Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P61278 (somatostatin)
22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pituitary tumours express both somatostatin and dopamine receptors. Medical treatment with somatostatin analogues is a cornerstone of GH- and TSH-secreting tumours, while treatment with dopamine agonists is a cornerstone of prolactin-secreting tumours. Dopamine agonists have also demonstrated some efficacy in patients with GH- and TSH-secreting adenomas. Neither ACTH-secreting nor clinically non-functioning tumours have a well-established medical treatment. Nevertheless, some recent results have indicated a potential usefulness of the dopamine agonist cabergoline in patients with pituitary-dependent Cushing's disease. Combination treatment with both somatostatin analogues and dopamine agonists has been poorly investigated. Some studies conducted in small series have documented an additive effect of both drugs in patients with GH-secreting adenomas. Of mention is that none of the studies were randomised and cross-sectional so that the results should be confirmed by other well-designed studies. No data are available in other pituitary tumour histotypes. Preliminary observations in patients with clinically non-functioning adenomas are very promising.
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PMID:Combined therapy of somatostatin analogues and dopamine agonists in the treatment of pituitary tumours. 1741 90

Dopamine (DA) regulates both prolactin (PRL) secretion and gene expression, whereas somatostatin (SRIF) inhibits GH secretion with unclear effects on GH gene expression. We therefore tested the effects of SRIF analogs and chimeric SRIF/DA compounds BIM 23A760 and BIM 23A761 on GH and PRL secretion and gene expression in primary rat pituitary cultures and pituitary tumor GH(3) and MMQ cells. Chimeric SRIF/DA molecules suppressed GH release with a similar efficacy to SRIF receptor subtype 2 agonists in rat pituitary and GH(3) cells. After 24 h, BIM 23A760 and BIM 23A761 did not exert additive effects on GH secretion, and after 48 h were less effective than the combination of respective mono-receptor agonists in GH(3) cells. Real-time PCR did not reveal changes in GH mRNA levels after treatment with SRIF analogs and SRIF/DA molecules. SRIF/DA compounds suppressed PRL and PRL mRNA in rat pituitary and MMQ cells with a similar efficacy to D(2)-DA receptor agonist. In GH(3) cells, they suppressed PRL and PRL mRNA levels with a similar efficacy to SRIF receptor subtype 2 agonists. SRIF/DA molecules did not exhibit additive effects on PRL secretion and mRNA levels as compared with cotreatment with mono-receptor ligands. The results show that SRIF analogs and SRIF/DA molecules inhibit GH and PRL secretion and suppress PRL but not GH gene expression.
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PMID:Regulation of growth hormone and prolactin gene expression and secretion by chimeric somatostatin-dopamine molecules. 1765 61

Somatostatin (SRIF) influences the release of two important neuromodulators of retinal circuitry, dopamine (DA) and nitric oxide (NO). The aim of the present study was to examine whether DA and NO modulate SRIF release in rat retina, and the mechanisms involved in their actions. Retinas of adult female Sprague--Dawley rats (250--300 g) were mechanically detached from the eyecup and ex vivo experiments were performed. Retinal explants were incubated in the presence of dopaminergic [DA (10 microM, 100 microM and 200 microM), apomorphine (nonselective D1/D2 agonist, 0.50 mM, 1.0 microM and 10 microM), A68930 (D1 selective agonist, 0.50 microM, 1.0 microM and 10 microM), quinpirole (D2 selective agonist, 0.50 microM, 1.0 microM and 10 microM), SCH 23390 (D1 selective antagonist, 250 nM and 500 nM) and sulpiride (D2 selective antagonist, 100 microM and 200 microM)], and nitrinergic agents [arginine (62.5 microM--5mM), SIN-1 (50 microM, 100 microM and 500 microM) and 8-Br-cGMP (50 microM, 250 microM and 500 microM)]. SRIF levels were quantified using radioimmunoassay (RIA). Dopamine had no effect on SRIF levels. Apomorphine produced a concentration dependent decrease and increase in SRIF levels, suggestive of pre- and postsynaptic effects. A68930 (10 microM) and SCH 23390 (250 nM and 500 nM) mimicked and reversed apomorphine's postsynaptic actions, respectively. Quinpirole had no effect, but blockade of D2 autoreceptors by sulpiride (200 microM) afforded an increase in SRIF levels. Arginine and SIN-1 increased, and 8-Br-cGMP attenuated SRIF levels. These results show that dopamine D1 receptors, and NO/peroxynitrite agents modulate SRIF release in the retina suggesting that the triad SRIF--DA--NO have reciprocal interactions via which they regulate retinal circuitry and vision transduction.
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PMID:Dopamine (D1) receptor activation and nitrinergic agents influence somatostatin levels in rat retina. 1796 53

Since the initial use of medical treatment for acromegaly, several advances have been made in the understanding of the pathophysiology of growth hormone producing tumors, resulting in the development of multiple medical options and novel treatments. Currently there are three major classes of medication available for the treatment of acromegaly: somatostatin receptor ligands, growth hormone receptor antagonists, and dopamine agonists. Somatostatin receptor ligands are the treatment of choice for acromegaly due to their effectiveness in controlling growth hormone excess in approximately 60% of patients and their beneficial effects on tumor volume. Clinical trials have demonstrated efficacy of pegvisomant in up to 97% of patients, but long term data and safety have yet to be established. Dopamine agonists are inexpensive, but their use is hampered by their lack of efficacy compared to other medications. Medical therapy has an established role as adjuvant therapy after non-curative surgery, as well as primary therapy for selected patients unsuitable for surgical resection. Medical treatment to control growth hormone hypersecretion is often needed after radiation therapy until the effects are evident. Preliminary data suggest a potential role for medical treatment prior to surgical resection, surgical debulking to improve medical efficacy, and combination therapy with multiple medications from the three classes. More studies are required, however, to validate the utility of these approaches in treating acromegaly. With the available therapies, disease control can be achieved in nearly all patients with acromegaly.
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PMID:Medical therapy: options and uses. 1816 11

Dopamine and somatostatin are both involved in the negative control of normal pituitary cells. Dopamine subtype 2 receptor (D2DR) and somatostatin receptor (sst) agonists, mainly directed to sst2, are used in the treatment of pituitary adenomas. Nevertheless, a majority of corticotroph and gonadotroph adenomas and a third of somatotroph adenomas are still not sufficiently controlled by these treatments. D2DR and sst1, 2, 3 and 5 are present in most pituitary adenomas. These receptors may interact by heterodimerization as shown for sst1-sst5, sst5-D2DR, sst2-sst3 and sst2-D2DR suggesting possible additive effects. D2DR and sst2 agonist cotreatment showed limited additivity on GH secretion in acromegaly. Moreover, new chimeric compounds with sst2, D2DR and sst5 affinity have shown an increased control of secretion and/or proliferation of different types of pituitary adenomas in cell culture. Together with the multi-sst ligand drugs recently developed, these dopamine-somatostatin ligands represent a new opportunity in the combinatory treatment of pituitary adenomas.
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PMID:Relevance of coexpression of somatostatin and dopamine D2 receptors in pituitary adenomas. 1824 80

Dopamine D2 and somatostatin receptors (sstrs) were reported to affect non-functioning pituitary adenoma (NFPA) proliferation in vitro. However, the reported results differ according to the experimental conditions used. We established an experimental protocol allowing reproducible evaluation of NFPA cell proliferation in vitro, to test and compare the antiproliferative effects of dopamine and somatostatin analogs (alone or in combination) with the activity of the dopamine-somatostatin chimeric molecule BIM-23A760. The protocol was utilized by four independent laboratories, studying 38 fibroblast-deprived NFPA cell cultures. Cells were characterized for GH, POMC, sstr1-sstr5, total dopamine D2 receptor (D2R) (in all cases), and D2 receptor long and short isoforms (in 15 out of 38 cases) mRNA expression and for alpha-subunit, LH, and FSH release. D2R, sstr3, and sstr2 mRNAs were consistently observed, with the dominant expression of D2R (2.9+/-2.6 copy/copy beta-glucuronidase; mean+/-s.e.m.), when compared with sstr3 and sstr2 (0.6+/-1.0 and 0.3+/-0.6 respectively). BIM-23A760, a molecule with high affinity for D2R and sstr2, significantly inhibited [3H]thymidine incorporation in 23 out of 38 (60%) NFPA cultures (EC50=1.2 pM and Emax=-33.6+/-3.7%). BIM-23A760 effects were similar to those induced by the selective D2R agonist cabergoline that showed a statistically significant inhibition in 18 out of 27 tumors (compared with a significant inhibition obtained in 17 out of 27 tumors using BIM-23A760, in the same subgroup of adenomas analyzed), while octreotide was effective in 13 out of 27 cases. In conclusion, superimposable data generated in four independent laboratories using a standardized protocol demonstrate that, in vitro, chimeric dopamine/sstr agonists are effective in inhibiting cell proliferation in two-thirds of NFPAs.
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PMID:Efficacy of a dopamine-somatostatin chimeric molecule, BIM-23A760, in the control of cell growth from primary cultures of human non-functioning pituitary adenomas: a multi-center study. 1850 6

Dopamine agonists (DA) and somatostatin (SS) analogues have been proposed in the treatment of ACTH-producing neuro-endocrine tumours that cause Cushing's syndrome. Inversely, glucocorticoids (GCs) can differentially influence DA receptor D(2) or SS receptor subtype (sst) expression in rodent models. If this also occurs in human neuro-endocrine cells, then cortisol-lowering therapy could directly affect the expression of these target receptors. In this study, we investigated the effects of the GC dexamethasone (DEX) on D(2) and sst expression in three human neuro-endocrine cell lines: BON (carcinoid) and TT (medullary thyroid carcinoma) versus DMS (small cell lung cancer), which is severely GC resistant. In BON and TT, sst(2) mRNA was strongly down-regulated in a dose-dependent manner (IC(50) 0.84 nM and 0.16 nM), whereas sst(5) and especially D(2) were much more resistant to DEX treatment. Sst(2) down-regulation was abrogated by a GC receptor antagonist and reversible in time upon GC withdrawal. At the protein level, DEX also induced a decrease in the total number of SS (-52%) and sst(2)-specific (-42%) binding sites. Pretreatment with DEX abrogated calcitonin inhibition by sst(2)-preferring analogue octreotide in TT. In DMS, DEX did not cause significant changes in the expression of these receptor subtypes. In conclusion, we show that GCs selectively down-regulate sst(2), but not D(2) and only to a minor degree sst(5) in human neuro-endocrine BON and TT cells. This mechanism may also be responsible for the low expression of sst(2) in corticotroph adenomas and underwrite the current interest in sst(5) and D(2) as possible therapeutic targets for a medical treatment of Cushing's disease.
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PMID:Differential regulation of human dopamine D2 and somatostatin receptor subtype expression by glucocorticoids in vitro. 1885 17

While surgery remains the first-line treatment of most aggressive pituitary adenomas, medical therapy is important as second-line or adjunctive therapy in a large proportion of patients. Dopamine agonists (DAs) are the best treatment for prolactinomas, but when DAs are not tolerated, new somatostatin receptor subtype 5 (SSTR(5)) inhibitors may offer an alternative in the future. Unfortunately, these are unlikely to be effective in DA-resistant prolactinomas. In acromegaly, the existing somatostatin analogs, octreotide and lanreotide, will remain the medical treatment of choice for the foreseeable future. There is an urgent need for medical therapies in Cushing's disease, and the SSTR(5) analogs could offer an effective treatment in a proportion of patients within the next few years. Finally, the medical management options for non-functioning pituitary adenomas are also very limited, and a new chimeric agent with activity towards dopamine receptors, SSTR(5) and SSTR(2) may help reduce adenoma recurrence in the future.
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PMID:Future treatment strategies of aggressive pituitary tumors. 1900 39

Abstract The relative potencies of dopamine and somatostatin to inhibit prolactin secretion by pituitary cells in primary culture were compared. Hormone secretion was evaluated under basal conditions as well as after challenging it with thyrotropin-releasing hormone, vasoactive intestinal peptide or with drugs affecting either the activity of adenylate cyclase (forskolin), and protein kinase C (phorbol 12 myristate 13 acetate), or eliciting Ca(2) (+) fluxes in the cell by various ways (A23187, a Ca(2+) ionophore, the dihydropyridine agonist BAY-K-8644, or K(+) depolarization which activates voltage-sensitive Ca(2+) channels). In order to test whether all effects of dopamine and somatostatin were mediated by inhibitory guanosine triphosphate binding proteins, the experiments were systematically carried out in the presence or absence of pertussis toxin, an agent which selectively uncouples given subsets of G proteins from corresponding receptors. Dopamine markedly inhibited basal as well as thyrotropin-releasing hormone-, vasoactive intestinal peptide-, forskolin- and BAY-K-8644-stimulated release of prolactin. In contrast, dopamine was only able to induce partial inhibition of hormone release when secretion was triggered by tumour-promoting activator, A23187 or K(+) depolarization. Under all conditions tested, inhibition by somatostatin was significant, but of limited amplitude. Pertussis toxin completely reversed the effects of somatostatin. In contrast, complete reversal of dopamine effects by pertussis toxin was only achieved after hormone stimulation by tumour-promoting activator, alone or with A23187. Under all other conditions a residual dopamine inhibition was maintained in the presence of the toxin. The amplitude of this residual toxin resistant inhibition was comparable in all other cases to that observed for unstimulated (basal) prolactin release. It is concluded that: 1) As expected, dopamine is a potent inhibitor of secretory processes involving cyclic AMP accumulation or voltage-sensitive Ca(2+) channel activation. In contrast, the amine is only a partial inhibitor of exocytosis resulting from non-voltage-sensitive Ca(2+) channel-gated increase in Ca(2+) or direct activation of protein kinase C. 2) Somatostatin is a partial inhibitor of prolactin under all conditions tested. Dopamine and all somatostatin effects are mediated by pertussis toxin-sensitive G proteins. However, a small, but significant, proportion of dopamine inhibition is resistant to pertussis toxin and can thus be assumed to involve a distinct mode of action. This alternate mechanism of dopamine inhibition operates under all conditions except after treatment with tumour-promoting activator, suggesting that it can be inactivated by protein kinase C stimulation.
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PMID:Differential mechanisms of dopamine and somatostatin inhibition of prolactin secretion from anterior pituitary cells. 1921 42

Dopamine and serotonin are the two important key neurotransmitters, which participate in the formation and regulation of various physiological parameters in the normal and pathological states. It is very interesting and important in both fundamental and practical respect to analyze interactions of dopamine and serotonin with somatostatin--a peptide hormone suppressing the secretion of many other regulatory peptides and various bioactive substances. In the present work, a huge amount of experimental data on the interactions of dopamine and serotonin with somatostatin was collected and analyzed. Literature sources mainly cover the period of 1970 - 2006. Compilation of an information database on dopamine/serotonin--somatostatin interactions has been the next stage. Analysis of the effects of dopamine and somatostatin revealed unilateral influence of these endogenous regulators and also of the induced and/or inhibited peptides on the level of depression, stress, food intake, angiogenesis and cancerogenesis, thus making it possible to increase and prolong their effects via cascade mechanisms. Potentially possible combinations of somatostatin and dopamine analogs, and chimeric somatostatin/dopamine molecules are proposed for the treatment and correction of different pathological states, including acromegaly, prolactinemia, and hyperinsulinism.
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PMID:[Research of interactions in the dopamine-serotonin-somatostatin system promises new outlook in fundamental and practical respects]. 1944 33


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