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)

Radiolabeled somatostatin analogs have demonstrated potential as cancer therapeutic agents. Many of these agents are based on the analog octreotide (OC). Recently it has been shown that substitution of a tyrosine for phenylalanine in the 3-position and changing the C-terminus from an alcohol to an acid improves the targeting of somatostatin-rich tissues. The compound, 1,4,8,11-tetraazacyclotetradecane-N,N',N",N"'-tetraacetic acid-Tyr3-octreotate (TETA-Y3-TATE), was synthesized and radiolabeled with 64Cu. The receptor binding properties of 64Cu-TETA-Y3-TATE showed an estimated Kd value of 549 pM in somatostatin receptor-positive CA20948 tissue membrane. High tumor uptake was observed in two animal tumor models. Tumor uptakes of 2.37 %ID/g in CA20948 tumor-bearing rats and 21.60 %ID/g in AR42J tumor-bearing SCID mice were observed at 1 h, compared with 1.09 %ID/g and 11.24 %ID/g for 64Cu-TETA-OC. Higher uptake in other somatostatin-receptor rich tissues was also observed, compared with 64Cu-TETA-OC. Positron emission tomography (PET) imaging with 64Cu-TETA-Y3-TATE in a baboon showed significant uptake in the pituitary and adrenals, and clearance through the kidneys. 64Cu-TETA-Y3-TATE, a new OC analog for binding somatostatin receptors, demonstrated significantly greater uptake in somatostatin-rich tissues in two tumor-bearing animal models, and demonstrated great potential as a radiopharmaceutical for imaging and therapy of somatostatin receptor-positive tissues.
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PMID:In vitro and in vivo evaluation of 64Cu-TETA-Tyr3-octreotate. A new somatostatin analog with improved target tissue uptake. 1036 97

64Cu [T1/2 = 12.8 h; beta+ = 0.655 MeV (19%); beta- = 0.573 MeV (40%)] has shown promise as a radioisotope for targeted radiotherapy. It has been demonstrated previously that the somatostatin analogue 64Cu-TETA-octreotide (64Cu-TETA-OC, where TETA is 1,4,8,11-tetraazacyclotetradecane-N,N',N",N"'-tetraacetic acid) significantly inhibited the growth of somatostatin receptor-positive CA20948 rat pancreatic tumors in Lewis rats (C. J. Anderson et al., J. Nucl. Med., 39: 1944-1951, 1998). In this study, we evaluated the radiotherapeutic efficacy of a new 64Cu-labeled somatostatin analogue, 64Cu-TETA-Tyr3-octreotate (64Cu-TETA-Y3-TATE), in CA20948 tumor-bearing rats. A single dose of 15 mCi (555 MBq) of 64Cu-TETA-Y3-TATE was shown to be more effective in reducing tumor burden than the same dose of 64Cu-TETA-OC. In multiple dose experiments, tumor-bearing rats were administered three doses of either 10 or 20 mCi (370 or 740 MBq) of 64Cu-TETA-Y3-TATE at 48-h intervals. Rats given 3x10 mCi (3x370 MBq) showed extended mean survival times compared with rats given a single dose; however, no complete regressions occurred. Complete regression of tumors was observed for all rats treated with 3x20 mCi (3x740 MBq), with no palpable tumors for approximately 10 days; moreover, the mean survival time of these rats was nearly twice that of controls. Toxicity was determined by physical appearance and hematological and enzyme analysis, which revealed no overt toxicity and only transient changes in blood and liver chemistry. Absorbed dose estimates showed the dose-limiting organ to be the kidneys. The radiotherapy results, along with absorbed dose estimates to target and clearance organs, confirm that 64Cu-labeled somatostatin analogues warrant continued consideration as agents for targeted radiotherapy.
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PMID:Radiotherapy and dosimetry of 64Cu-TETA-Tyr3-octreotate in a somatostatin receptor-positive, tumor-bearing rat model. 1058 78

An understanding of the metabolic fate of radiometal-labeled peptides is important due to their application in the areas of diagnostic imaging and targeted radiotherapy. Radioisotopes of copper ((64)Cu, T(1/2) = 12.7 h; (67)Cu, T(1/2) = 62 h) have been labeled to monoclonal antibodies (mAbs) and peptides and have applications in the areas of PET imaging and targeted radiotherapy of cancer. Copper-64-TETA-D-Phe(1)-octreotide ([(64)Cu]TETA-OC) has been shown to bind to the somatostatin receptor, both in vitro and in vivo, and this agent inhibited the growth of somatostatin-receptor positive tumors in rats. Copper-64-TETA-OC, however, showed a retention of activity in the blood, liver, and bone marrow, suggesting possible dissociation of (64)Cu from TETA-OC in vivo. The purpose of this study was to determine if (64)Cu dissociates from [(64)Cu]TETA-OC and binds to the protein, superoxide dismutase (SOD) in rat liver. The liver metabolism of [(64)Cu]TETA-OC was examined in normal rats using a gel-electrophoresis assay specific for SOD and size-exclusion chromatography. The major metabolite in rat liver at 20 h postinjection had a molecular weight of 32 kDa as shown by size-exclusion chromatography. A gel electrophoresis assay specific for the detection of SOD [nitro-blue tetrazolium (NBT)] showed that a (64)Cu-labeled protein isolated from rat liver homogenates comigrated with SOD. Evaluating the metabolic fate of copper radiopharmaceuticals demonstrated that Cu(II) dissociates from macrocyclic chelators such as TETA and binds to proteins in high concentrations, namely SOD in rat liver.
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PMID:In vivo transchelation of copper-64 from TETA-octreotide to superoxide dismutase in rat liver. 1089 74

Copper-64 (T(1/2) = 12.7 h; beta(+), 17.4%; beta(-), 39%) has been used both in positron emission tomography imaging and in radiotherapy. Copper-64 radiopharmaceuticals have shown tumor growth inhibition with a relatively low radiation dose in animal models; however, the mechanism of cytotoxicity has not been fully elucidated. These studies incorporate the use of somatostatin receptor-positive AR42J rat pancreatic tumor cells in vitro to understand the cell killing mechanism of (64)Cu by focusing on subcellular distribution of the somatostatin analogues (64)Cu-labeled 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid-octreotide ((64)Cu-TETA-OC) and (111)In-labeled diethylenetriaminepentaacetic acid-octreotide ((111)In-DTPA-OC). Cell uptake and organelle isolation studies were conducted on (64)Cu-TETA-OC and (111)In-DTPA-OC. Nuclear localization of (64)Cu and (111)In from (64)Cu-TETA-OC and (111)In-DTPA-OC, respectively, increased over time, with 19.5 +/- 1.4% and 6.0 +/- 1.0% in the cell nucleus at 24 h, respectively. In pulse-chase experiments, in which (64)Cu-TETA-OC was incubated with AR42J cells for 4 h, it was found that the nuclear localization of (64)Cu increased significantly over the next 20 h (from 9.8 +/- 1.0% to 26.3 +/- 5.4%). In a control pulse-chase experiment, levels of (64)Cu from [(64)Cu]cupric acetate decreased from 4 to 24 h postadministration (20.6 +/- 8.7 to 5.4 +/- 1.9), suggesting that the redistribution mechanism, or the kinetics of (64)Cu from (64)Cu-TETA-OC is different from that for (64)Cu from [(64)Cu]cupric acetate. The amount of (64)Cu from (64)Cu-TETA-OC also increased in the mitochondria over time, with 21.1 +/- 3.6% in the mitochondria at 24 h postadministration. These results suggest that localization of substantial quantities of (64)Cu to the cell nucleus and mitochondria may contribute to cell killing with (64)Cu radiopharmaceuticals.
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PMID:Subcellular localization of radiolabeled somatostatin analogues: implications for targeted radiotherapy of cancer. 1458 84

Many synthetic peptides have been developed for diagnosis and therapy of human cancers based on their ability to target specific receptors on cancer cell surface or to penetrate the cell membrane. Chemical modifications of amino acid chains have significantly improved the biological activity, the stability and efficacy of peptide analogues currently employed as anticancer drugs or as molecular imaging tracers. The stability of somatostatin, integrins and bombesin analogues in the human body have been significantly increased by cyclization and/or insertion of non-natural amino acids in the peptide sequences. Moreover, the overall pharmacokinetic properties of such analogues and others (including cholecystokinin, vasoactive intestinal peptide and neurotensin analogues) have been improved by PEGylation and glycosylation. Furthermore, conjugation of those peptide analogues to new linkers and bifunctional chelators (such as AAZTA, TETA, TRAP, NOPO etc.), produced radiolabeled moieties with increased half life and higher binding affinity to the cognate receptors. This review describes the most important and recent chemical modifications introduced in the amino acid sequences as well as linkers and new bifunctional chelators which have significantly improved the specificity and sensitivity of peptides used in oncologic diagnosis and therapy.
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PMID:New Insights in the Design of Bioactive Peptides and Chelating Agents for Imaging and Therapy in Oncology. 2876 81