title: Relative potencies of the somatostatin analogs octreotide, BIM-23014, and RC-160 on the inhibition of hormone release by cultured human endocrine tumor cells and normal rat anterior pituitary cells.
abstract: In the present study we investigated the effects of the somatostatin (SS) analogs octreotide, RC-160, and BIM-23014 on GH release by cultured cells of human GH-secreting pituitary tumors, in normal rat anterior pituitary cells, and on gastrin release by cultured cells from a human gastrinoma. In all GH-secreting adenomas and in rat anterior pituitary cells, RC-160 was the most potent compound. RC-160 significantly inhibited GH-, PRL, and/or alpha-subunit release by human GH-secreting pituitary adenoma cells in concentrations as low as 10(-12)-10(-14) M, whereas at the same concentrations, octreotide and BIM-23014 did not inhibit or were significantly less effective in inhibiting GH release (P < 0.01, RC-160 vs. octreotide and BIM-23014). In rat anterior pituitary cell cultures, the IC50 values for inhibition of GH release were, in rank order of potency, 0.1, 5.3, 47, 48, and 99 pM for RC-160, SS-14, BIM-23014, octreotide, and SS-28, respectively. Maximal inhibitory effects by the three analogs were the same in the human GH adenoma cell cultures and the rat anterior pituitary cell cultures (-60%). On the basis of these data, RC-160 appears to be about 500 times more potent than octreotide and BIM-23014 in inhibiting GH release by rat anterior pituitary cells in vitro. Forskolin (100 microM) as well as pretreatment of the cells with pertussis toxin significantly diminished the inhibitory effects of the three SS analogs and those of SS-14 and SS-28 to the same extent. The latter data suggest that octreotide, RC-160, and BIM-23014 act mainly via a pertussis toxin-sensitive G-protein and an adenylyl cyclase-dependent mechanism. In the human gastrinoma culture, RC-160 inhibited gastrin release significantly more than octreotide at 10(-12)- and 10(-14)-M concentrations (P < 0.01). In conclusion, the SS analogs octreotide, RC-160, and BIM-23014 may have significant different potencies of inhibition of hormone release in vitro, with RC-160 being the most potent SS analog and octreotide and BIM-23014 having similar potencies. Depending on the pharmacokinetic properties of these three octapeptide SS analogs, these observations may have consequences for the medical therapy of patients with SS receptor-positive endocrine tumors.
authors.affiliation: Department of Medicine III, Erasmus University, Rotterdam, The Netherlands.
authors.forename: L J
authors.initials: LJ
authors.lastname: Hofland
authors.forename: P M
authors.initials: PM
authors.lastname: van Koetsveld
authors.forename: M
authors.initials: M
authors.lastname: Waaijers
authors.forename: J
authors.initials: J
authors.lastname: Zuyderwijk
authors.forename: S W
authors.initials: SW
authors.lastname: Lamberts
mesh_terms: D000236:Adenoma / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002478:Cells, Cultured; D004701:Endocrine Gland Neoplasms / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015408:Gastrinoma / Q000378:metabolism; D005755:Gastrins / Q000378:metabolism; D013006:Growth Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D015282:Octreotide / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010903:Pituitary Gland, Anterior / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012016:Reference Values; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D053561:Somatostatin-28; D014407:Tumor Cells, Cultured
chemical_list: D005755:Gastrins; D010456:Peptides, Cyclic; C060347:lanreotide; C051458:vapreotide; D013004:Somatostatin; D053561:Somatostatin-28; D013006:Growth Hormone; D015282:Octreotide