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)

Rat AR42J pancreas cells, which express somatostatin-SSTR2 type receptors, responded to SSTR2-selective somatostatin (SRIF) agonist ligands with a dose-dependent increase in intracellular Ca2+. In addition to SRIF-14 and SRIF-28, the most potent SRIF peptides were the cyclic octapeptides, BIM-23014C, BIM-23023, SMS 201-995, and the cyclic hexapeptides, MK-678 and BIM-23027. The SSTR3 and SSTR5-selective ligands, BIM-23056 and BIM-23052, were inactive and weakly active, respectively. None of the SRIF peptides stimulated inositol phosphate turnover, indicating that Ca2+ mobilization was independent of phospholipase C activation. Incubation in calcium-free medium abolished the increase in intracellular Ca2+. These results indicate that activation of SSTR2 receptors in AR42J cells opens cell-surface calcium channels.
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PMID:Somatostatin (SSTR2) receptors mediate phospholipase C-independent Ca2+ mobilization in rat AR42J pancreas cells. 766 56

To further investigate the antineoplastic efficacy and safety of somatostatin analogues, 2 trials were performed. Octreotide, SMS 201-995 (Sandostatin), was escalated in doses ranging from 1,500 micrograms to 6,000 micrograms daily in 14 patients with carcinoid. Somatuline, (BIM 23014C, Angiopeptin, Lanreotide) was given in doses ranging from 2,250 micrograms to 9,000 micrograms daily to 13 neuroendocrine patients (6 carcinoid, 2 atypical carcinoid, 3 pancreatic islet cell and 2 small cell lung cancer patients). All patients successfully completed dose escalations without significant adverse effects and were evaluable for toxicity. The dose limiting side-effect of octreotide was the injection volume. No dose limiting adverse effects have been observed with somatuline. Carcinoid syndrome symptoms were better controlled with higher octreotide doses. Thirteen patients were evaluable for octreotide's antitumor efficacy with a partial response observed in 4 (31%), stable disease in 2 and progressive disease in 7 patients. Radiographic changes of increased tumor necrosis occurred in 5 patients and was independent of response. Somatuline resulted in a partial response in 4 patients (2 carcinoids, 1 gastrinoma and 1 small cell lung cancer) (31%), stable disease in 1 atypical carcinoid, and progressive disease in 8 (4 carcinoid, 1 atypical carcinoid, 2 islet cell and 1 multi-drug resistant small cell lung cancer). Six of the 8 carcinoid patients had radiographic changes of increased necrosis. Dose escalation of somatostatin analogues is well tolerated and may be associated with antitumor activity in some neuroendocrine neoplasms.
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PMID:Somatostatin analogue phase I trials in neuroendocrine neoplasms. 768 64

Rat cerebellar nuclei contain somatotropin release-inhibiting factor (SRIF) receptors that bind [125I][Leu8,D-Trp22,Tyr25]SRIF-28 but do not bind [125I][Tyr0,D-Trp8]SRIF-14. The aim of the present study was to investigate the pharmacological profile of these receptors by means of binding experiments on tissue sections and quantitative autoradiography. Competition experiments indicated the presence of a single class of [125I][Leu8,D-Trp22,Tyr25]SRIF-28 binding sites in the lateral cerebellar nuclei, showing similar affinities for SRIF-14 and SRIF-28, but low affinity for short-chained analogs. The IC50 values for somatostatin analogs to compete with the binding of [125I][Leu8,D-Trp22,Tyr25]SRIF-28 in the lateral cerebellar nuclei ranked as follows: [Leu8,D-Trp22,Tyr25]SRIF-28 approximately SRIF-14 approximately SRIF-28 < CGP 23996 < D-Phe-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-NH2 (BIM 23052) < SMS 201-995 approximately N-Ahep-(7-10)SRIF-14-Bzl << MK 678 < D-Phe-Phe-Tyr-D-Trp-Lys-Val-Phe-D-Nal-NH2 (BIM 23056) < D-Phe-c[Cys-Tyr-D-Trp-Lys-Abu-Cys]Nal-NH2 (NC 8-12). Optimum binding of [125I][Leu8,D-Trp22,Tyr25]SRIF-28 did not require divalent cations, and was partly inhibited by guanosine 5' triphosphate. It appears from this study that the rat lateral cerebellar nuclei contain a pure population of receptors exhibiting the same binding characteristics as the recently cloned sstr1 somatostatin receptor. These nuclei could thus provide a useful model in which to investigate the characteristics of native sstr1.
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PMID:Pharmacological characterization of somatostatin receptors in rat cerebellar nuclei. 769 15

Somatostatin (SST) and its analogs injected into the CSF induce different gastric acid response patterns. Five SST receptors have been characterized (SSTR-1 to -5). We studied the influence of selective SSTR-2, -3 and -5 ligands on basal gastric acid secretion after intracisternal (i.c.) injection in conscious rats equipped with chronic gastric and i.c. cannulae. Compared with pre-injection level, the SSTR-3 agonist, BIM-23056 (1 microgram) increased acid secretion by 274 +/- 43% while the SSTR-2 agonist, DC 32-87 (1 microgram) inhibited acid secretion by 50.7 +/- 13.3%. SST-14 (1 microgram), the SSTR-5 agonist, BIM-23052, (0.5-1 microgram), SSTR-3 (0.5 micrograms) and -2 (0.5 microgram) or vehicle injected i.c. did not modify basal acid secretion. These results show that the activation of brainstem SSTR-3 receptors stimulate and SSTR-2 inhibit basal gastric acid secretion in conscious rats with chronic gastric fistulae.
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PMID:Influence of intracisternal injection of somatostatin analog receptor subtypes 2, 3 and 5 on gastric acid secretion in conscious rats. 777 3

The effects of the somatostatin analogue, angiopeptin (BIM-23014), on neoendothelial function, as evidenced by formation of prostaglandin (PG) I2 and by acetylcholine-induced relaxation (formation of endothelial-derived relaxing factor), were investigated in the rabbit aorta. A balloon catheter injury of the thoracic and abdominal aorta was induced in New Zealand White rabbits. Animals treated with angiopeptin for 2 or 4 wk were compared with untreated rabbits at 2 or 4 wk after the induction of injury, as well as to sham-operated controls. When the rabbits were killed, vascular rings were assessed for arachidonic acid-stimulated PGI2 formation, acetylcholine-induced relaxation, and the degree of intimal hyperplasia. Vascular rings from animals treated with angiopeptin exhibited enhanced acetylcholine-induced relaxation; however, angiopeptin treatment had no effect on arachidonic acid-stimulated PGI2 formation. Intimal hyperplasia in treated animals was reduced by 36%. Treatment with another somatostatin analogue, BIM-23030, did not enhance relaxation or inhibit intimal hyperplasia. These data suggest that treatment with angiopeptin may inhibit intimal hyperplasia in part by its beneficial effect on neoendothelial function.
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PMID:Angiopeptin enhances acetylcholine-induced relaxation and inhibits intimal hyperplasia after vascular injury. 790 5

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.
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PMID: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. 790 31

Using a combination of polymerase chain reaction and genomic library screening we have cloned a human gene for a subtype of the somatostatin (SST) receptor (SSTR) termed human SSTR5 (hSSTR5), which is located on chromosome 16. The predicted amino acid sequence of hSSTR5 displays 75% sequence identity with a recently identified rat SSTR [Mol. Pharmacol. 42:939-946 (1992)], suggesting that it is the human homologue of this receptor. hSSTR5 consists of a 363-residue polypeptide exhibiting a putative seven-transmembrane domain topology typical of G protein-coupled receptors. The receptor displays considerable sequence identity to hSSTR1 (42%), hSSTR2 (48%), hSSTR3 (47%), and hSSTR4 (46%). Membranes prepared from COS-7 cells transiently expressing the hSSTR5 gene bound 125I-Leu8,D-Trp22,Tyr25-SST-28 (125I-LTT-SST-28) with high affinity and in a saturable manner. SST-14, SST-28, and various synthetic SST peptide agonists produced dose-dependent inhibition of radioligand binding with the following rank order of potency: LTT-SST-28 > SST-28 > D-Trp8-SST-14 > SST-14 approximately RC-160 approximately BIM 23014 > MK-678 > SMS 201-995. hSSTR5 bound SST-28 with a 12.6-fold greater affinity (Ki = 0.19 nM), compared with SST-14 (Ki = 2.24 nM), indicating that the receptor is SST-28 selective. Addition of GTP, guanosine-5'-O-(3-thio)triphosphate, Na+ ions, or pertusis toxin greatly reduced 125I-LTT-SST-28 binding, thereby indicating that hSSTR5 is coupled to pertussis toxin-sensitive G proteins. Both SST-14 and SST-28 displayed dose-dependent inhibition of forskolin-stimulated cAMP accumulation, consistent with functional coupling of the receptor to adenylyl cyclase inhibition. Northern blot analysis of SSTR5 mRNA revealed a 2.4-kilobase transcript in normal rat pituitary and GH3 rat pituitary tumor cells and a 4.0-kilobase transcript in normal human pituitary. Reverse transcriptase polymerase chain reaction revealed expression of the hSSTR gene in fetal human pituitary and hypothalamus but not in human cerebral cortex. In situ hybridization of the rat pituitary showed that SSTR5 mRNA is selectively localized in the anterior lobe. SSTR5 mRNA was not expressed in four human pituitary tumors (somatotroph adenoma, prolactinoma, and chromophobe adenomas) or in a human insulinoma. Although hSSTR5 displays approximately 75% sequence identity with rat SSTR5, the two receptors display significantly different pharmacological profiles, especially with respect to their binding affinities for the SST analogue SMS 201-995.
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PMID:Molecular cloning, functional characterization, and chromosomal localization of a human somatostatin receptor (somatostatin receptor type 5) with preferential affinity for somatostatin-28. 790 5

Somatostatin (SRIF) is a cyclic tetradecapeptide hormone initially isolated from ovine hypothalami. It inhibits endocrine and exocrine secretion, as well as tumor cell growth, by binding to specific cell surface receptors. Its potent inhibitory activity, however, is limited by its rapid enzymatic degradation and the consequent short plasma half-life. Octreotide is a short SRIF analog with increased duration of action compared to SRIF. Octreotide is approved for the treatment of acromegaly, amine precursor uptake and decarboxylation-omas, complications of pancreatic surgery and severe forms of diarrhea. Preclinical studies have focussed on the anticancer effects of octreotide and the related SRIF analogs BIM 23014 and RC-160. In vitro at nanomolar concentrations, these analogs inhibit the growth of tumor cells that express high affinity SRIF receptors. Accordingly, SRIF analogs, such as octreotide, potently inhibit the growth of SRIF receptor-positive tumors in various rodent models, and, in particular, xenotransplanted human tumors in nude mice. The range of cancers susceptible to octreotide and related SRIF analogs includes mammary, pancreatic, colorectal and lung malignancies. Moreover, an indirect antiproliferative effect of SRIF analogs is achievable in SRIF receptor-negative tumors, whose growth is driven by factors (gastrin, insulin-like growth factor-1, etc.) that are downregulated by SRIF. The use of radiolabeled somatostatin analogs represents a new diagnostic approach. [111In-DTPA]octreotide was developed for gamma camera imaging of SRIF receptor-positive malignancies, such as gasteroenteropancreatic tumors. Visualization of SRIF receptor-positive tumors in humans is emerging as an important methodology, both in tumor staging and predicting therapeutic response to octreotide. Recently, five SRIF receptor subtypes (SSTR1-5) have been cloned, all of which bind SRIF with high affinity. In contrast, SRIF receptor subtypes 1-5 have different binding profiles for short SRIF analogs. Octreotide, SSTR5, show moderate affinity for SSTR3 and fail to bind with high affinity to the other subtypes (SSTR1 and 4). Accordingly, the oncological profile of these three analogs is apparently similar. In conclusion, somatostatin analogs are a promising class of compounds for diagnosis and treatment of cancer. Current work is focussed on the identification of further SRIF receptor subtype-selective analogs with potential in oncology.
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PMID:Somatostatin analogs for diagnosis and treatment of cancer. 791 34

The recent molecular cloning of the genes and cDNAs encoding multiple somatostatin (SRIF) receptor subtypes has allowed for the individual expression of these receptors in mammalian cells and characterization of their respective pharmacological profiles. Previously, we fully described and compared the pharmacological properties of the first three SRIF receptor subtypes, SRIF receptor type (SSTR)1, SSTR2, and SSTR3. In the present study, we have investigated the properties of the newly cloned SRIF receptor subtypes SSTR4 and SSTR5 with regard to pharmacological profiles, the regulation of high affinity agonist binding to these receptors by stable GTP analogues, Na+, or prior exposure to agonists, and the inhibition of forskolin-stimulated cAMP accumulation mediated by these receptors. We labeled SSTR4 and SSTR5 expressed in Chinese hamster ovary (CHO-K1) and COS-1 cells, respectively, with the metabolically stable SRIF analogue 125I-CGP 23996. Radioligand binding competition studies were performed using SRIF analogues of differing structures, including hexapeptide analogues similar to MK-678, octapeptide analogues similar to SMS 201-995, pentapeptide analogues similar to c[Ahep-Phe-D-Trp-Lys-Thr(Bzl)], and linear SRIF analogues. SSTR4 bound compounds in all structural classes with high to moderate affinities, and several compounds were identified that are > 100-fold selective for SSTR4, compared with the other cloned SRIF receptors, including the linear SRIF analogue BIM-23052 and the CGP 23996-like SRIF analogue L-362,855. In contrast, SSTR5 bound very few SRIF analogues with high affinity. Both receptors could be regulated by prior exposure to agonist. In addition, agonist binding to SSTR4 was reduced by stable GTP analogues, Na+, and pertussis toxin, but agonist binding to SSTR5 was not affected by these treatments. SSTR4 is efficiently coupled to the inhibition of adenylyl cyclase activity, whereas SSTR5 appears not to couple to this cellular effector system. Such differences between the cloned SRIF receptors provide useful strategies for identifying regions of these receptor subtypes that may be involved in ligand-binding specificities and G protein and cellular effector system coupling. The identification of subtype-selective SRIF analogues may lead to more specific therapeutic interventions.
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PMID:Characterization of cloned somatostatin receptors SSTR4 and SSTR5. 810 85

In order to evaluate the diagnostic reliability of somatostatin receptor scintigraphy (SRS) in patients treated with somatostatin analogs, ten patients with metastatic neuroendocrine tumors were investigated before and during continuous treatment. Different somatostatin analogs were used for therapy: five patients received octreotide (Sandostatin, Sandoz, Switzerland) and five were treated with BIM 23014 (Lanreotide, Ipsen Biotech, France) within the scope of a clinical phase II study. The SRS findings were analyzed in terms of biodistribution of the labeled somatostatin analog and tumor visualization comparing the two studies in each patient. Whereas liver, spleen, and kidney uptake were decreased during octreotide treatment and increased on lanreotide therapy, tumor accumulation was intensified in all but one patient. Our results suggest that the diagnostic value of SRS is not necessarily restricted during treatment with somatostatin analogs. Indeed, tumor visualization may even be enhanced in this therapeutic setting.
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PMID:Diagnostic reliability of somatostatin receptor scintigraphy during continuous treatment with different somatostatin analogs. 833 Aug 70


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