scholarly journals DG3173 (somatoprim), a unique somatostatin receptor subtypes 2-, 4- and 5-selective analogue, effectively reduces GH secretion in human GH-secreting pituitary adenomas even in Octreotide non-responsive tumours

2012 ◽  
Vol 166 (2) ◽  
pp. 223-234 ◽  
Author(s):  
U Plöckinger ◽  
U Hoffmann ◽  
M Geese ◽  
A Lupp ◽  
M Buchfelder ◽  
...  
Keyword(s):  
Dose Response ◽  
Somatostatin Receptor ◽  
Somatostatin Receptors ◽  
Clinical Effectiveness ◽  
Significant Negative Correlation ◽  
Somatostatin Analogues ◽  
Receptor Subtypes ◽  
Gh Secretion ◽  
Somatostatin Receptor Subtypes ◽  
Tumour Characteristics

ObjectiveSomatostatin analogues (SSA) reduce autonomous GH secretion by activating somatostatin receptors (sst) 2 and 5 in 50–60% of acromegalic patients. However, by inhibiting insulin secretion these SSA reduce glucose tolerance. DG3173 is a novel SSA with additional binding to sst4 and low insulin-suppressing activity. We investigated the effect of DG3173, including its relation to specific tumour characteristics, on GH secretion in human somatotroph adenoma cell cultures (hSA) in comparison with Octreotide.MethodsTwenty-seven hSA were characterised immunohistochemically for their hormone- and sst-expression, granularity and pre-surgical therapy with SSA. GH was determined in supernatants of hSA treated with DG3173 or Octreotide in time- (n=6) and dose–response (n=21) experiments. A positive response was defined as GH suppression to below 80% of baseline.ResultsIn the dose–response experiments DG3173 suppressed GH secretion in more adenomas than Octreotide (10/21 vs 5/21), including 38% (6/16) of Octreotide non-responders. In responders the extent of GH suppression and IC50 were comparable for both SSA. The response-rate of both SSA was higher in monohormonal vs bihormonal adenomas, yet GH declined similarly in both groups. Neither pre-surgical SSA (n=6) nor tumour morphology was related to the GH response. However, semi-quantitative analysis indicated a small but significant negative correlation between the GH response to Octreotide and the immunoreactivity scores of sst2 expression.ConclusionsDG3173 equalled Octreotide in suppressing GH secretion in hSA. Since DG3173 suppressed GH in some Octreotide-non-responsive adenomas, its clinical effectiveness will be worth testing. Moreover, its reduced insulin-suppressive potency would make it a valuable alternative to Octreotide.

scholarly journals Somatostatin receptor subtype expression in the human heart: differential expression by myocytes and fibroblasts

2005 ◽  
Vol 187 (3) ◽  
pp. 379-386 ◽  
Author(s):  
William H T Smith ◽  
R Unnikrishnan Nair ◽  
Dawn Adamson ◽  
Mark T Kearney ◽  
Stephen G Ball ◽  
...  
Keyword(s):  
Cardiac Myocytes ◽  
Human Heart ◽  
Cardiac Fibroblasts ◽  
Somatostatin Receptor ◽  
Somatostatin Receptors ◽  
Cell Types ◽  
Somatostatin Analogues ◽  
Receptor Subtypes ◽  
Somatostatin Receptor Subtypes ◽  
Human Cardiac Fibroblasts

In acromegaly, somatostatin receptor ligands (SRLs) can ameliorate left ventricular hypertrophy (LVH) and their use is associated with demonstrable improvements in various parameters of cardiac function. It remains unclear as to whether these beneficial effects are principally attributable to falling GH and IGF-I levels, or whether SRLs exert independent direct effects on the heart via somatostatin receptors. To help address this issue, we have sought to investigate somatostatin receptor expression in human heart. A human heart cDNA library was probed using PCR techniques to determine expression of somatostatin receptor subtypes. Subsequently, human heart biopsies and human cardiac fibroblasts and myocytes were analysed to determine whether expression differed between cardiac chambers or cell types. mRNAs for four of the five somatostatin receptor subtypes (sst1, sst2, sst4 and sst5) were shown to be co-expressed by the human heart. These receptors were present in both atrial and ventricular tissue. Human cardiac myocytes expressed mRNA for only sst1 and sst2, while human cardiac fibroblasts expressed all four subtypes found in whole heart tissue. The expression of functional somatostatin receptors on human cardiac fibroblasts was confirmed by mobilisation of intracellular calcium in response to somatostatin. The presence of cardiac somatostatin receptors raises the possibility of a direct effect of somatostatin analogues on the heart. Furthermore, the differential expression of somatostatin receptor subtypes by human cardiac myocytes and fibroblasts opens up the possibility of differential modulation of the cell types in the heart by subtype-specific somatostatin analogues.

Somatostatin receptors

1995 ◽  
Vol 269 (6) ◽  
pp. G813-G820 ◽  
Author(s):  
T. Reisine
Keyword(s):  
Somatostatin Receptor ◽  
Somatostatin Receptors ◽  
Somatostatin Analogues ◽  
Receptor Subtypes ◽  
Binding Domains ◽  
Somatostatin Receptor Subtypes ◽  
Selective Agonists ◽  
The Individual ◽  
Subtype Selective ◽  
Biological Actions

Somatostatin induces its biological actions by activating a family of receptor subtypes. The recent cloning of five somatostatin receptor subtypes has led to the development of subtype-selective agonists. These compounds are revealing distinct functions of the individual receptor subtypes. Mutagenesis studies have revealed domains of several of the receptors involved in specific recognition of somatostatin analogues. Molecular modeling of both of these ligand-binding domains and the constrained somatostatin analogues that they interact with may lead to the development of nonpeptide somatostatin drugs that could be useful in the treatment of tumors and various metabolic, gastrointestinal, and central nervous system disorders.

scholarly journals The clinical–molecular interface of somatostatin, dopamine and their receptors in pituitary pathophysiology

2009 ◽  
Vol 42 (5) ◽  
pp. 361-370 ◽  
Author(s):  
Diego Ferone ◽  
Federico Gatto ◽  
Marica Arvigo ◽  
Eugenia Resmini ◽  
Mara Boschetti ◽  
...  
Keyword(s):  
Medical Treatment ◽  
Dopamine Receptors ◽  
Pituitary Adenomas ◽  
Somatostatin Receptor ◽  
Somatostatin Receptors ◽  
Somatostatin Analogues ◽  
Receptor Activation ◽  
Receptor Subtypes ◽  
Experimental Drugs ◽  
Somatostatin Receptor Subtypes

The role of somatostatin and dopamine receptors as molecular targets for the treatment of patients with pituitary adenomas is well established. Indeed, dopamine and somatostatin receptor agonists are considered milestones for the medical therapy of these tumours. However, in recent years, the knowledge of the expression of subtypes of somatostatin and dopamine receptors in pituitary adenomas, as well as of the coexpression of both types of receptors in tumour cells, has increased considerably. Moreover, recent insights suggest a functional interface of dopamine and somatostatin receptors, when coexpressed in the same cells. This interaction has been suggested to occur via dimerisation of these G-protein-coupled receptors. In addition, there was renewed interest around the concept of cell specificity in response to ligand-induced receptor activation. New experimental drugs, including novel somatostatin analogues, binding to multiple somatostatin receptor subtypes, as well as hybrid somatostatin–dopamine compounds have been generated, and recently a completely novel class of molecules has been developed. These advances have opened new perspectives for the medical treatment of patients with pituitary tumours poorly responsive to the present clinically available drugs, and perhaps also for the treatment of other categories of neuroendocrine tumours. The aim of the present review is to summarise the novel insights in somatostatin and dopamine receptor pathophysiology, and to bring these new insights into perspective for the future strategies in the medical treatment of patients with pituitary adenomas.

scholarly journals Expression of Somatostatin Receptor 2 in Somatotropinoma Correlated with the Short-Term Efficacy of Somatostatin Analogues

2017 ◽  
Vol 2017 ◽  
pp. 1-7 ◽  
Author(s):  
Wenjuan Liu ◽  
Lina Xie ◽  
Min He ◽  
Ming Shen ◽  
Jingjing Zhu ◽  
...  
Keyword(s):  
Tumor Size ◽  
Tumor Volume ◽  
Somatostatin Receptor ◽  
Somatostatin Analogues ◽  
Receptor Subtypes ◽  
Short Term ◽  
Pituitary Growth Hormone ◽  
Term Efficacy ◽  
Somatostatin Receptor Subtypes ◽  
Pretreated Group

The expression of somatostatin receptor subtypes (SSTRs) in pituitary growth hormone- (GH-) secreting adenomas may predict the response to somatostatin analogues (SSA). Our aim was to evaluate the value of the immunohistochemical (IHC) scores of 2 subtypes, SSTR2 and SSTR5, in predicting the short-term efficacy of SSA therapy in patients with active acromegaly. Ninety-three newly diagnosed acromegalic patients were included in our study. These patients were categorized into either a SSA-pretreated group (SA, n=63) or a direct-surgery group (DS, n=30), depending on whether or not presurgical SSA treatment was received. IHC analysis, using a 12-grade scoring system, with rabbit monoclonal antibodies against SSTR2 and SSTR5, was performed on all adenoma tissues. The reduction of GH, IGF-1, and tumor size after treatment with SSA for 3 months was measured. Compared with that in the DS group, SSTR2 expression was lower in the SA group. Additionally, in the SA group, SSTR2 expression was positively correlated with the reduction of IGF-1 and tumor volume. However, there was no correlation between the SSTR5 score and the efficacy of SSA. In conclusion, the protein expression of SSTR2, but not of SSTR5, is a valuable indicator in predicting biochemical and tumor size response to short-term SSA treatment in acromegalic patients.

Novel insights in somatostatin receptor physiology

2007 ◽  
Vol 156 (suppl_1) ◽  
pp. S3-S11 ◽  
Author(s):  
Giovanni Tulipano ◽  
Stefan Schulz
Keyword(s):  
Somatostatin Receptor ◽  
Somatostatin Receptors ◽  
Somatostatin Analogs ◽  
Receptor Subtypes ◽  
Ligand Complex ◽  
Endosomal Sorting ◽  
Intracellular Vesicle ◽  
Molecular Events ◽  
Somatostatin Receptor Subtypes

The experimental data reviewed in the present paper deal with the molecular events underlying the agonist-dependent regulation of the distinct somatostatin receptor subtypes and may suggest important clues about the clinical use of somatostatin analogs with different pattern of receptor specificity for the in vivo targeting of tumoral somatostatin receptors. Somatostatin receptor subtypes are characterized by differential β-arrestin trafficking and endosomal sorting upon agonist binding due, at least in part, to the differences in their C-terminal tails. Moreover, the subcellular expression pattern of somatostatin receptor subtypes and their activity in response to agonist treatment are affected by intracellular complements, such as proteins involved in intracellular vesicle trafficking. Different somatostatin analogs may induce distinct conformations of the receptor/ligand complex, preferentially coupled to either receptor signaling or receptor endocytosis.

scholarly journals Effect of GHRH and GHRP-2 treatment in vitro on GH secretion and levels of GH, pituitary transcription factor-1, GHRH-receptor, GH-secretagogue-receptor and somatostatin receptor mRNAs in ovine pituitary cells

2004 ◽  
pp. 235-242 ◽  
Author(s):  
M Yan ◽  
M Hernandez ◽  
R Xu ◽  
C Chen
Keyword(s):  
Transcription Factor ◽  
Somatostatin Receptor ◽  
Receptor Subtypes ◽  
Pituitary Cells ◽  
Dependent Manner ◽  
Gh Secretion ◽  
Somatostatin Receptor Subtypes ◽  
Transcription Factor 1

OBJECTIVE: Growth hormone (GH)-releasing hormone (GHRH) and GH-releasing peptides (GHRPs) stimulate the release of GH through their specific receptors on somatotropes. Combined GHRH and GHRP administration causes a synergistic GH release in vivo by an unknown mechanism. The current study focuses on the direct action of GHRH and GHRP on several molecular targets in somatotropes. DESIGN AND METHODS: To clarify the mechanism of action, ovine somatotropes were used to measure the expression of mRNAs encoding for GH, pituitary transcription factor-1 (Pit-1), GH-secretagogue receptor (GHS-R), GHRH-R, somatostatin receptor subtypes (sst-1 and sst-2) and GH release after GHRH and GHRP-2 treatment for 0.5, 1, 1.5 and 2 h. RESULTS: GHRH (10 nM), GHRP-2 (100 nM) and combined GHRH-GHRP-2 increased the levels of GH mRNA and GH release from 0.5 to 2 h in a time-dependent manner. The levels of Pit-1, GHRH-R and GHS-R mRNA were increased after 0.5 h treatment of cells with GHRH and GHRP-2. The levels of sst-1 but not sst-2 mRNA were significantly increased after 0.5 and 1 h of GHRH treatment. In contrast, both sst-1 and sst-2 mRNA expression was inhibited after 0.5-2 h of GHRP treatment. CONCLUSIONS: These data demonstrate a direct in vitro modification of ovine somatotropes by GHRH and GHRP-2 resulting in altered GHRH-R, GHS-R, Pit-1, sst-1, sst-2 and GH gene expression; this may underlie the regulatory action of GHRH and GHRP-2 on GH secretion.

scholarly journals Somatostatin receptor expression in parathyroid neoplasms

2019 ◽  
Vol 8 (8) ◽  
pp. 1213-1223 ◽  
Author(s):  
Sara Storvall ◽  
Helena Leijon ◽  
Eeva Ryhänen ◽  
Johanna Louhimo ◽  
Caj Haglund ◽  
...  
Keyword(s):  
Primary Hyperparathyroidism ◽  
Parathyroid Carcinoma ◽  
Somatostatin Receptor ◽  
Somatostatin Receptors ◽  
Receptor Expression ◽  
Benign Tumors ◽  
Receptor Subtypes ◽  
Receptor Imaging ◽  
Somatostatin Receptor Subtypes ◽  
Parathyroid Adenomas

Introduction Parathyroid carcinoma represents a rare cause of primary hyperparathyroidism. Distinguishing carcinoma from the benign tumors underlying primary hyperparathyroidism remains challenging. The diagnostic criteria for parathyroid carcinoma are local and/or metastatic spreading. Atypical parathyroid adenomas share other histological features with carcinomas but lack invasive growth. Somatostatin receptors are commonly expressed in different neuroendocrine tumors, but whether this also holds for parathyroid tumors remains unknown. Aim Our aim is to examine the immunohistochemical expression of somatostatin receptor 1–5 in parathyroid typical adenomas, atypical adenomas and carcinomas. Methods We used a tissue microarray construct from a nationwide cohort of parathyroid carcinomas (n = 32), age- and gender-matched typical parathyroid adenomas (n = 72) and atypical parathyroid adenomas (n = 27) for immunohistochemistry of somatostatin receptor subtypes 1–5. We separately assessed cytoplasmic, membrane and nuclear expression and also investigated the associations with histological, biochemical and clinical characteristics. Results All parathyroid tumor subgroups expressed somatostatin receptors, although membrane expression appeared negligible. Except for somatostatin receptor 1, expression patterns differed between the three tumor types. Adenomas exhibited the weakest and carcinomas the strongest expression of somatostatin receptor 2, 3, 4 and 5. We observed the largest difference for cytoplasmic somatostatin receptor 5 expression. Conclusions Parathyroid adenomas, atypical adenomas and carcinomas all express somatostatin receptor subtypes 1–5. Somatostatin receptor 5 may serve as a potential tumor marker for malignancy. Studies exploring the role of somatostatin receptor imaging and receptor-specific therapies in patients with parathyroid carcinomas are needed.

Nuclear medicine techniques for the imaging and treatment of neuroendocrine tumours

2011 ◽  
Vol 18 (S1) ◽  
pp. S27-S51 ◽  
Author(s):  
Jaap J M Teunissen ◽  
Dik J Kwekkeboom ◽  
R Valkema ◽  
Eric P Krenning
Keyword(s):  
Nuclear Medicine ◽  
Neuroendocrine Tumours ◽  
Somatostatin Receptor ◽  
Somatostatin Analogues ◽  
Imaging Modalities ◽  
Tumour Regression ◽  
Receptor Subtypes ◽  
Receptor Imaging ◽  
Imaging Method ◽  
Somatostatin Receptor Subtypes

Nuclear medicine plays a pivotal role in the imaging and treatment of neuroendocrine tumours (NETs). Somatostatin receptor scintigraphy (SRS) with [111In-DTPA0]octreotide has proven its role in the diagnosis and staging of gastroenteropancreatic NETs (GEP-NETs). New techniques in somatostatin receptor imaging include the use of different radiolabelled somatostatin analogues with higher affinity and different affinity profiles to the somatostatin receptor subtypes. Most of these analogues can also be labelled with positron-emitting radionuclides that are being used in positron emission tomography imaging. The latter imaging modality, especially in the combination with computed tomography, is of interest because of encouraging results in terms of improved imaging quality and detection capabilities. Considerable advances have been made in the imaging of NETs, but to find the ideal imaging method with increased sensitivity and better topographic localisation of the primary and metastatic disease remains the ultimate goal of research. This review provides an overview of the currently used imaging modalities and ongoing developments in the imaging of NETs, with the emphasis on nuclear medicine and puts them in perspective of clinical practice. The advantage of SRS over other imaging modalities in GEP-NETs is that it can be used to select patients with sufficient uptake for treatment with radiolabelled somatostatin analogues. Peptide receptor radionuclide therapy (PRRT) is a promising new tool in the management of patients with inoperable or metastasised NETs as it can induce symptomatic improvement with all Indium-111, Yttrium-90 or Lutetium-177-labelled somatostatin analogues. The results that were obtained with [90Y-DOTA0,Tyr3]octreotide and [177Lu-DOTA0,Tyr3]octreotate are even more encouraging in terms of objective tumour responses with tumour regression and documented prolonged time to progression. In the largest group of patients receiving PRRT, treated with [177Lu-DOTA0,Tyr3]octreotate, a survival benefit of several years compared with historical controls has been reported.

scholarly journals Constitutive Somatostatin Receptor Subtype-3 Signaling Suppresses Growth Hormone Synthesis

2014 ◽  
Vol 28 (4) ◽  
pp. 554-564 ◽  
Author(s):  
Tamar Eigler ◽  
Anat Ben-Shlomo ◽  
Cuiqi Zhou ◽  
Ramtin Khalafi ◽  
Song-Guang Ren ◽  
...  
Keyword(s):  
Transcriptional Repression ◽  
Glycogen Synthase ◽  
Somatostatin Receptor ◽  
Pituitary Tumors ◽  
Serine Phosphorylation ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Hormone Synthesis ◽  
Gh Secretion ◽  
Somatostatin Receptor Subtypes

Abstract Somatostatin signals through somatostatin receptor subtypes (SSTR) 2 and 5 to attenuate GH secretion. Although expressed in normal pituitary glands and in GH-secreting pituitary tumors, SSTR3 function was unclear, and we have now determined the role of SSTR3 in somatotroph function. Stable rat pituitary tumor cell (GC) transfectants of human SSTR3 (GpSSTR3WT) showed suppression of rat (r) GH promoter activity, GH mRNA expression, and secreted GH concordant with suppressed cAMP/protein kinase A (PKA) signaling. In contrast, cAMP levels and GH expression were unchanged in cells expressing a mutant SSTR3 DRY motif (GpSSTR3R141A). GH expression was rescued by treatment of GpSSTR3WT with forskolin and 8-bromo-cAMP. GpSSTR3WT exhibited activation of glycogen synthase kinase3-β (GSK3-β), a PKA substrate, which was also reversed by 8-Bromo-cAMP treatment. Moreover, SSTR3-dependent GH transcriptional inhibition was rescued by inhibition of GSK3-β. GpSSTR3WT exhibited elevated Pit-1 serine phosphorylation and decreased Pit-1 occupancy of the rGH promoter with sustained Pit-1 expression. GSK3-β and Pit-1 physically interacted with each other, indicating that Pit-1 may be a GSK3-β phosphorylation substrate. In conclusion, constitutive SSTR3 activity mediates transcriptional repression of GH through cAMP/PKA, leading to subsequent activation of GSK3-β and increased Pit-1 phosphorylation and ultimately attenuating Pit-1 binding to the rGH promoter.

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