UNIPROT:P61278 - FACTA Search

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

Primary lymphoma of the central nervous system, until recently representing about 1% of all brain tumours, shows a dramatically increased incidence in the general population as well as in high-risk groups (immunocompromised, AIDS), and may rise up to 6% in a population of AIDS patients. The clinical presentation is variable and cannot reliably be distinguished from other intracerebral tumours. At present, CT and MRI are the methods of choice for diagnosing cerebral lymphomas. However, their characteristics are not specific. The radiological picture may suggest glioma, meningioma, metastatic carcinoma or even a cerebrovascular accident. A labelled somatostatin analogue (pentetreotide) has been proposed as a new tracer for the imaging of somatostatin receptors, which have been identified by immunocytochemical or radioimmunoassay techniques in several organ systems. Somatostatin receptors were also identified in surgical biopsy samples from patients with Hodgkin and non-Hodgkin lymphoma and extracerebral lymphoma has already been visualised in vivo by means of In-111-labelled pentetreotide. While CT images of the brain showed a regression of the tumour after radiotherapeutic treatment, the scintigraphic images showed persistence of the tumoural tissue, corresponding with the clinical evolution and outcome. Furthermore, the absence of extra-cerebral lymphoma tissue, seen on the whole body images, was confirmed by post-mortem examination. To our knowledge, this is the first report of a primary intracerebral lymphoma visualised by means In-111-pentetreotide.
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PMID:Primary cerebral lymphoma visualised by means of In-111-pentetreotide scintigraphy. 992 25

Human gliomas, especially of low-grade type, have been shown to express high-affinity somatostatin receptor type 2 (J-C. Reubi et al., Am. J. Pathol, 134: 337-344, 1989). We enrolled seven low-grade and four anaplastic glioma patients in a pilot study using the diffusible peptidic vector 90Y-labeled DOTA0-D-Phe1-Tyr3-octreotide (DOTATOC) for receptor targeting. The radiopharmakon was locoregionally injected into a stereotactically inserted Port-a-cath. DOTATOC competes specifically with somatostatin binding to somatostatin receptor type 2 in the low nanomolar range as shown by a displacement curve of 125I-[Tyr3]-octreotide in tumor tissue sections. Diagnostic (111)In-labeled DOTATOC-scintigraphy following local injection displayed homogeneous to nodular intratumoral vector distribution. The cumulative activity of regionally injected peptide-bound 90Y amounted to 370-3300 MBq, which is equivalent to an effective dose range between 60 +/- 15 and 550 +/- 110 Gy. Activity was injected in one to four fractions according to tumor volumes; 1110 MBq of 90Y-labeled DOTATOC was the maximum activity per single injection. We obtained six disease stabilizations and shrinking of a cystic low-grade astrocytoma component. The only toxicity observed was secondary perifocal edema. The activity:dose ratio (MBq:Gy) represents a measure for the stability of peptide retention in receptor-positive tissue and might predict the clinical course. We conclude that SR-positive human gliomas, especially of low-grade type, can be successfully targeted by intratumoral injection of the metabolically stable small regulatory peptide DOTATOC.
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PMID:Locoregional regulatory peptide receptor targeting with the diffusible somatostatin analogue 90Y-labeled DOTA0-D-Phe1-Tyr3-octreotide (DOTATOC): a pilot study in human gliomas. 1035 35

True gigantism is rare in early childhood and is usually due to excess GH secretion from a pituitary adenoma. We report a case in which the endocrine abnormality is secondary to an optic glioma. Careful endocrine evaluation has shown that GH peak amplitude was not increased but rather there was failure of GH levels to suppress to baseline and a lack of pulsatility. There is no evidence of a direct secretory role for the tumour and we postulate that the tumour is affecting GH secretion through an effect on somatostatin tone. Specific tumour therapy is not indicated for this patient in the absence of mass effect or visual disturbance. The GH excess is being treated with somatostatin analogue (Octreotide) and as he has developed precocious puberty he is also receiving long acting GnRH analogue (Zoladex). This boy appears likely to have neurofibromatosis type 1 (NF1) which raises the question of subtle GH excess in NF1 patients with tall stature.
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PMID:Gigantism due to growth hormone excess in a boy with optic glioma. 1101 81

Gliomas differ from non-malignant glial cells in the overexpression or mutations of genes involved in cell cycle or growth regulation. One example is the overexpression of the somatostatin receptor subtype 2 (sst2), especially of the splice variant sst2A. The reasons for this overexpression are not known. However, the coding sequence and part of the promoter region is not mutated. In accordance to this, the sst2 is functionally active and is internalised upon agonist stimulation. Immunoelectronmicroscopic studies show that the activated sst2 is internalised via caveolin-positive endosomal vesicles and later accumulates in multivesicular bodies and lysosomal compartments. The activated sst2 is found to be co-localised with the inhibitory G-protein Gialpha at the plasma membrane and in early endosomal vesicles. Multiple signal transduction pathways are induced. Stimulation of sst2 lowers cAMP levels elicited by forskolin and activates the protein tyrosine phosphatase SHP-2. In contrast to other sst2-expressing cells a long term antiproliferative effect of somatostatin or sst2-selective agonists are not detected in cultivated glioma cells. However, continuous stimulation of sst2 decreases the expression of genes promoting tumour survival.
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PMID:Somatostatin receptors in gliomas. 1108 2

The somatostatin receptor subtype sst2A is highly expressed, non-mutated and functionally active in gliomas. After stimulation of cultivated human U343 glioma cells with somatostatin, octreotide (sst2-, sst3- and sst5-selective peptide agonist) or the sst2-selective non-peptide agonist L-054,522 multiple signal transduction pathways are induced: elevated cAMP levels are reduced, protein tyrosine phosphatases (especially SHP2) are activated and mitogen-activated protein kinases are inhibited. Stimulation of the phosphatases resulted in dephosphorylation of activated receptors for EGF and PDGF (epidermal and platelet-derived growth factor), and as a consequence the mitogen-activated protein kinases ERK 1 and 2 (p42/p44) were de-phosphorylated in co-stimulation experiments. Furthermore, somatostatin or sst2-selective agonists reduced EGF-stimulated expression of the AP-1 complex (c-jun/c-jun) on the transcriptional and translational level. These experiments show that the interaction of stimulatory and inhibitory receptors are important mechanisms for the regulation of signal cascades and gene expression.
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PMID:Influence of the somatostatin receptor sst2 on growth factor signal cascades in human glioma cells. 1122 55

In various cell types, the neuro- and endocrine peptide somatostatin induces inhibitory and anti-secretory effects. Since somatostatin receptors, especially of the subtype sst2A, are constantly over-expressed in gliomas, we investigated the influence of somatostatin and the receptor subtype-selective peptide/non-peptide agonists octreotide and L-054,522 on the secretion of the most important angiogenesis factor produced by gliomas, vascular endothelial growth factor (VEGF). Cultivated cells from solid human gliomas of different stages and glioma cell lines secreted variable amounts of VEGF, which could be lowered to 25% to 80% by co-incubation with somatostatin or sst2-selective agonists (octreotide and L-054,522). These effects were dose-dependent at nanomolar concentrations. Stimulation with different growth factors (EGF, bFGF) or hypoxia considerably increased VEGF production over basal levels. Growth factor-induced VEGF synthesis could be suppressed to <50% by co-incubation with somatostatin or an sst2-selective agonist; this was less pronounced in hypoxia-induced VEGF synthesis. The effects were detected at the protein and mRNA levels. These experiments indicate a potent anti-secretory action of somatostatin or sst2 agonists on human glioma cells that may be useful for inhibiting angiogenesis in these tumors.
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PMID:Somatostatin inhibits the production of vascular endothelial growth factor in human glioma cells. 1130 89

The expression of the five somatostatin receptor subtypes, sst1-5 was compared on tissue containing glial tumours (glioblastomas or oligodendrogliomas), medulloblastomas, and on normal human cortex. By semiquantitative reverse transcription coupled to polymerase chain reaction, the receptor expression profiles were high in cortex and in tissue containing oligodendrogliomas. It was moderate in medulloblastomas. Tissue containing glioblastomas displayed lower expression of somatostatin receptor subtypes, sst1 and sst3 being mostly expressed. By 125I-Tyr0DTrp8 somatostatin-14 or 125I-Leu8DTrp22 Tyr25 somatostatin-28 autoradiography combined with synaptophysin immunohistochemistry, it was possible to differentiate between isolated tumoral cell component infiltrating the cerebral parenchyma (cortex or white matter) and tumoral tissue (without residual parenchyma) in glioblastomas or oligodendrogliomas. Glial tumoral tissue per se presented few somatostatin receptors. By contrast, medulloblastoma tumoral cells exhibited numerous octreotide sensitive somatostatin receptors. sst2 immunocytochemistry demonstrated immunostaining of neuronal cells and neuropile; sst2 and sst3 immunostaining was identified on glioblastoma proliferating vessels endothelial cells and on medulloblastomas tumoral cells. Faint sst2 immunostaining among glial tumoral cells was due to microglia, while glioma cells did not significantly stain. In summary, medulloblastoma tumoral cells express sst2/sst3 receptors at a high level while glioma cells do not. In gliomas, sst expression is restricted to endothelial cells on proliferating vessels (displaying both sst2 and sst3 receptors), including parenchyma and reactive microglia (only sst2). The differential expression of sst2/sst3 receptors on gliomas and medulloblastomas has implications for the therapy of these tumours.
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PMID:Comparison of somatostatin receptor expression in human gliomas and medulloblastomas. 1204 21

Nuclear medicine is engaged with the detection of pathological processes with the help of radionuclides. An interesting approach is to target antigens, symporters, or receptors with diagnostic and therapeutic radionuclides. Different peptide receptors like somatostatin, bombesin/GRP or VIP are (over)expressed on cancer cells, and are therefore an ideal target for the diagnosis and therapy in nuclear medicine with radiolabeled peptides. The somatostatin analogue OctreoScan [octreotide coupled with diethylene-triamine-pentaacetate (DTPA)] can be labeled with In-111 and is widely used in nuclear oncology for the staging of different tumors (e.g., carcinoids). Other peptides like neurotensin, bombesin/GRP, and VIP are under (pre)clinical investigations. The staging of metastatic medullary thyroid cancer (MTC) with the conventional radiological procedures is sometimes difficult. The high sensitivity of the pentagastrin stimulation test in detecting primary or metastatic MTC indicates the presence of tumor, but its localization is often not possible. This reaction of the tumor cells to the pentagastrin stimulation test suggests a widespread expression of the corresponding receptor type on human MTC. Indeed, autoradiographic studies demonstrated cholecystokinin (CCK)-B/gastrin receptors not only in over 90% of MTCs, but in a high percentage of small cell lung cancers, stromal ovarian, and potentially a variety of other tumors, including gastrointestinal adenocarcinomas, neuroendocrine tumors, and malignant glioma. The aim of our recent work was to develop and systematically optimize suitable radioligands for targeting CCK-B receptors in vivo and to investigate their role in the staging and therapy of MTC and other CCK-B receptor expressing malignancies. For this purpose, a variety of CCK/gastrin-related peptides, all having in common the C-terminal CCK receptor binding tetrapeptide sequence -Trp-Met-Asp-PheNH(2) or derivatives thereof, were investigated. They were members of the gastrin- or cholecystokinin families, or possessed characteristics of both, which differ by the intramolecular position of a tyrosyl moiety. Their stability and affinity were studied and optimized in vitro and in vivo; their biodistribution and therapeutic efficacy were tested in preclinical models. Best tumor uptake and tumor-to-nontumor ratios were obtained with members of the gastrin family, due to their superior selectivity and affinity for the CCK-B receptor subtype. Radiometal-labeled derivatives of minigastrin showed excellent targeting of CCK-B receptor expressing tissues in animals and healthy human volunteers. Preclinical therapy experiments in MTC-bearing animals showed significant antitumor efficacy. In a subsequent clinical study, 75 MTC patients with metastatic MTC were investigated; 43 suffered of known, 32 of occult disease. CCK-B receptor scintigraphy was performed with (111)In-DTPA-D-Glu(1)-minigastrin. The normal organ uptake was essentially confined to the stomach (and to a lower extent, to the gallbladder and, in premenopausal women, to normal breast tissue) as a result of CCK-B receptor specific binding, and to the kidneys as excretory organs. All tumor manifestations known from conventional imaging were visualized as early as 1 h p.i., with increasing tumor-to-background ratios over time; at least one lesion was detected in 29/32 patients with occult disease (patient-based sensitivity 91%). Among them were local recurrences, lymph node, pulmonary, hepatic, splenic, and bone (marrow) metastases. Eight patients with advanced metastatic disease were injected in a dose-escalation study with potentially therapeutic activities of a (90)Y-labeled minigastrin derivative at 4-6-weekly intervals (30-50 mCi/m(2) per injection for a maximum of four injections). Hematologic and renal were identified as the dose-limiting toxicities at the 40 and 50 mCi/m(2) levels. Two patients experienced partial remissions, 4 stabilization of their previously rapidly progressing disease. These data suggest that CCK-B receptor ligands may be a useful new class of receptor binding peptides for diagnosis and therapy of a variety of (CCK-B receptor expressing) tumor types. They allow for a sensitive and reliable staging of patients with metastatic MTC. Initial therapeutic results are promising, but nephrotoxicity is a major concern to be solved.
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PMID:Cholecystokinin-B (CCK-B)/gastrin receptor targeting peptides for staging and therapy of medullary thyroid cancer and other CCK-B receptor expressing malignancies. 1265 27

Patients suffering from malignant glioma have a very poor prognosis. New therapy approaches for gliomas are necessary; these tumors are attractive targets for gene therapy. Our research concentrated on evaluation of the use of the Herpes Simplex Virus-thymidine kinase (tk) enzyme and the somatostatin receptor subtype 2 (sst2). DOTA-Tyr3-octreotate is an analog of somatostatin with high affinity for sst2. It shows rapid internalization in sst2-positive tumor cells in vitro and in vivo. For gene therapy, we used the adenoviral vector Ad5.tk.sstr, which carries the tk gene and the sst2 gene. The aim of our study was to compare uptake of the tk substrate 1-(2-fluoro-2-deoxy-beta-D-ribofuranosyl)-5-[*I]iodouracil (FIRU) labeled with 125I and the somatostatin analog 111In-DOTA-Tyr3-octreotate in several glioma cell lines after infection with Ad5.tk.sstr. Uptake of 125I-FIRU was measured in rat 9L-tk glioma cells without infection with Ad5.tk.sstr. Results showed that the uptake of 125I-FIRU was concentration and time dependent. We also used several rat and human glioma cell lines for infection with Ad5.tk.sstr. Forty-eight hours after infection, uptake studies were performed using 125I-FIRU and 111In-DOTA-Tyr3-octreotate. In all cell lines, the uptake of 125I-FIRU and 111In-DOTA-Tyr3-octreotate increased with increasing multiplicity of infection of virus and showed that the uptake of 111In-DOTA-Tyr3-octreotate was higher than that of 125I-FIRU in all cell lines. We conclude that the sst2 imaging and therapy modality is most promising for glioma gene therapy, either alone or in combination with HSV-tk suicide gene therapy. Therapy can be performed using combinations of DOTA-Tyr3-octreotate radiolabeled with 177Lu or 90Y, 131I-FIRU and/or the prodrug ganciclovir.
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PMID:Molecular imaging and treatment of malignant gliomas following adenoviral transfer of the herpes simplex virus-thymidine kinase gene and the somatostatin receptor subtype 2 gene. 1506 19

Here we characterize the intracellular effectors of the antiproliferative activity of somatostatin in glioma cell lines and post-surgical specimens. The responsiveness to somatostatin correlated with the expression of the phosphotyrosine phosphatase DEP-1/PTPeta, identified in C6 and U87MG cells, in which somatostatin inhibited cell growth. The expression of a dominant negative mutant of DEP-1/PTPeta in C6 cells abolished somatostatin effects, confirming the involvement of this phosphotyrosine phosphatase in such effects. Somatostatin treatment increased the activity of DEP-1/PTPeta and inhibited ERK1/2 activation. Conversely, basic fibroblast growth factor-dependent MEK phosphorylation was not affected, suggesting a direct effect on ERK1/2. In vitro experiments showed that PTPeta was able to interact and dephosphorylate ERK1/2 activated by basic fibroblast growth factor. Furthermore, by transfecting PTPeta in the somatostatin-unresponsive, DEP-1/PTPeta-deficient U373MG cells, the somatostatin-dependent control of cell proliferation was recovered. Finally we evaluated the requirement for DEP-1/PTPeta in somatostatin inhibition of cell proliferation in post-surgical specimens derived from different grade human gliomas. Although all of the glioma analyzed expressed somatostatin receptor mRNA, DEP-1/PTPeta expression was limited to 8 of 22 of the tumors. Culturing seven gliomas, a correlation between the expression of DEP-1/PTPeta and the somatostatin antiproliferative effects was identified. In conclusion we propose that the expression and activation of DEP-1/PTPeta is required for somatostatin inhibition of glioma proliferation.
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PMID:The expression of the phosphotyrosine phosphatase DEP-1/PTPeta dictates the responsivity of glioma cells to somatostatin inhibition of cell proliferation. 1512 17

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