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)

Radiolabelled tumour receptor-binding peptides can be used for in vivo scintigraphic imaging. Recently, the somatostatin analogue [Tyr3]octreotide (D-Phe-c(Cys-Tyr-D-Trp-Lys-Thr-Cys)-Thr(ol)) was derivatized with the chelator DOTA (tetra-azacyclododecane-tetra-acetic acid), enabling stable radiolabelling with both the high-energy beta particle-emitter yttrium-90 and the Auger electron-emitter indium-111. The thus produced radiolabelled compounds are promising for peptide receptor radionuclide therapy. Our previous in vitro and in vivo (rat) experiments with these radiolabelled compounds showed favourable binding and biodistribution characteristics with high uptake and retention in the target organs. We also demonstrated receptor-specific, time- and temperature-dependent internalization of radiolabelled [DOTA0,Tyr3]octreotide in somatostatin receptor subtype 2 (sst2)-positive rat pancreatic tumour cell lines. In this study we have investigated the effects of differences in the amount of injected peptide on tissue distribution of 111In-labelled [DOTA0, Tyr3]octreotide in normal, i.e. non-tumour-bearing, and CA20948 tumour-bearing rats. This was done in order to find the amount of peptide at which the highest uptake in target tissues is achieved, and thereby to increase the potential of radionuclide therapy while simultaneously ensuring the lowest possible radiotoxicity in normal organs. Uptake of radiolabelled [DOTA0,Tyr3]octreotide in sst2-positive organs showed different bell-shaped functions of the amount of injected peptide, being highest at 0.05 (adrenals), 0.05-0. 1 (pituitary and stomach) and 0.25 (pancreas) microg. Uptake in the tumour was highest at 0.5 microg injected peptide. The highest uptake was found at peptide amounts that were lower than those reported for [111In-DTPA0]octreotide ((D-Phe-c(Cys-Phe-D-Trp-Lys-Thr-Cys)-Thr(ol), DTPA = diethylene-triamine-penta-acetic acid), consistent with the higher receptor affinity of the first compound. Our observations of mass-dependent differences in uptake of radiolabelled [DOTA0, Tyr3]octreotide, being the resultant of a positive effect of increasing amounts of peptide on, for example, receptor clustering and a negative effect of receptor saturation, are of consequence for rat radionuclide therapy studies with radiolabelled peptides and may also be of consequence for human radionuclide therapy studies with this compound.
 ...
PMID:Tumour uptake of the radiolabelled somatostatin analogue [DOTA0, TYR3]octreotide is dependent on the peptide amount. 1039 16

Hepatocellular carcinoma is responsible in France for approximately 5,500 deaths per year. Incidence rates are growing and the general status of patients is improving mainly because of earlier diagnosis and improvement in the treatment of complications of liver cirrhosis. In most of the cases the severity of the underlying liver disease is the prominent prognostic factor. Its treatment remains a difficult challenge for oncologists. Unfortunately surgery is usually contraindicated. Most trials of systemic chemotherapy are disappointing with poor response rates and severe side effects; new drugs and direct delivery in the hepatic artery appear to be of interest. Results with interferon are interesting but requires more studies. The lack of efficacy of antiandrogenic and antiestrogenic treatments were recently demonstrated; a recent randomized study showing the interest of somatostatin requires confirmation. Reports on radiotherapy are anecdotals. A lot of studies using liver directed therapies were conducted worldwide. Percutaneous ethanol injections (PEI) are well tolerated and are highly effective in small solitary tumors (> 70% of complete necrosis) but less in larger tumors; recurrences are frequent. No randomized trial have been performed concerning PEI but survival rates seem similar to those of surgery. A randomized controlled trial recently demonstrates that injection of acetic acid is more effective than injection of ethanol. Chemoembolization was extensively studied because of the demonstration of objective responses but all trials failed to demonstrate an improvement in survival. Intraarterial injection of radioactive Lipiodol achieves the same response rate and the same survival than chemoembolization but is significantly best tolerated. This treatment is superior to best supportive cares in patients with portal vein thrombosis. In conclusion, despite the fact that this disease is very frequent we have currently too many treatment options and are lacking of simple rules. The best treatment remains prevention, and the efficacy of hepatitis B vaccination was recently demonstrated in Taiwan.
 ...
PMID:[Nonsurgical treatment of hepatocellular carcinoma]. 1041 27

CCK exhibits a potent cytoprotective activity against acute gastric lesions, but its role in ulcer healing has been little examined. In this study we determined whether exogenous CCK or endogenously released CCK by camostate, an inhibitor of luminal proteases, or by the diversion of pancreatico-biliary secretion from the duodenum, could affect ulcer healing. In addition, the effects of antagonism of CCK-A receptors (by loxiglumide, LOX) or CCK-B receptors (by L-365,260), an inhibition of NO-synthase by N(G)-nitro-L-arginine (L-NNA), or sensory denervation by large neurotoxic dose of capsaicin on CCK-induced ulcer healing were examined. Gastric ulcers were produced by serosal application of acetic acid and animals were sacrificed 9 days after ulcer induction. The area of ulcers and blood flow at the ulcer area were determined. Plasma levels of gastrin and CCK and luminal somatostatin were measured by RIA and mucosal biopsy samples were taken for histological evaluation and measurement of DNA synthesis. CCK given s.c. reduced dose dependently the ulcer area; the threshold dose of CCK being 1 nmol/kg and the dose inhibiting this area by 50% being 5 nmol/kg. This healing effect of CCK was accompanied by a significant increase in the GBF at ulcer margin and the rise in luminal NO production, plasma gastrin level and DNA synthesis. Concurrent treatment with LOX, completely abolished the CCK-8-induced acceleration of the ulcer healing and the rise in the GBF at the ulcer margin, whereas L-365,260 remained without any influence. Treatment with camostate or diversion of pancreatic juice that raised plasma CCK level to that observed with administration of CCK-8, also accelerated ulcer healing and this effect was also attenuated by LOX but not by L-365,260. Inhibition of NO-synthase by L-NNA significantly delayed ulcer healing and reversed the CCK-8 induced acceleration of ulcer healing, hyperemia at the ulcer margin and luminal NO release, and these effects were restored by the addition to L-NNA of L-arginine but not D-arginine. Capsaicin denervation attenuated CCK-induced ulcer healing, and the accompanying rise in the GBF at the ulcer margin and decreased plasma gastrin and luminal release of somatostatin when compared to those in rats with intact sensory nerves. Detectable signals for CCK-A and B receptor mRNAs as well as for cNOS mRNA expression were recorded by RT-PCR in the vehicle control gastric mucosa. The expression of CCK-A receptor mRNA and cNOS mRNA was significantly increased in rats treated with CCK-8 and camostate, whereas CCK-B receptor mRNA remained unaffected. We conclude that CCK accelerates ulcer healing by the mechanism involving upregulation of specific CCK-A receptors, enhancement of somatostatin release, stimulation of sensory nerves and hyperemia in the ulcer area, possibly mediated by NO.
 ...
PMID:Acceleration of ulcer healing by cholecystokinin (CCK): role of CCK-A receptors, somatostatin, nitric oxide and sensory nerves. 1045 43

Human thymomas are rare tumours which usually develop in the chest. The diagnosis via guided biopsy, the evaluation of the extent of the tumour and its boundaries with adjacent organs, the choice of the appropriate therapeutic option, and the assessment of response to treatment are usually made with computed tomography (CT) alone or in combination with magnetic resonance imaging (MRI). More recently, radiopharmaceuticals and nuclear medicine procedures have been used increasingly in the imaging and functional characterization of benign and malignant thymic disorders. Two groups of radiopharmaceuticals have been used. The first includes several oncotropic tracers, such as 201Tl-chloride, 99mTc-sestamibi and 18F-fluorodeoxyglucose, which are significantly concentrated in thymic tumours. Their uptake correlates with tumour grades and cellularity. The second class includes two radioligands: [(111)In-DTPA-D-Phe1]-octreotide (DTPA, diethylenetriamine penta-acetic acid) and [(111)In-DTPA-Arg1]-substance P, which bind to specific receptors. [(111)In-DTPA-Arg1]-substance P binds to its receptors that are largely expressed in the thymus of patients with autoimmune diseases. [(111)In-DTPA-D-Phe1]-octreotide recognizes the somatostatin receptor subtype 2. In patients with active disease investigated in our institution [(111)In-DTPA-D-Phe1]-octreotide has been shown to concentrate in the majority of thymoma deposits. Conversely, it is not concentrated in adult patients with benign lymphofollicular thymic hyperplasia. This finding has had a significant impact on the management of patients with myasthenia gravis as it differentiates early-stage thymoma from benign hyperplasia, unlike CT and MRI, which often fail to distinguish between the two. In addition to its role in diagnostic imaging, somatostatin receptor scintigraphy also enables us to select patients with advanced or metastatic thymoma unresponsive to conventional therapies, who might benefit from a somatostatin analogue-based treatment, serving thus as a link between diagnosis and therapy. In this article, we discuss and analyse the results of functional imaging with different radiopharmaceuticals, primarily those that we have obtained with [(111)In-DTPA-D-Phe1]-octreotide.
 ...
PMID:Functional imaging of thymic disorders. 1057 58

Neuroendocrine tumours of the gastro-entero-pancreatic tract are an uncommon clinical entity and are believed to arise from the endocrine cells of the gastrointestinal tract. Somatostatin receptor imaging is a diagnostic tool which allows visualization of somatostatin receptor bearing tumours. This scintigraphic procedure is performed with indium-111 labelled octreotide, a somatostatin analogue, chelated with diethylene triamine penta-acetic acid. Radionuclide imaging consists in detecting the biodistribution of somatostatin receptors, normally expressed on the cell surface of neuroendocrine gastro-entero-pancreatic tumours. To date, five types of this receptor have been cloned: indium-111-labelled-pentetreotide can visualize tumours expressing type 2 and 5 receptors. The results of our study, which involved 81 neuroendocrine gastro-entero-pancreatic tumour patients, confirm the superior sensitivity of somatostatin receptor imaging (61%) for primary tumour evaluation with respect to conventional imaging modalities such as computed tomography (40%) or ultrasound (28%). Scintigraphic findings in metastatic liver disease proved to have a sensitivity of 89% for somatostatin receptor imaging, versus 81% and 88% for computed tomography and ultrasound, respectively. In 23% of patients, lesions were found with somatostatin receptor imaging which had been missed using the other diagnostic modalities; in 26% of the patients the therapeutic approach was modified after somatostatin receptor imaging.
 ...
PMID:Imaging of neuroendocrine gastro-entero-pancreatic tumours using radiolabelled somatostatin analogues. 1060 28

The purpose of this study was to design poly(lactide-co-glycolide) (PLGA) microspheres for the continuous delivery of the somatostatin analogue, vapreotide, over 2-4 weeks. The microspheres were produced by spray-drying and the desired characteristics, i.e. high encapsulation efficiency and controlled release over 2-4 weeks, achieved through optimizing the type of polymer, processing solvent, and co-encapsulated additive. The in vitro release was tested in fetal bovine serum preserved with 0.02% of thiomersal. Furthermore, formulations were injected intramuscularly into rats to obtain pharmacokinetic profiles. Encapsulation efficiency was between 34 and 91%, depending on the particular formulation. The initial peptide release (within 6 h) was lowest, i.e. <20%, when acetic acid was used as processing solvent and highest, i.e. 57%, with dichloromethane. The various co-encapsulated additives generally lowered the encapsulation efficiency by 15-30%. The best formulation in terms of low burst and effective drug serum levels (>1 ng/ml) over 21-28 days in rats was the one made with end-group uncapped PLGA 50:50, the solvent acetic acid and the additive polyethyleneglycol. In conclusion, the optimization of formulation parameters allowed us to produce vapreotide-loaded PLGA microspheres of suitable characteristics for therapeutic use.
 ...
PMID:In vitro and in vivo evaluation of a somatostatin analogue released from PLGA microspheres. 1077 25

A human midgut carcinoid tumor was successfully transplanted into nude mice and propagated for five consecutive generations (30 months) with well-preserved phenotype. Tumor cells in nude mice expressed identical neuroendocrine markers as the original tumor, including somatostatin receptors (somatostatin receptors 1 to 5) and vesicular monoamine transporters (VMAT1 and VMAT2). Because of the expression of somatostatin receptors and VMAT1 and VMAT2 the grafted tumors could be visualized scintigraphically using the somatostatin analogue 111In-octreotide and the catecholamine analogue 123I-metaiodobenzylguanidine. The biokinetics of the somatostatin analogue 111In-octreotide in the tumors was studied and showed a high retention 7 days after administration. Cell cultures were re-established from transplanted tumors. Immunocytochemical and ultrastructural studies confirmed the neuroendocrine differentiation. The human origin of transplanted tumor cells was confirmed by cytogenetic and fluorescence it situ hybridization analyses. Spontaneous secretion of serotonin and its metabolite, 5-hydroxyindole acetic acid, from tumor cells was demonstrated. The tumor cells increased their [Ca2+]i in response to beta-adrenoceptor stimulation (isoproterenol) and K+-depolarization. All somatostatin receptor subtypes could be demonstrated in cultured cells. This human transplantable carcinoid tumor, designated GOT1, grafted to nude mice, will give unique possibilities for studies of somatostatin receptor- and VMAT-mediated radionuclide uptake as well as for studies of secretory mechanisms.
 ...
PMID:A transplantable human carcinoid as model for somatostatin receptor-mediated and amine transporter-mediated radionuclide uptake. 1115 12

Lanreotide, a synthetic octapeptide analog of a native hormone somatostatin, was labeled with a commonly available, inexpensive radionuclide 99mTc. Labeling was accomplished by reduction of the cysteine bridge, which provided sulfhydryl groups for chelation with 99mTc. Stannous chloride was used as reducing agent, while tartrate acted as transchelating agent. Lanreotide (100 microg), stannous chloride dihydrate (100 microg) and tartaric acid (64 microg) were dissolved in acetate/acetic acid buffer (pH 2.8). After overnight (approximately 18 h) incubation, approximately 444 MBq (12 mCi) 99mTc was added and kept in boiling water for 30 min. More than 97% labeling efficiency was confirmed by RP-HPLC, ITLC-SG and C18 cartridge analysis. Radiolabeling results in one major peak when analyzed by reverse-phase HPLC. The stability of the 99mTc-peptide bond was evaluated by cysteine challenge studies.
 ...
PMID:Technetium-99m direct radiolabeling of lanreotide: a somatostatin analog. 1157 98

Endocrine cells containing gastrin/cholecystokinin (CCK)-like immunoreactivity were localized to the islet tissue in the pancreas of the spiny dogfish. Most of these cells were located in the 'intestinal' lobe of the pancreas; only occasional cells were observed in the 'splenic' lobe. The gastrin/CCK-like immunoreactive cells were often co-localized with the 'classical' pancreas hormones (insulin, glucagon and somatostatin). Radioimmunoassay of water extracts with a C-terminally directed antiserum revealed high levels of immunoreactive material in the intestinal part (48.6 +/- 19.9 pmol/g) and lower levels (4.5 +/- 0.6 pmol/g) in the splenic part. Acetic acid extracts of the intestinal lobe contained low levels (6.8 +/- 3.3 pmol/g) of gastrin/CCK-like immunoreactivity, whereas corresponding extracts of the splenic part showed no immunoreactivity. When the extracts were subjected to DEAE ion-exchange chromatography the gastrin/CCK-like peptides eluted as a major peak. After Sephadex gel filtration, pooled immunoreactive material from the main DEAE chromatographic peak eluted at a position close to that of CCK4. Further characterization by ion-exchange and reversed-phase HPLC showed that, in general, the immunoreactive material behaved like the shorter forms of the gastrin/CCK family (CCK4/G5 and CCK8/Cae 3-10).
 ...
PMID:Endocrine cells with gastrin/cholecystokinin-like immunoreactivity in the pancreas of the spiny dogfish, Squalus acanthias. 1250 16

Somatostatin analogs promising for peptide receptor scintigraphy (PRS) and peptide receptor radionuclide therapy (PRRT) are D-Phe-c(Cys-Tyr-D-Trp-Lys-Thr-Cys)-Thr(ol) (Tyr 3-octreotide) and D-Phe-c(Cys-Tyr-D-Trp-Lys-Thr-Cys)-Thr (tyr3-octreotate). For radiotherapeutic applications these peptides are being labeled with the beta(-) particle emitters 177Lu or 90Y. We evaluated the therapeutic effects of these analogs chelated with tetra-azacyclododecatatro-acetic acid (DOTA) and labeled with 90Y or 177Lu in an in vitro colony-forming assay using the rat pancreatic tumor cell line CA20948. Furthermore, we investigated the effects of incubation time, radiation dose, and specific activity of [177Lu-DOTA]-D-Phe1-c (Cys-Tyr-D-Trp-Lys-Thr-Cys)-Thr (177Lu-octreotate). 177Lu-octreotate could reduce tumor growth to 100% cell kill and effects were dependent on radiation dose, incubation time, and specific activity used. Similar concentrations of 177Lu-DOTA, which is not bound to the cells, had a less pronounced effect on the tumor cell survival. Both tyr3-octreotide and tyr3-octreotate labeled with either 177Lu or 90Y, using DOTA as chelator, were able to control tumor growth in a dose-dependent manner. In all concentrations used radiolabeled tyr3-octreotate had a higher tumor kill compared to radiolabeled tyr3-octreotide, labeled with 177Lu or 90Y. This is in accordance with the higher affinity of tyr3-octreotate for the subtype 2 (sst2)-receptor compared to tyr3-octreotide, leading to a higher amount of cell-associated radioactivity, resulting in a significantly higher tumor radiation dose. In conclusion, tyr3-octreotate labeled with 177Lu or 90Y is the most promising analog for PRRT.
 ...
PMID:Tyr3-octreotide and Tyr3-octreotate radiolabeled with 177Lu or 90Y: peptide receptor radionuclide therapy results in vitro. 1462 24


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>