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)

Chemotherapy was considered the standard for treatment of neuroendocrine tumors during the 1970s and 1980s. During the 1980s both interferon alfa and somatostatin analogue therapies were developed and significantly improved the clinical management of malignant neuroendocrine tumors. Surgery remains the cornerstone of treatment and should always be considered in patients with neuroendocrine tumors, even if a cure is not possible. Tumor reduction is always of beneficial value for patients undergoing medical treatment. Since the introduction of biotherapy, no real breakthrough in medical treatment has come forward, but new insights into tumor biology will probably improve therapeutic regimens in the near future. Somatostatin subtype receptor determination in tumor tissues and development of subtype-specific analogues for therapy are two new approaches. The gene for multiple neoplasia type I was cloned recently, and it will increase our understanding of the development of neuroendocrine tumors and give new insights into tumor pathophysiology. The current medical treatment of neuroendocrine tumors is based on chemotherapy for the more highly proliferating tumors, such as malignant endocrine pancreatic tumors and foregut carcinoids, whereas biotherapy, including interferon alfa and somatostatin analogues, is used in slow-growing neoplasms such as midgut carcinoids. These treatments can be supplemented by liver embolizations and chemoembolization to reduce the masses in the liver. When these treatments fail, tumor-targeted irradiation can be attempted, such as 131I-MIBG (metaiodobenzylguanidine) and 90Y DOTA (1,4,7,10-tetraazacyclododecane-N,N(I),N(II),N(III)-tetraacetic acid)-octreotide. The treatment of neuroendocrine gut and pancreatic tumors necessitates a multimodal approach, and more effective medical treatment is being developed.
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PMID:Advances in chemotherapy and biotherapy of endocrine tumors. 946 86

1,4,7,10-tetraazacyclododecane-N,N',N",N'''-tetraacetic acid (DOTA)-lanreotide is a universal somatostatin (SST) receptor subtype ligand that binds to a large variety of human tumors. We report the case of a patient with metastatic gastrinoma who was treated with 90Y-DOTA-lanreotide. Before treatment, dosimetry with 111In-DOTA-lanreotide (150 MBq, 10 nmol) indicated a dose of 5.8 mGy/MBq for the recurrent abdominal gastrinoma, and a mean dose of approximately 1.0 mGy/MBq for liver metastases (i.e., 56 and approximately 10 mGy/MBq for 90Y-DOTA-lanreotide, respectively). After four infusions of 90Y-DOTA-lanreotide (each 1 GBq, approximately 30 nmol) over a 6-mo period, the 111In-DOTA-lanreotide scintigraphy of the liver had returned to a nearly normal condition and a remarkably decreased uptake by the recurrent gastrinoma was calculated (approximately 5 mGy/MBq for 90Y-DOTA-lanreotide). The imaging results were well-correlated with a 25% regression of the liver metastases as indicated by CT. Blood, urine and whole-body clearances of 111In-DOTA-lanreotide and 90Y-DOTA-lanreotide were very similar. The DOTA-lanreotide promises to be useful for functional tumor diagnosis (111In-DOTA-lanreotide) and receptor-mediated tumor radiotherapy (90Y-DOTA-lanreotide).
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PMID:Response to treatment with yttrium 90-DOTA-lanreotide of a patient with metastatic gastrinoma. 986 48

Direct attachment of unprotected DOTA (1,4,7,10-tetraazacyclododecane-N',N",N"',N""-tetraacetic acid) to partially suitably protected octreotide or [Tyr3]-octreotide leads after deprotection to [DOTA-DPhe1]-octreotide (III) and [DOTA-DPhe1,Tyr3]-octreotide (IV). These DOTA-containing somatostatin analogs, when labeled with a radiotherapeutic nuclide, are useful as antitumor agents. The partially protected peptides are accessible via solid phase peptide synthesis (SPPS) followed by selective cleavage under mild acidic conditions from the resin.
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PMID:Direct synthesis of [DOTA-DPhe1]-octreotide and [DOTA-DPhe1,Tyr3]-octreotide (SMT487): two conjugates for systemic delivery of radiotherapeutical nuclides to somatostatin receptor positive tumors in man. 987 36

The clinical importance of somatostatin type-2 receptors (SSTR2) and the study of novel analogues of somatostatin such as OctreoScan or [Tyr3]-octreotide containing DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) as metal chelator led us to develop a methodology to monitor the expression of SSTR2 on tumours of pancreatic origin (e.g. rat AR4-2J cancer cells). Usual binding assay protocols using the commercial [125I][Tyr1]-somatostatin radioligand failed, even in the presence of a cocktail of protease inhibitors with a broad spectrum of activity, possibly due to the high susceptibility of this tracer to proteases expressed in pancreatic cells. We prepared our own radioligand [125I][Tyr2]-octreotide which was shown to be much more resistant to degradation after incubation with AR4-2J plasma membranes. As expected, the increased stability of [125I][Tyr3]-octreotide was associated with good binding to SSTR2. Addition of appropriate protease inhibitors further increased the specific binding of [125I][Tyr3]-octreotide to AR4-2J plasma membranes without affecting the stability of the tracer, suggesting that the protease inhibitors also protect the integrity of SSTR2. Optimal conditions (time, temperature, medium) were developed for a binding assay in 96-well plates using AR4-2J plasma membranes in order to make the assay suitable for high-throughput analysis. This protocol was the basis for studying the in vivo regulation of SSTR2 expression in AR4-2J cells implanted into scid mice after exposure to different compounds.
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PMID:A microplate binding assay for the somatostatin type-2 receptor (SSTR2). 1007 56

Somatostatin analogs labeled with radionuclides are of considerable interest in nuclear oncology as diagnostic or therapeutic tools for somatostatin receptor (SSTR)-expressing tumors. We investigated the suitability of DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) as a replacement for the widely used diethylenetriaminepentaacetic acid, to enable stable labeling of somatostatin analogs with both therapeutic (90Y) and diagnostic (111In) radionuclides. The three clinically relevant somatostatin agonists, octreotide, vapreotide, and lanreotide, together with the newly designed Tyr3-octreotide (TyrOc), were conjugated to DOTA and labeled with 90Y or 111In. For all DOTA-somatostatin analogs tested, irrespective of the incorporated radionuclide, we observed favorable biodistribution profiles in AR4-2J tumor-bearing mice: 1) a rapid clearance from all SSTR-negative tissues except kidney; 2) a specific uptake in SSTR-positive tissues, including tumor; and 3) an excellent tumor penetration. The main route of excretion was via the kidneys. Nevertheless, DOTATOC was clearly superior to the other DOTA-somatostatin analogs tested, as well as OctreoScan, as indicated by the highest tumor-to-nontarget-tissue ratio, including the tumor-to-SSTR-positive-tissue ratios. The presence of different SSTR subtypes in the SSTR-positive tissues possibly contributes to these differential uptakes. We assume that the very favorable behavior of DOTATOC in our mouse model makes this radioligand very promising for future applications in nuclear oncology.
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PMID:Preclinical comparison in AR4-2J tumor-bearing mice of four radiolabeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-somatostatin analogs for tumor diagnosis and internal radiotherapy. 1096 2

Radiolabeled somatostatin analogs have demonstrated effectiveness for targeted radiotherapy of somatostatin receptor-positive tumors in both tumor-bearing rodent models and humans. A radionuclide of interest for cancer therapy is reactor-produced (177)Lu (t(1/2) = 6.64 d; beta(-) [100%]). The high therapeutic efficacy of the somatostatin analog (177)Lu-DOTA-Tyr(3)-octreotate (DOTA-Y3-TATE, where DOTA is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) was previously demonstrated in a tumor-bearing rat model (Erion et al., J. Nucl. Med. 1999;40:223P; de Jong et al., Int. J. Cancer, 2001; 92:628-633). In the current study, the toxicity and dosimetry of (177)Lu-DOTA-Y3-TATE were determined in both normal and tumor-bearing rats. Doses of (177)Lu-DOTA-Y3-TATE ranging from 0 to 123 mCi/kg were administered to rats and complete blood counts (CBCs) and blood chemistries were analyzed out to 6 weeks. No overt signs of toxicity were observed with (177)Lu-DOTA-Y3-TATE (i.e., lethargy, weight loss, scruffy coat or diarrhea) at any of the dose levels. Blood chemistries and CBCs were normal except for the white blood cell counts, which showed a dose-dependent decrease. The maximum tolerated dose was not reached at 123 mCi/kg. The biodistribution of (177)Lu-DOTA-Y3-TATE was determined in CA20948 rat pancreatic tumor-bearing rats, and the data were used to estimate human absorbed doses to normal tissues. The dose-limiting organ was determined to be the pancreas, followed by the adrenal glands. The absorbed dose to the rat CA20948 tumor was estimated to be 336 rad/mCi (91 mGy/MBq). These data demonstrate that (177)Lu-DOTA-Y3-TATE is an effective targeted radiotherapy agent at levels that show minimal toxicity in this rat model.
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PMID:Toxicity and dosimetry of (177)Lu-DOTA-Y3-octreotate in a rat model. 1174 91

Since the discovery of somatostatin (sst) in 1973, numerous chemical and biological studies have been carried out to develop sst analogs with enhanced resistance to proteases and prolonged activity. Three highly potent sst analogs-octreotide, lanreotide, and vapreotide-are now available in the clinic, and demonstrate efficacy in the treatment of tumors of the pituitary and the gastroenteropancreatic tract. The most striking effect is the control of hormone hypersecretion associated with these tumors. Available data on growth suppression in patients indicate a limited antiproliferative action, tumor shrinkage is observed in 10-20% patients, and tumor stabilization in about half of the patients for duration of 8-16 months. Eventually, however, all patients escape from sst analog therapy with regard to both hormone hypersecretion and tumor growth, the only exception being observed in acromegalic patients who do not experience tachyphylaxis even after more than 10 years of daily octreotide injection. The mechanism underlying the escape phenomenon is not yet clarified. Regarding the molecular mechanisms involved in sst antineoplastic activity, both indirect and direct effects via specific somatostatin receptors (SSTRs) expressed in the target cells have be described. Direct action may result from blockade of mitogenic growth signal or induction of apoptosis following interaction with SSTRs. Indirect effects may be the result of reduced or inhibited secretion of growth-promoting hormones and growth factors that stimulate the growth of various types of cancer; also, inhibition of angiogenesis or influence on the immune system are important factors. Five SSTR subtypes have been identified so far, which are variably expressed in a variety of tumors such as gastroenteropancreatic (GEP) tumors, pituitary tumors, and carcinoid tumors. Although all five SSTR subtypes are linked to adenylate cyclase, they are now known to affect multiple other cellular signaling systems and hence they differentially participate in the regulation of the various cellular processes. The finding of several laboratories that SSTR-expressing tumors frequently contain two or more SSTR subtypes, and the recent discovery that SSTR subtypes might form homo/heterodimers to create a novel receptor with different functional characteristics, expand the array of selective SSTR activation pathways and subsequent intracellular signaling cascades. This may lead to improved clinical protocols that take into account possible synergistic interactions between the SSTR subtypes present on the same cancer cell. Radiolabeled sst analogs, such as [(111)In]-[diethylenetriamine pentaacetic acid (DTPA)-D-Phe(1)]-octreotide (OcreoScan), have proved to be very useful for tumor scintigraphy and internal radiotherapy of SSTR overexpressing tumors. The recent introduction of the metal chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) considerably improved the stability of the radioconjugates, making possible the incorporation of a variety of radionuclides, such as (90)Y for receptor-mediated radionuclide therapy or (68)Ga for positron emission tomography (PET). Another promising area is the development of sst conjugates incorporating cytotoxic anticancer drugs.
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PMID:Somatostatin analogs and radiopeptides in cancer therapy. 1238 36

Somatostatin receptors type 2 (sst(2)) are expressed in high concentration on numerous neudoendocrine tumors. The successful use of radiolabeled somatostatin analogs in imaging promoted further studies in utilizing them in radiopeptide therapy. The somatostatin analog [(90)Y-DOTA-D-Phe(1)-Try3]octreotide (DOTATOC) (DOTA: 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid) possesses favorable characteristic for its therapeutic use; shows high affinity for sst(2), moderately high affinity for sst(5), and intermediate affinity for sst(3); high hydrophilicity; stable and facile labeling with (111) In and (90) Y. In this article we report our experience with (90)Y-DOTATOC in neuroendocrine tumors. Eighty-seven patients with neuroendocrine tumors were treated with a cumulated activity ranging from 7.4 to 20.2 GBq. Most patients responded with stabilization of disease (48%); however, objective responses were observed in 28% of patients (5% complete response). No major acute reactions were observed up to the activity of 5.55 GBq per cycle. The dose limiting was bone marrow toxicity and the maximal tolerated dose was defined as 5.18 GBq.
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PMID:90Y-DOTA-D-Phe1-Try3-octreotide in therapy of neuroendocrine malignancies. 1265 26

Earlier studies have shown that modification of the octapeptide octreotide in positions 3 and 8 may result in compounds with increased somatostatin receptor affinity that, if radiolabelled, display improved uptake in somatostatin receptor-positive tumours. The aim of a recent research study in our laboratory was to employ the parallel peptide synthesis approach by further exchanging the amino acid in position 3 of octreotide and coupling the macrocyclic chelator DOTA(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) to these peptides for labelling with radiometals like gallium-67 or -68, indium-111, yttrium-90 and lutetium-177. The purpose was to find radiopeptides with an improved somatostatin receptor binding profile in order to extend the spectrum of targeted tumours. A first peptide, [111In,90Y-DOTA]-1-Nal3-octreotide (111In,90Y-DOTA-NOC), was isolated which showed an improved profile. InIII-DOTA-NOC exhibited the following IC50 values (nM) when studied in competition with [125I][Leu8, d-Trp22, Tyr25]somatostatin-28 (values for YIII-DOTA-NOC are shown in parentheses): sstr2, 2.9 +/- 0.1 (3.3 +/- 0.2); sstr3, 8 +/- 2 (26 +/- 1.9); sstr5, 11.2 +/- 3.5 (10.4 +/- 1.6). Affinity towards sstr1 and 4 was very low or absent. InIII-DOTA-NOC is superior to all somatostatin-based radiopeptides having this particular type of binding profile, including DOTA-lanreotide, and has three to four times higher binding affinity to sstr2 than InIII,YIII-DOTA-Tyr3-octreotide (InIII,YIII-DOTA-TOC). In addition, [111In]DOTA-NOC showed a specific and high rate of internalization into AR4-2J rat pancreatic tumour cells which, after 4 h, was about two times higher than that of [111In]DOTA-TOC and three times higher than that of [111In]DOTA-octreotide ([111In]DOTA-OC). The internalized radiopeptides were externalized intact upon 2 h of internalization followed by an acid wash. After 2-3 h of externalization a plateau is reached, indicating a steady-state situation explained by reactivation of the receptors followed by re-endocytosis. Biodistribution studies in CA 20948 tumour-bearing rats showed rapid clearance from all sstr-negative tissues except the kidneys. At 4 h the uptake of [111In]DOTA-NOC in the tumour and sstr-positive tissues, such as adrenals, stomach and pancreas, was three to four times higher than that of [111In]DOTA-TOC. Differential blocking studies indicate that this is at least partially due to the uptake mediated by sstr3 and sstr5. These very promising preclinical data justify the use of this new radiopeptide for imaging and potentially internal radiotherapy studies in patients.
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PMID:DOTA-NOC, a high-affinity ligand of somatostatin receptor subtypes 2, 3 and 5 for labelling with various radiometals. 1293 48

177Lu of specific activity approximately 100-110 TBq/g and radionuclidic purity of approximately 100% was obtained by irradiation of enriched Lu2O3 (60.6% 176Lu) target for 7 days at a thermal neutron flux of 3 x 10(13)n/cm2/sec. The 177Lu labeling of a macrocyclic bifunctional chelating agent viz. 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) has been extensively studied. Lanreotide, [beta-naphthyl-Ala-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2] a disulfide-linked cyclic octapeptide and a somatostatin analog, reported to bind with a wide variety of tumors expressing somatostatin receptors, was conjugated with DOTA. The peptide-BFCA conjugate was characterized with the help of high-resolution two-dimensional proton NMR spectroscopy. The 177Lu labeling of the DOTA-lanreotide conjugate has been standardized to give a radiolabeling yield of 85%. The tracer showed specific binding with A-431 human epidermoid carcinoma and IMR-32 human brain neuroblastoma cells.
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PMID:177Lu-DOTA-lanreotide: a novel tracer as a targeted agent for tumor therapy. 1524 66

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