Somatostatin receptor (SSTR) subtype-selective analogues differentially suppress in vitro growth hormone and prolactin in human pituitary adenomas. Novel potential therapy for functional pituitary tumors.

Abstract

Previously, we have shown somatostatin receptor (SSTR) subtype-specific regulation of growth hormone (GH), thyroid-stimulating hormone, and prolactin (PRL) secretion in human fetal pituitary cultures, where GH and thyroid-stimulating hormone are mediated by both SSTR2 and SSTR5, whereas SSTR2 preferentially mediates PRL secretion. We now tested SSTR subtype-selective analogues in primary human GH-and PRL-secreting pituitary adenoma cultures. Analogue affinities determined by membrane radioligand binding in cells stably expressing human SSTR forms were either SSTR2 or SSTR5-selective. Analogues preferential either for SSTR2, including octreotide, lanreotide, and novel compounds with improved affinity for SSTR2, or new SSTR5-selective compounds suppressed GH in tumor cell cultures (up to 44% of control; P Ͻ 0.0005). However, novel analogues from both groups were 30-40% more potent than octreotide and lanreotide in suppressing GH ( P Ͻ 0.05). Heterologous analogue combinations containing both SSTR2-and SSTR5-selective compounds were more potent in decreasing GH than analogues used alone ( P Ͻ 0.05), or than combinations of compounds specific for the same receptor subtype ( P Ͻ 0.005). In contrast, SSTR2-selective analogues did not suppress PRL release from six cultured prolactinomas studied. However, new SSTR5-selective analogues suppressed in vitro PRL secretion (30-40%; P Ͻ 0.05) in four of six prolactinomas. These results suggest that both SSTR2 and SSTR5 are involved in GH regulation in somatotroph adenoma cells, whereas SSTR5 exclusively regulates PRL secretion from prolactinoma cells. Thus, somatostatin analogues with improved selective binding affinity for these receptor subtypes may be effective in the treatment of either GH-or PRL-secreting adenomas. ( J. Clin. Invest. 1997. 100: 2386-2392.)

Function and expression of somatostatin receptors of the endocrine pancreas

“…Agonists A very recent study (Ludvigsen et al, 2007) evaluated the effects of the following agonists on insulin and glucagon secretion from isolated rat pancreatic islets: SOM230 (panagonist), SSTR1-selective (BIM-23926 IC50 of 3.6 nM for SSTR1 and > 800 nM for other SSTRs (Zatelli et al, 2002)), SSTR2-selective (BIM-23120, IC50 of 0.34 nM for SSTR2, and over 200 nM for other SSTRs (Zatelli et al, 2001;Zatelli et al, 2002;Shimon et al, 1997b;Shimon et al, 1997a;Saveanu et al, 2001)) and SSTR5-selective (BIM-23206, IC50 of 2.4 nM for SSTR5 and more than 15 nM for other 4 SSTRs). SOM230 was a superior inhibitor of insulin secretion as compared to octreotide or SST-14 after a longer incubation period of 48 hours.…”

Differential β-Arrestin Trafficking and Endosomal Sorting of Somatostatin Receptor Subtypes

“…The fact that naturally occurring somatostatin peptides have only short half-lives has necessitated the development of stable somatostatin peptide analogs including octreotide and lanreotide. Although SS-14 binds with high affinity to all five somatostatin receptors, octreotide and lanreotide bind only to sst 2 with high affinity and to sst 3 and sst 5 with moderate affinity (1,11).…”

“…Five genes encoding six different somatostatin receptor subtypes (sst 1 , sst 2A , sst 2B , sst 3 , sst 4 , sst 5 ) have been cloned. These receptors are widely expressed in the central nervous system and periphery, and multiple somatostatin receptor subtypes often coexist in the same cell (1,2).…”

“…These receptors are widely expressed in the central nervous system and periphery, and multiple somatostatin receptor subtypes often coexist in the same cell (1,2). The high density of somatostatin receptors on human neuroendocrine tumors (3)(4)(5) has been used clinically to treat the symptoms of hormonal hypersecretion in patients with growth hormoneand thyrotropin-secreting pituitary adenomas and patients harboring islet cell or carcinoid tumors (6 -8). Moreover, it has allowed the development of somatostatin receptor scintigraphy for tumor imaging as well as somatostatin receptor-targeted radiotherapy (9,10).…”

Análise da expressão da filamina A nos tumores hipofisários e suas implicações clínicas e terapêuticas

“…Outros autores identificaram o SSTR5 como o subtipo mais abundante, seguido pelo SSTR2 (94) . Os adenomas secretores de GH e de PRL apresentam maior expressão de SSTR5 (95)(96)(97) . A ativação do SSTR2 e do SSTR5…”