The multi-ligand somatostatin analogue SOM230 inhibits ACTH secretion by cultured human corticotroph adenomas via somatostatin receptor type 5

Abstract

Objective: Currently, there is no effective medical treatment for patients with pituitary-dependent Cushing's disease. A novel somatostatin (SS) analogue, named SOM230, with high binding affinity to SS receptor subtypes sst 1 , sst 2 , sst 3 and sst 5 was recently introduced. We compared the in vitro effects of the sst 2 -preferring SS analogue octreotide (OCT) and the multi-ligand SOM230 on ACTH release by human and mouse corticotroph tumour cells. Methods: By quantitative RT-PCR the sst subtype expression level was determined in human corticotroph adenomas. In vitro, the inhibitory effect of OCT and SOM230 on ACTH release by dispersed human corticotroph adenoma cells and mouse AtT20 corticotroph adenoma cells was determined. In addition, the influence of dexamethasone on the responsiveness to OCT and SOM230 was studied. Results: Corticotroph adenomas expressed predominantly sst 5 mRNA (six out of six adenomas), whereas sst 2 mRNA expression was detected at significantly lower levels. In a 72 h incubation with 10 nmol/l SOM230, ACTH release was inhibited in three out of five cultures (range 2 30 to 2 40%). Ten nmol/l OCT slightly inhibited ACTH release in only one of five cultures (2 28%). In AtT20 cells, expressing sst 2 , sst 3 and sst 5 , SOM230 inhibited ACTH secretion with high potency (IC 50 0.2 nmol/l). Dexamethasone (10 nmol/l) pre-treatment did not influence the sensitivity of the cells to the inhibitory effect of SOM230, suggesting that sst 5 is relatively resistant to negative control by glucocorticoids. Conclusions: The selective expression of sst 5 receptors in corticotroph adenomas and the preferential inhibition of ACTH release by human corticotroph adenoma cells by SOM230 in vitro, suggest that SOM230 may have potential in the treatment of patients with pituitary-dependent Cushing's disease.European Journal of Endocrinology 152 645-654

Preclinical and clinical experiences with the role of somatostatin receptors in the treatment of pituitary adenomas

“…Indeed, relatively low levels of sst 2 mRNA in a series of primary human corticotrope adenomas of patients with CD were found. On the other hand, a predominant expression of sst 5 mRNA in corticotrope adenomas was observed (42). This sst mRNA profile in human corticotrope adenomas, i.e.…”

Effects of type I interferons on IGF-mediated autocrine/paracrine growth of human neuroendocrine tumor cells

“…cDNA synthesis and quantitative PCR using the TaqMan Gold nuclease assay and the ABI PRISM 7700 sequence detection system (PerkinElmer Applied Biosystems, Groningen, The Netherlands) were performed as described in detail previously (13). The primer and probe sequences were purchased from Biosource (Nivelles, Belgium).…”

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“…Compared to octreotide, SOM-230 is more potent at suppressing ACTH release and at inhibiting CRH-induced ACTH release in corticotroph tumour cells (91)(92)(93). Dexamethasone (10 nM) pre-treatment of mouse corticotroph cells fails to suppress SOM-230 inhibition of CRH-induced ACTH release whereas the suppressive effect of octreotide is blocked (92).…”