forename: G
authors.initials: G
authors.lastname: Gunz
authors.forename: A
authors.initials: A
authors.lastname: Saveanu
authors.forename: A
authors.initials: A
authors.lastname: Barlier
authors.forename: H
authors.initials: H
authors.lastname: Dufour
authors.forename: J
authors.initials: J
authors.lastname: Taylor
authors.forename: J
authors.initials: J
authors.lastname: Dong
authors.forename: S
authors.initials: S
authors.lastname: Kim
authors.forename: J P
authors.initials: JP
authors.lastname: Moreau
authors.forename: M D
authors.initials: MD
authors.lastname: Culler
mesh_terms: D000172:Acromegaly / Q000188:drug therapy; D000328:Adult; D005260:Female; D015870:Gene Expression; D019382:Human Growth Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D008297:Male; D015282:Octreotide / Q000627:therapeutic use*; D009842:Oligopeptides / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D010911:Pituitary Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D011388:Prolactin / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D011954:Receptors, Dopamine / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000235:genetics; D017481:Receptors, Somatostatin / Q000235:genetics / Q000378:metabolism*
chemical_list: C111784:BIM 23197; D009842:Oligopeptides; D010879:Piperazines; D012333:RNA, Messenger; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D017481:Receptors, Somatostatin; D019382:Human Growth Hormone; C094573:somatostatin receptor 5; D011388:Prolactin; C093733:somatostatin receptor 2; D015282:Octreotide