Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P61278 (somatostatin)
 22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Paediatric oncology continues to search for improved methods for the early detection and effective treatment of solid tumours, especially those of the nervous system, which constitute 50% of all solid tumours in children and adolescents. These tumours, including neuroblastoma, meningioma, low-grade astrocytoma and medulloblastoma express somatostatin receptors and can be imaged effectively using 111In-octreotide. In addition to improved imaging techniques, somatostatin analogues are being developed for use in radioreceptor-guided surgery, as a component of adjuvant chemotherapy and for supportive treatment. Radioreceptor-guided surgery utilises 125I-Tyr3-octreotide or 125I-lanreotide to detect tumour foci within minutes of injection. It allows the detection of 0.1-1.0 mg tumour (1 x 10(5) to 1 x 10(6) tumour cells). This technique has successfully located foci of occult tumour in children with neuroblastoma. Somatostatin analogues are also currently being studied as tumour growth inhibitors between regular chemotherapy cycles and for the treatment of chemotherapy-induced pancreatitis in children with leukaemia. Research on somatostatin receptor subtype expression in paediatric tumours suggests that further investigation of analogue effects on growth inhibition and induction of differentiation will contribute to improved therapy for children with solid tumours.
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PMID:Clinical use of somatostatin analogues in paediatric oncology. 881 66

A 4-month-old infant suffering from Stage IVs neuroblastoma (NB IVs; Pepper's syndrome) was repeatedly examined by I-123 MIBG and somatostatin analog in-111 pentetreotide (SMS) scintigraphy, during a 2-year period. Treatment was restricted to surgery of the primary tumor. I-123 MIBG and SMS scan results were positive in the primary tumor and liver, but I-123 MIBG yielded very poor images and failed to reliably detect bone marrow metastases in the lower limbs and skull, whereas SMS precisely visualized these lesions. Six months after diagnosis, the infant was in complete clinical remission. I-123 MIBG and SMS images had returned to normal at 1 year. The prognostic implication of positive SMS imaging, in combination with positive or negative I-123 MIBG scan results, is not known in NB IVs and requires further investigation.
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PMID:Could somatostatin scintigraphy be superior to MIBG scan in the staging of stage IVs neuroblastoma (Pepper's syndrome)? 881 64

Somatostatin possesses antisecretory and antiproliferative activity on some human tumors. We herein report that, in a human neuroblastoma cell line, the somatostatin analogue BIM 23014 inhibited mitogen-activated protein (MAP) kinase activity stimulated by either insulin-like growth factor-1, whose receptor bears a tyrosine kinase, or carbachol, which acts at a G-protein coupled receptor. In a human small cell lung carcinoma line BIM inhibited serum-stimulated MAP kinase activation. These inhibitory actions occur in a dose range quite similar to that observed for suppression of proliferation induced by the analogue in the same cell lines. The decrease in cAMP elicited by the analogue in the two cell lines is not responsible for its inhibitory action on MAP kinase and cell growth. Moreover, the analogue did not modify intracellular [Ca2+] and pH. An involvement of a phosphatase activity is suggested.
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PMID:A somatostatin analogue inhibits MAP kinase activation and cell proliferation in human neuroblastoma and in human small cell lung carcinoma cell lines. 895 39

The international workshop on metaiodobenzylguanidine (MIBG) and radiolabeled somatostatin analogs held in Rome in June, 1994 addressed a wide range of topics which might be classified into five broad general themes: Theme 1. The role of MIBG for the location of neuroendocrine tumors. A) The range of tumors in which MIBG scintigraphy is effective (pheochromocytomas, neuroblastoma, chemodectoma and other APUDomas). B) The increasing popularity of 123I as a radiolabel for MIBG (potential advantages in planar and SPECT imaging). C) MIBG as the prototype of a family of radiopharmaceuticals exploiting the biogenic amine uptake and storage mechanisms. (Other radiohalides 124I, 125I, 87Br, 211At, 18F; other PET radiopharmaceuticals such as 11C-epinephrine, 11C-hydroxyephedrine). Theme 2. The role of MIBG as an in vivo scintigraphic probe of the sympathetic nervous system. A) Cardiac sympathetic innervation (in cardiomyopathy, myocardial infarction, and as a prognostic index for cardiac transplantation). B) Pulmonary MIBG uptake as index of pulmonary endothelial/sympathetic function (MIBG by both the intravenous and inhaled routes of administration). Theme 3. MIBG for the radiopharmaceutical therapy of neuroendocrine tumors. A) Treatment of neuroblastoma early in the natural history of the disease (MIBG therapy as initial management, MIBG therapy combined with other modalities--e.g., chemotherapy and bone marrow transplantation). Theme 4. The role of radiolabeled somatostatin analogs for the location of neuroendocrine and other tumors. A) The range of tumors in which somatostatin receptor radiopharmaceutical scintigraphy is effective (pituitary tumors, central nervous system tumors, carcinoids, islet cell tumors, medullary thyroid carcinoma, small cell lung cancer, APUDomas). B) The superiority of 111In over 123I as a radiolabel (the future of potential 99mTc and other labels). C) Somatostatin receptor scintigraphy in autoimmune and other disorders. D) Pentetreotide as the prototype of a wide range of radiolabeled peptides as radiopharmaceuticals for the in vivo depiction of the receptors for peptide hormones, lymphokines, paracrine and other information transmitting molecules (the general concepts include the use of long-acting, slowly degraded analogs and the development of generally applicable labeling techniques. Examples include 123I-ANF, labeled interleukins and other lymphokines). Theme 5. Comparisons of MIBG and pentetreotide scintigraphy for the location of neuroendocrine tumors. A) The range of neuroendocrine and other tumors (e.g., pheochromocytomas, neuroblastomas, carcinoids, islet cell tumors and other APUDomas).
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PMID:Ten years of experience with MIBG applications and the potential of new radiolabeled peptides: a personal overview and concluding remarks. 900 76

Five distinct human somatostatin receptor subtypes have recently been cloned and characterized. Previous studies have suggested that these receptor subtypes might display coexistent localization, based on in situ hybridization or immunoblockage experiments. Here we provide evidence for coexistence of somatostatin receptor subtypes 2 and 5 in the human neuroblastoma cell line LA-N-2, using a combined approach with RT-PCR and receptor binding studies with somatostatin analogues. Somatostatin receptor subtypes simultaneously localized to a single cell might serve distinct functions in terms of targeting to different intraneuronal compartments or subtype specificity against so far unidentified somatostatin-related peptides.
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PMID:Coexistence of somatostatin receptor subtypes in the human neuroblastoma cell line LA-N-2. 900 11

Neural-crest tumours, including neuroblastomas, express somatostatin receptors. This can be shown by radionuclide labelling of octreotide, a somatostatin analogue. Studies on imaging with this substance have dealt with childhood neuroblastomas. Olfactory neuroblastoma (aesthesioneuroblastoma) is a rare tumour in which somatostatin receptor content has not been analysed, nor have radionuclide methods for diagnostic purposes been described. We report a case of olfactory neuroblastoma, in which scanning with 111In-labelled octreotide was performed. A strong uptake was seen at the base of the skull. This was confirmed as a recurrent tumour by magnetic resonance (MR) imaging. Uptake was also observed in the neck and chest, indicating extensive spread of the disease. Somatostatin receptor expression has been shown to correlate with prognosis in childhood neuroblastoma. The accuracy of labelled octreotide in the diagnosis of olfactory neuroblastoma indicates that it might be useful in radionuclide therapy of patients with advanced disease, when no other treatment modalities are available.
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PMID:Somatostatin receptor imaging of olfactory neuroblastoma. 901 33

1. In this study we have investigated neuropeptide Y (NPY) and somatostatin (SRIF) receptor-mediated elevation of intracellular Ca2+ concentration ([Ca2+]i) in the human neuroblastoma cell line SH-SY5Y. 2. The Ca(2+)-sensitive dye fura 2 was used to measure [Ca2+]i in confluent monolayers of SH-SY5Y cells. Neither NPY (30-100 nM) nor SRIF (100 nM) elevated [Ca2+]i when applied alone. However, when either NPY (300 pM-1 microM) or SRIF (300 pM-1 microM) was applied in the presence of the cholinoceptor agonist carbachol (1 microM or 100 microM) they evoked an elevation of [Ca2+]i above that caused by carbachol alone. 3. The elevation of [Ca2+]i by NPY was independent of the concentration of carbachol. In the presence of 1 microM or 100 microM carbachol NPY elevated [Ca2+]i with a pEC50 of 7.80 and 7.86 respectively. 4. In the presence of 1 microM carbachol the NPY Y2 selective agonist peptide YY(3-36) (PYY(3-36)) elevated [Ca2+]i with a pEC50 of 7.94, the NPY Y1 selective agonist [Leu31, Pro34]-NPY also elevated [Ca2+]i when applied in the presence of carbachol, but only at concentrations > 300 nM. The rank order of potency, PYY(3-36) > or = NPY > > [Leu31, Pro34]-NPY indicates that an NPY Y2-like receptor is involved in the elevation of [Ca2+]i. 5. In the presence of 1 microM carbachol, SRIF elevated [Ca2+]i with a pEC50 of 8.24. The sst2 receptor-preferring analogue BIM-23027 (c[N-Me-Ala-Tyr-D-Trp-Lys-Abu-Phe]) elevated [Ca2+]i with a pEC50 of 8.63, and the sst5-receptor preferring analogue L-362855 (c[Aha-Phe-Trp-D-Trp-Lys-Thr-Phe]) elevated [Ca2+]i with a pEC50 of approximately 6.1. Application of the sst3 receptor-preferring analogue BIM-23056 (D-Phe-Phe-Tyr-D-Trp-Lys-Val-Phe-D-Nal-NH2, 1 microM) to SH-SY5Y cells in the presence of carbachol neither elevated [Ca2+]i nor affected the elevations of [Ca2+]i caused by a subsequent coapplication of SRIF. The rank order of potency, BIM-23026 > or = SRIF > > L-362855 > > > BIM-23026 suggests that an sst2-like receptor is involved in the elevation of [Ca2+]i. 6. Block of carbachol activation of muscarinic receptors with atropine (1 microM) abolished the elevation of [Ca2+]i by the SRIF and NPY. 7. Muscarinic receptor activation, not a rise in [Ca2+]i, was required to reveal the NPY or SRIF response. The Ca2+ channel activator maitotoxin (2 ng ml-1) also elevated [Ca2+]i but subsequent application of either NPY or SRIF in the presence of maitotoxin caused no further changes in [Ca2+]i. 8. The elevations of [Ca2+]i by NPY and SRIF were abolished by pretreatment of the cells with pertussis toxin (200 ng-ml-1, 16 h). This treatment did not significantly affect the response of the cells to carbachol. 9. NPY and SRIF appeared to elevate [Ca2+]i by mobilizing Ca2+ from intracellular stores. Both NPY and SRIF continued to elevate [Ca2+]i when applied in nominally Ca(2+)-free external buffer. Thapsigargin (100 nM), an agent which discharges intracellular Ca2+ stores, also blocked the NPY and SRIF elevations of [Ca2+]i. 10. Delta-Opioid receptor agonists applied in the presence of carbachol also elevate [Ca2+]i in SH-SY5Y cells. When NPY (30 nM) or SRIF (100 nM) was applied together with a maximally effective concentration of the delta-opioid receptor agonist DPDPE ([D-Pen2,5]-enkephalin) (1 microM), the resulting elevations of [Ca2+]i were not greater than those caused by application of DPDPE alone. 11. Thus, in SH-SY5Y cells, NPY and SRIF can mobilize Ca2+ from intracellular stores via activation of NPY Y2 and sst2-like receptors, respectively. Neither NPY nor SRIF elevated [Ca2+]i when applied alone. The requirements for the elevations of [Ca2+]i by NPY and SRIF are the same as those for delta- and mu-opioid receptor and nociceptin receptor mobilization of [Ca2+]i in SH-SY5Y cells.
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PMID:Neuropeptide Y Y2 receptor and somatostatin sst2 receptor coupling to mobilization of intracellular calcium in SH-SY5Y human neuroblastoma cells. 903 49

Neuroblastoma is a pediatric cancer for which a cure is elusive for most children with disseminated disease. Neuroblastomas possess receptors for somatostatin (SS). Some SS analogues can inhibit their proliferation. In addition, when SS analogues were used as agents for scintigraphy, neuroblastoma tumor sites can be localized with high efficiency. In this study, to better characterize the SS receptor subtype(s) (sst1-5) present in primary tumors and metastases of neuroblastoma, we show that: (1) The ligand 125I-Tyr11-SS-14 binding on membrane proteins from primary tumors and metastases of neuroblastoma cell line IGR-N-91 developed in nude mice shows similar values of Kd (in order of 0.1 nM) and Bmax (in order of fmol/mg) by filter-retention assay. These data are close to those measured on two other neuroblastoma cell lines: SK-N-SH and IGR-N-835 or to that measured on the rat cerebral cortex. (2) The IGR-N-91 sublines derived from primary tumor and metastases show one major complex of 57 kD by the chemical cross-linking assay using the ligands: 125I-SS-14 and 125I-BIM23014. One similar major complex of 57 kD was also detected in SK-N-SH and IGR-N-835 or in the cerebral cortex. (3) Addition of excess nonlabeled peptides selective for sst2 (BIM23014, BIM23060, BIM23068) suppressed the formation of the complex 57 kD whereas addition of BIM23052 or BIM23056 (sst5 and sst3 selective respectively) does not. This pharmacological profile corresponds to sst2. (4) Only RNA message of sst2 gene is detected in IGR-N-91 cells and its metastases derived sublines by reverse-transcription-polymerase chain reaction and Northern hybridization in keeping with the presence of sst2. (5) In human biopsies, the complex of 57 kD corresponding to sst2 is consistently detected in three samples of the histological subset of the disease: benign ganglioneuroma, ganglioneuroblastoma and immature neuroblastoma. Therefore, the sst2 should be considered as the primary target to develop more potent SS analogues for neuroblastoma therapy or/and scintigraphy.
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PMID:Somatostatin-14 mainly binds the somatostatin receptor subtype 2 in human neuroblastoma tumors. 905 84

1. We have used somatostatin (SRIF) receptor subtype-selective ligands to determine some of the operational characteristics of somatostatin receptors in Neuro2A mouse neuroblastoma cells. The potent SRIF1-receptor selective ligand, BIM-23027, was able to displace completely the specific binding of radioiodinated somatostatin, [125I]-Tyr11-SRIF-14, with a pIC50 of 10.3, suggesting that Neuro2A cells contain predominantly receptors of the SRIF1 receptor group. The rank order of affinities for several somatostatin analogues tested in competition studies, together with the high affinity of BIM-23027, indicate that the majority of receptors in Neuro2A cells are of the sst2 subtype. 2. The stable radioligand, [125I]-BIM-23027, bound with high affinity (Kd = 13 pM, Bmax = 0.2 pmol mg-1 protein) to Neuro2A cell membranes, but its binding was only partially reversible at room temperature and below. Thus at 4 degrees C, only 36% of the bound ligand dissociated within 2 h. In contrast, 60% of the ligand dissociated at 15 degrees C and 89% of the ligand dissociated at 37 degrees C. 3. Equilibrium binding of [125I]-BIM-23027 was partially (25%) inhibited by 10 microM GTP, and by 120 mM NaCl (42% inhibition) but this inhibition was increased to 75% when sodium chloride and GTP were added together. This effect of GTP and sodium chloride was also seen in dissociation experiments. After incubation to equilibrium with [125I]-BIM-23027, dissociation was initiated with excess unlabelled ligand in the presence of GTP (10 microM) and sodium chloride (120 mM). Under these conditions 67% of the ligand dissociated at 4 degrees C, 81% at 15 degrees C and 93% at 37 degrees C. Binding was totally inhibited by pretreatment of cells with pertussis toxin. 4. Functionally, BIM-23027 inhibited forskolin-stimulated cyclic AMP accumulation in a concentration-dependent manner with an IC50 of 1.0 nM and a maximal inhibition of 37%. This effect was abolished by pretreatment of the cells with pertussis toxin. However, unlike in studies reported with the recombinant sst2 receptor, no rise in intracellular calcium concentration was observed with SRIF-14. 5. We conclude that Neuro2A cells provide a stable neuronal cell line for the study of functionally coupled endogenous somatostatin receptors of the sst2 type. In addition, we have found that activation of the receptor is associated with ligand-receptor internalisation.
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PMID:Somatostatin receptors in Neuro2A neuroblastoma cells: operational characteristics. 911 97

Neuroblastoma, a childhood tumour of the sympathetic nervous system, may in some cases differentiate to a benign ganglioneuroma or regress due to apoptosis. Somatostatin may inhibit neuroblastoma growth and induce apoptosis in vitro and was therefore investigated. Using a radioimmunoassay, we found that all ganglioneuromas contained high somatostatin concentrations (> 16 pmol/g), significantly higher than neuroblastomas (n = 117, median 2.8 pmol/g), healthy adrenals, Wilms' tumours, phaeochromocytomas and other neuroendocrine tumours (P < 0.001). Neuroblastomas contained more somatostatin than control tumours (P < 0.001-0.05). Neuroblastomas amplified for the MYCN oncogene contained less somatostatin than non-amplified tumours (1.2 pmol/g versus 4.0 pmol/g, respectively; P = 0.026). In a clinically unfavourable neuroblastoma subset (age > 12 months, stage 3 or 4) 16 children with high concentrations of somatostatin in primary tumours had a better prognosis than 23 with low somatostatin (46.7% versus 0% survival at 5 years, P < 0.005). Scintigraphy using 111In-pentetreotide identified tumours expressing high-affinity somatostatin receptors in vivo. However, no significant correlation was found between somatostatin receptor expression and peptide content in 15 tumours. Similarly, human SH-SY5Y neuroblastoma xenografts grown in nude rats showed low somatostatin concentrations, but were positive for somatostatin receptor scintigraphy. Treatment of these rats with the somatostatin analogue octreotide seemed to upregulate in vivo receptor expression of somatostatin and vasoactive intestinal peptide more effectively than 13-cis retinoic acid. In conclusion, somatostatin in neuroblastoma is associated with differentiation to benign ganglioneuromas in vivo and favourable outcome in advanced tumours. Furthermore, somatostatin receptor scintigraphy may identify tumours with high-affinity receptors in children that might benefit from targeted therapy using synthetic somatostatin analogues.
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PMID:Somatostatin in neuroblastoma and ganglioneuroma. 951 58


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