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)

Therapeutic efficacy of a synthetic somatostatin analogue for the treatment of carcinoid tumors is still controversial. In vivo studies performed in our laboratory showed that a somatostatin analogue, SMS 201-995, significantly inhibited growth of human pancreatic carcinoid (BON) tumors xenotransplanted into athymic nude mice. In the present study, however, SMS 201-995 did not inhibit in vitro growth of BON cells, but rather SMS 201-995 stimulated growth in a dose-dependent fashion. The growth-stimulatory effect was likely mediated through the reduction of cyclic AMP production. Unsuccessful treatment of certain types of carcinoid tumor with SMS 201-995 may be partly due to the direct growth-stimulatory effect of SMS 201-995 on carcinoid cells.
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PMID:Unexpected growth-stimulatory effect of somatostatin analogue on cultured human pancreatic carcinoid cells. 135 20

Development of effective treatment for patients with carcinoid tumors has been hampered by lack of an experimental model. The authors have established the only long-term cell line of a functioning human pancreatic carcinoid tumor (BON) that produces tumors in nude mice. In this study the authors examined the effect of three agents, alpha-interferon (IFN), a somatostatin analog, SMS 201-995 (SMS), and an inhibitor of polyamine biosynthesis, alpha-difluoromethylornithine (DFMO), on the growth of BON tumors. BON was implanted bilaterally as 3-mm2 pieces (subcutaneously [sc]) into male BALB/c nude mice. In the first study, 23 mice were randomized to four groups: control, IFN (1 x 10(6) units, sc, four times a day), IFN + SMS (300 micrograms/kg, intraperitoneally, three times a day), and IFN + 3% DFMO in drinking water. Treatments were initiated on day of tumor implantation. In the second study, mice were randomized to six groups: control, IFN, SMS, DFMO, IFN + SMS, IFN + DFMO, and IFN + SMS + DFMO. Treatments were started on day 15 after tumor implantation. Tumor area and body weights were measured weekly. In both studies mice were killed on day 28 after BON implantation and tumors removed, weighed, and analyzed for DNA and RNA content. In the first study, IFN either alone or in combination with SMS or DFMO suppressed BON tumor growth. When treatment was initiated after established tumor growth (study 2), however, the only effective treatments for suppression of growth of BON were IFN + DFMO and IFN + DFMO + SMS.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Novel therapy for the treatment of human carcinoid. 170 83

The authors have established a long-term tissue culture cell line (BON) derived from a metastatic human carcinoid tumor of the pancreas. The cells have been in continuous passage for 46 months. Tissue culture cells produce tumors in a dose-dependent fashion after SC inoculation of cell suspensions in athymic nude mice. BON tumors, grown in nude mice, are histologically identical to the original tumor; they possess gastrin and somatostatin receptors, synthesize serotonin and chromogranin A, and have a doubling time of approximately 13 days. The antiproliferative effects of the long-acting somatostatin analogue, SMS 201-995 (300 micrograms/kg, t.i.d.), and 2% alpha-difluoromethylornithine on BON xenografts in nude mice were examined. Tumor size was significantly decreased by day 14 of treatment with either agent and at all points of analysis thereafter until the animals were killed (day 33). In addition, tumor weight, DNA, RNA, and protein contents were significantly decreased in treated mice compared with controls. Establishment of this human carcinoid xenograft line, BON, provides an excellent model to study further the biological behavior of carcinoid tumors and the in vivo effect of chemotherapeutic agents on tumor growth.
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PMID:Establishment and characterization of a human carcinoid in nude mice and effect of various agents on tumor growth. 171 29

Somatostatin is known to inhibit hormone release from various neuroendocrine cells. In order to understand the mechanisms underlying somatostatin's action we performed patch-clamp experiments in GH3 pituitary, rMTC 44-2 thyroid and BON carcinoid cells. Calcium-mediated hormone release depended on the intracellular calcium concentration and thus on the calcium influx through voltage-gated calcium channels. In addition to inhibiting the cAMP-dependent secretory pathway, somatostatin reduced the calcium inward currents and thereby hormone release. The inhibition of voltage-gated calcium channels by somatostatin was mediated by "signal transducing" Go proteins. Thus, somatostatin's actions on hormone release involve both cAMP and intracellular calcium as second messengers. Patch-clamp experiments of voltage-gated calcium channels allow functional studies on the coupling of somatostatin receptors to cellular effector systems.
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PMID:Molecular mechanisms of somatostatin's inhibition of hormone release: participation of voltage-gated calcium channels and G-proteins. 810 Nov 78

The study of functioning human endocrine tumors has been hampered by a lack of suitable in vitro models. We have established the first permanent cell line of a human pancreatic carcinoid tumor (BON) in culture. BON cells grow in monolayer culture and form colonies in soft agar. Injection of BON cells into nude mice produces transplantable tumors in a dose-dependent fashion. The histology of tumors in athymic mice from injection of dispersed, cultured BON cells is similar to the original histology of the resected tumor. Significant amounts of neurotensin, pancreastatin, and serotonin (5-HT) are demonstrated in the cells by radioimmunoassay (RIA) and the presence of chromogranin A, bombesin, and 5-HT is confirmed by immunocytochemistry. Numerous round and pleomorphic dense-core neurosecretory granules are present on electron microscopy. Functional receptors for acetylcholine, 5-HT, isoproterenol, and somatostatin are present on cultured cells. BON cells possess a specific transport system for uptake of 5-HT from the medium; this uptake system may be a route for regulation of autocrine effects of 5-HT on carcinoid cells. This unique human carcinoid tumor cell line should provide the opportunity for new insight into the biology of carcinoid tumors and of specific intracellular mechanisms for secretagogue action in the release of amines and peptides.
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PMID:Characterization of a human pancreatic carcinoid in vitro: morphology, amine and peptide storage, and secretion. 810 75

The extent of apoptosis identified by in situ DNA nick end labelling (TUNEL) on tissue samples obtained from patients with neuroendocrine tumors was correlated with the clinical outcome in patients treated with high-dose somatostatin analog (lanreotide 12 mg/day), n = 8, or other biotherapy including interferon-alpha (IFN-alpha), n = 4, low-dose somatostatin analog (octreotide or lanreotide), n = 3, or a combination of both, n = 1. Biopsies were obtained before the start of treatment and/or after 6 months and 12 months. After 6 months of treatment, 5 patients receiving high-dose somatostatin analog showed a biochemical response (decrease in different neuroendocrine tumor markers) and 4 of these showed an increase in apoptotic index (AI: percentage of apoptotic cells) by 1.94 +/- 1.71%. At 12 months, AI was also increased in patients with a biochemical response (4.22 +/- 3.93%). However, none showed a decrease in tumor size on computerized tomography (CT) and none of the patients treated with low-dose somatostatin analog or IFN-alpha showed any significant increase in AI during treatment. In an experimental model, nude mice were xenografted with the neuroendocrine cell line (BON-1). From the 2nd day of tumor implantation, they received treatment with either placebo, high-dose octreotide, IFN-alpha, or a combination of both, for 28 days. In mice receiving treatment with high-dose octreotide (300 microg/kg, t.i.d) there was a threefold increase in apoptotic cells as compared to the placebo group (p = 0.0084), while the combination group had few cells with ultra-structural changes indicating apoptosis and the IFN-alpha treated group showed no significant changes. However, tumor growth inhibition was more pronounced in the combination group (p = 0.0011). This probably denotes that tumor growth inhibition could be achieved more efficiently by blocking the cell cycle than by inducing apoptosis. We concluded that treatment with high-dose somatostatin analogs may induce apoptosis in neuroendocrine tumors, while this is not found during treatment with low-dose somatostatin analogs or IFN-alpha. We also found that an increase in AI during high-dose somatostatin analog treatment was correlated with the biochemical response, but not with the tumor size as detected by CT in patients or with the tumor mass in the experimental model.
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PMID:Induction of apoptosis in neuroendocrine tumors of the digestive system during treatment with somatostatin analogs. 940 51

Somatostatin, also known as somatotropin release-inhibiting factor (SRIF), is a natural cyclic peptide inhibitor of pituitary, pancreatic, and gastrointestinal secretion. Its long-acting analogs are in clinical use for treatment of various endocrine syndromes and gastrointestinal anomalies. These analogs are more potent inhibitors of the endocrine release of GH, glucagon, and insulin than the native SRIF; hence, they do not display considerable physiological selectivity. Our goal was to design effective and physiologically selective SRIF analogs with potential therapeutic value. We employed an integrated approach consisting of screening of backbone cyclic peptide libraries constructed on the basis of molecular modeling of known SRIF agonists and of high throughput receptor binding assays with each of the five cloned human SRIF receptors (hsst1-5). By using this approach, we identified a novel, high affinity, enzymatically stable, and long-acting SRIF analog, PTR-3173, which binds with nanomolar affinity to human SRIF receptors hsst2, hsst4, and hsst5. The hsst5 and the rat sst5 (rsst5) forms have the same nanomolar affinity for this analog. In the human carcinoid-derived cell line BON-1, PTR-3173 inhibits forskolin-stimulated cAMP accumulation as efficiently as the drug octreotide, indicating its agonistic effect in this human cell system. In hormone secretion studies with rats, we found that PTR-3173 is 1000-fold and more than 10,000-fold more potent in inhibiting GH release than glucagon and insulin release, respectively. These results suggest that PTR-3173 is the first highly selective somatostatinergic analog for the in vivo inhibition of GH secretion, with minimal or no effect on glucagon and insulin release, respectively.
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PMID:Novel long-acting somatostatin analog with endocrine selectivity: potent suppression of growth hormone but not of insulin. 1114 12

G-protein-coupled receptor 100 (GPR100) was discovered by searching the human genome database for novel G-protein-coupled peptide receptors. Full-length GPR100 was amplified from a cDNA library of the neuroendocrine cell line BON, which is derived from a human pancreas carcinoid. The open-reading frame, present on a single exon, coded for a protein of 374 amino acids with highest sequence identity (43%) to the human orphan somatostatin- and angiotensin-like peptide receptor. The analysis of chromosomal localisation mapped the GPR100 gene to chromosome 1q21.2-q21.3. The stable expression of GPR100 in Chinese hamster ovary cells together with aequorin as calcium sensor and the promiscuous G-protein subunit alpha16 as signal transducer revealed bradykinin and kallidin as effectors to elicit a calcium response. Dose-response curves yielded EC50 values for both ligands in the low nanomolar range, while the respective analogues without arginine at the carboxy-terminus were inactive. Calcium mobilisation was inhibited by the phospholipase C blocker U73122, but not by pertussis toxin, suggesting the involvement of the G-protein subunit alphaq and not alphai or alphao in signal transduction. In line with the main function of kinins as peripheral hormones, we found that GPR100 was expressed predominantly in tissues like pancreas, heart, skeletal muscle, salivary gland, bladder, kidney, liver, placenta, stomach, jejunum, thyroid gland, ovary, and bone marrow, but smaller amounts were also detected in the brain and in cell lines derived from tumours of various origins.
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PMID:Identification and characterisation of GPR100 as a novel human G-protein-coupled bradykinin receptor. 1453 Feb 18

BON cells are human carcinoid cells that secrete serotonin (5-HT) and various peptides. Secretion of [(3)H]5-HT by cell cultures was investigated. Acetylcholine (Ach) stimulated secretion through a somatostatin-sensitive muscarinic pathway, whereas isoproterenol was inefficient. [(3)H]5-HT secretion also was induced by Ca(2+) in the presence of the ionophore A-23187 or after digitonin permeabilization. These two processes were insensitive to stomatostatin. Ba(2+) induced an efficient somatostatin-sensitive [(3)H]5-HT secretory response. Secretion also was analyzed at the single-cell level, using carbon fiber amperometry and evanescent-field fluorescence microscopy, after labeling the secretory vesicles by transfection of the cells with a NPY-GFP construct. Both techniques revealed slow kinetics of secretory responses, suggesting that ready-to-fuse vesicles do not accumulate in these cells. Single secretory vesicles were imaged either in resting conditions or after addition of Ca(2+) ions to digitonin-permeabilized cells. The three-dimensional movements of the vesicles before exocytosis were analyzed. The mean velocity of vesicles that released their content was lower than that of silent ones. Even in the case of mobile vesicles, exocytosis often was preceded by a period of arrest lasting at least 15 seconds, consistent with a docking/priming step.
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PMID:Serotonin secretion by human carcinoid BON cells. 1515 33

Somatostatin is a polypeptide hormone acting as an inhibitor of pituitary, pancreatic, and gastrointestinal secretion through specific membrane receptors of which five subtypes have been cloned (sst(1-5)). Somatostatin analogs are used in the clinic to treat patients with excessive hormone production due to a neuroendocrine tumor. The aim of this study was to investigate the biological activity of three new somatostatin receptor subtype selective analogs (BIM-23926, sst(1)-selective; BIM-23120, sst(2)-selective; and BIM-23206, sst(5)-selective) in the human neuroendocrine tumor cell line, BON-1, which expresses sst(1), sst(2), and sst(5) natively. Somatostatin-14 and octreotide were used as reference substances. Forskolin-induced cAMP accumulation and chromogranin A (CgA) secretion were inhibited by BIM-23120, BIM-23206, and somatostatin-14 in a dose-dependent manner. Cholecystokinin (CCK-8) stimulated activation of mitogen-activated protein (MAP) kinase was inhibited by BIM-23120 and BIM-23206, while BIM-23926 stimulated the activity. Selective BIM analogs showed a more efficient inhibitory effect on cAMP accumulation, CgA secretion, and MAP kinase activity than octreotide in BON-1 cells. This may be explained by the differences in affinity of the ligand to the receptor or by interaction between different sst subtypes. We conclude that increasing knowledge about sst physiology and expression in malignant disease indicates a need for new analogs that can be incorporated into the therapeutic arsenal.
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PMID:Subtype selective interactions of somatostatin and somatostatin analogs with sst1, sst2, and sst5 in BON-1 cells. 1545 57


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