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Oncology Reports Feb 2009Somatostatin receptors (SSTRs) are inhibitory G-protein coupled receptors that are ubiquitously expressed in normal and cancer cells. Somatostatins (SST) are the natural...
Somatostatin receptors (SSTRs) are inhibitory G-protein coupled receptors that are ubiquitously expressed in normal and cancer cells. Somatostatins (SST) are the natural ligands for SSTRs and act as inhibitory regulators of hormone secretion and proliferation. Octreotide and RC-160 (vapreotide) are two well tolerated SSTR2/SSTR5 selective somatostatin analogues (SSA) that have been used in the treatment of cancers with mixed outcomes. Loss-of-expression of SSTR2 in tumor tissues has been suggested to correlate to tumor progressions and to the poor outcomes of somatostatin analogue treatment in certain clinical trials. In this study, exogenous human SSTR2 was overexpressed in two cancer cell lines, capan-2 cells and A549 cells, which had different profiles of endogenous SSTR expression. It was shown that overexpression of SSTR2 dramatically inhibited the proliferation of SSTR2-positive and SSTR2-negative cancer cells. Further growth inhibition of these cancer cells overexpressing SSTR2 was observed by application of octreotide/RC-160 in a dose-dependent fashion. In addition, immunoassay demonstrated that SSA/SSTR2 inhibited proliferation via both cell cycle arresting and promoting apoptosis. The results suggested that SSTR2 could be a promising candidate for gene therapy for SSTR2-positive and SSTR2-negative tumors. The cellular level of SSTR2 might be a critical factor that could affect both tumor progression and the outcomes of somatostatin analogue treatment.
Topics: Adenoviridae; Antineoplastic Agents; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Gene Expression; Genetic Therapy; Genetic Vectors; Humans; Neoplasms; Octreotide; Receptors, Somatostatin; Reverse Transcriptase Polymerase Chain Reaction; Somatostatin; Transfection
PubMed: 19148511
DOI: No ID Found -
Expert Review of Gastroenterology &... Apr 2008Variceal bleeding is a life-threatening complication of portal hypertension. The recommended treatment includes the early administration of a vasoactive drug. Vapreotide... (Review)
Review
Variceal bleeding is a life-threatening complication of portal hypertension. The recommended treatment includes the early administration of a vasoactive drug. Vapreotide is a somatostatin analogue with a different receptor affinity to octreotide. It decreases portal pressure and blood flow of collateral circulation in rats with cirrhosis. The pivotal study of early administration of vapreotide in patients with cirrhosis and variceal bleeding has shown a significant improvement in bleeding control and, in the subset of patients with significant bleeding, a significant reduction in mortality. In addition, a meta-analysis of four randomized studies has shown a significant improvement in bleeding control. Vapreotide administrated via the intravenous route is simple to use, with practically no contraindications and few, usually minor, side effects.
Topics: Antineoplastic Agents; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Humans; Somatostatin
PubMed: 19072353
DOI: 10.1586/17474124.2.2.185 -
Anticancer Research 2008Protein phosphorylation/dephosphorylation of tyrosine residues is an important regulatory mechanism in cell growth and differentiation. Previously it has been reported...
Protein phosphorylation/dephosphorylation of tyrosine residues is an important regulatory mechanism in cell growth and differentiation. Previously it has been reported that RC-160, an octapeptide analog of somatostatin, and [D-Trp6]LHRH, an agonist of luteinizing hormone-releasing hormone (LHRH), stimulate receptor-mediated activity of tyrosine phosphatases (PTP) and reverse growth promotion of the tyrosine kinase (PTK) class of oncogenes in tumor cells. The effect of RC-160 and [D-Trp6]LHRH on protein phosphorylation was further examined in surgical specimens of human carcinomas. Protein extracts of human ovarian, liver, breast and prostate tumor samples were preincubated with epidermal growth factor (EGF) (10(-7) M) with or without [D-Trp6]LHRH or RC-160 (10(-6) M) at 25 degrees C for 2 h, followed by incubation for 10 min with [gamma-32p]ATP. SDS-PAGE, Western blotting, autoradiography and densitometry were then used to quantify the phosphorylation level of individual protein bands. It was found that EGF enhanced, and [D-Trp6]LHRH and RC-160 reduced phosphorylation of a prominent 300-kDa band. Two proteins (65 and 60 kDa), involved in growth control in tumor cell lines, were also identified in this study. The homology of substrate phosphorylation between induced PTK and PTP in the presence of hormones provided evidence that these substrates might be identical or related in tumors. These findings, along with the previous cell culture results, suggest that many solid tumors may respond to treatment with analogues of somatostatin and LHRH. Collectively, the results further support the hypothesis that these 60-, 65- and 300-kDa protein substrates may be involved in growth-message transduction.
Topics: Antineoplastic Agents; Antineoplastic Agents, Hormonal; Breast Neoplasms; Epidermal Growth Factor; Female; Humans; Liver Neoplasms; Male; Neoplasm Proteins; Neoplasms; Ovarian Neoplasms; Phosphorylation; Prostatic Neoplasms; Protein Tyrosine Phosphatases; Somatostatin; Triptorelin Pamoate
PubMed: 19035284
DOI: No ID Found -
Pancreas Jan 2008The aim of this study was to evaluate the efficacy of somatostatin and its analogues in prevention of postoperative complications after pancreaticoduodenectomy. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
The aim of this study was to evaluate the efficacy of somatostatin and its analogues in prevention of postoperative complications after pancreaticoduodenectomy.
METHODS
A literature search of the MEDLINE, EMBASE, and Cochrane databases was used to identify randomized controlled trials that compared somatostatin and its analogues with control group after pancreaticoduodenectomy. Meta-analytical techniques were applied to identify differences in outcomes between the 2 groups.
RESULTS
A total of 8 studies were identified according to our inclusion criteria, including 2 studies using somatostatin, 5 studies using octreotide, and 1 study using vapreotide. The use of somatostatin or its analogues did not significantly benefit for reducing the incidence of pancreatic fistula (odds ratio [OR] 95% confidence interval [CI], 0.64-1.37; P = 0.73), total pancreas-specific postoperative complications (OR 95% CI, 0.63-1.42; P = 0.79), delayed gastric emptying (OR 95% CI, 0.50-1.78; P = 0.86), total complication (OR 95% CI, 0.73-1.70; P = 0.61), mortality (OR 95% CI, 0.59-7.72; P = 0.97), and length of postoperative hospital stay (weighted mean difference 95% CI, -7.74 to 4.47; P = 0.60).
CONCLUSIONS
The use of somatostatin and its analogues does not significantly reduce postoperative complications after pan-creaticoduodenectomy.
Topics: Gastric Emptying; Humans; Length of Stay; MEDLINE; Octreotide; Pancreatic Fistula; Pancreaticoduodenectomy; Postoperative Complications; Randomized Controlled Trials as Topic; Somatostatin
PubMed: 18192875
DOI: 10.1097/mpa.0b013e3181343f5d -
Revista Medico-chirurgicala a... 2007Variceal bleeding in liver cirrhosis is a medical emergency with a high mortality. The therapeutic options in patients with portal hypertension are: treatment of acute... (Review)
Review
Variceal bleeding in liver cirrhosis is a medical emergency with a high mortality. The therapeutic options in patients with portal hypertension are: treatment of acute bleeding from varices, prevention of the first bleeding episode and prevention of rebleeding. Treatment of acute bleeding from varices includes: blood volume restitution, use of antibiotics for preventing bacterial infections, vasoactive drug therapy (terlipressin, somatostatin, vapreotide, octreotide), endoscopic band ligation for acute esophageal bleeding and endoscopic therapy with tissue adhesive (cyanoacrylate) for acute gastric variceal bleeding. Endoscopic treatments are best used in association with pharmacological therapy. In primary prophylaxis non-selective beta- blocker therapy and endoscopic band ligation are useful. Beta blockers, band ligation or both should be used for prevention of recurrent bleeding. In patients who fail endoscopic and pharmacological treatment for prevention of rebleeding TIPS and transplantation should be considered.
Topics: Anti-Bacterial Agents; Drug Therapy, Combination; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Hemostasis, Endoscopic; Humans; Ligation; Liver Cirrhosis; Sclerotherapy; Tissue Adhesives; Treatment Outcome; Vasoconstrictor Agents
PubMed: 17595842
DOI: No ID Found -
Gaceta Medica de Mexico 2006Early clinical trials in Mexico with analogs of luteinizing hormone-releasing hormone (LH-RH) also known as gonadotropin releasing hormone (Gn-RH), were reviewed.... (Review)
Review
Early clinical trials in Mexico with analogs of luteinizing hormone-releasing hormone (LH-RH) also known as gonadotropin releasing hormone (Gn-RH), were reviewed. Extensive clinical studies were carried out at IMSS with agonists of LH-RH, both in men and woman. All subjects responded to LH-RH agonists with a release of LH and FSH, but repeated administration of these analogs, initially aimed at stimulation of fertility (thought to stimulate fertility), was later shown to result in inhibition due to desensitization of pituitary gland and downregulation of LH-RH receptors. Various clinical investigations with LH-RH antagonists were also carried out. This included the first demonstration that LH-RHantagonists can suppress LH and FSH and sex steroid secretion in men and women. Various studies in Mexico with early LH-RH antagonists aimed at the development of new contraceptive methods were reviewed. Modern LH-RH antagonist Cetrorelix was shown to be effective in men and women and useful in treatment of uterine leiomyomas and benign prostatic hyperplasia. Major oncological studies were also carried out with agonist D-Trp6-LH-RH and antagonist Cetrorelix in men with prostate cancer, which demonstrated therapeutic efficacy of both types of analogs. Some endocrine studies with early analogs of somatostatin were also cited and a clinical trial with somatostatin analog vapreotide in patients with relapsed prostate cancer was reviewed. All these studies played a major role in introducing analogs of hypothalamic-releasing hormones into clinical medicine.
Topics: Clinical Trials as Topic; Female; Gonadotropin-Releasing Hormone; Humans; Male; Mexico; Prostatic Neoplasms; Somatostatin; Thyrotropin-Releasing Hormone
PubMed: 17022307
DOI: No ID Found -
Anti-cancer Drugs Jul 2006The somatostatin analogs octreotide, lanreotide and RC-160 (vapreotide) are known to have direct and indirect antitumor effects. Direct effects include the arrest of... (Review)
Review
The somatostatin analogs octreotide, lanreotide and RC-160 (vapreotide) are known to have direct and indirect antitumor effects. Direct effects include the arrest of tumor growth and stimulation of apoptosis, resulting in tumor shrinkage. Indirect antiproliferative effects may occur through antiangiogenesis, immunomodulatory effects and the suppression of tumor-stimulating growth factors. With a safety profile of somatostatin analogs established over 20 years of clinical use in the treatment of neuroendocrine tumors, somatostatin analogs are attractive therapeutic options for patients with non-neuroendocrine tumors. In early clinical trials of somatostatin analogs, however, some cancer patients responded well, while others showed a lack of benefit. This variability in clinical response may reflect the selective binding affinities of octreotide, lanreotide and RC-160, which bind with high affinity to just two of the five different somatostatin receptor subtypes. Treatment response may therefore depend on the specific receptor subtype(s) present in the tumor, the relative proportion of receptor(s) expressed on the tumor cell surface and the absolute quantity of each receptor subtype. Greater understanding of the role of somatostatin receptors, their binding affinities and modes of action has led to increased research into the use of somatostatin analogs, particularly octreotide, in cancer treatment as monotherapies, in combination with hormonal treatments and cytotoxic therapies, and in both adjuvant and neoadjuvant settings. A review of the literature suggests that the antitumor potential of somatostatin analogs should be investigated further and additional studies might determine how these analogs can best be used to improve the treatment of patients with non-neuroendocrine tumors.
Topics: Humans; Neoplasms; Receptors, Somatostatin; Somatostatin
PubMed: 16917205
DOI: 10.1097/01.cad.0000210335.95828.ed -
Journal of Hepato-biliary-pancreatic... 2006The Achilles' heel of operative pancreatectomies is the pancreaticoenterostomy for proximal resections and the pancreatic parenchymal closure for distal resections.... (Randomized Controlled Trial)
Randomized Controlled Trial Review
BACKGROUND/PURPOSE
The Achilles' heel of operative pancreatectomies is the pancreaticoenterostomy for proximal resections and the pancreatic parenchymal closure for distal resections. Inhibition of pancreatic exocrine secretions by somatostatin analogues has been suggested to decrease pancreas-specific complications, but this topic remains controversial.
METHODS
We performed a randomized, prospective, placebo-controlled, multicenter trial of the use of perioperative vapreotide, a potent somatostatin analogue, in pancreatic resections for presumed neoplasms in 381 patients without chronic pancreatitis. We also reviewed the literature on the use of somatostatin and its analogues after pancreatectomy.
RESULTS
When compared to the placebo, perioperative vapreotide had no effect on overall pancreas-specific complications (30.4% vs 26.4%), mortality (0% vs 1.4%), overall complications (40% vs 42%), and duration of hospitalization; there were no differences in complications per type of resection with use of vapreotide--proximal versus distal resection. Seven other prospective, randomized trials provide differing results.
CONCLUSIONS
Our study with vapreotide failed to show any benefit when administered perioperatively (and for 7 days postoperatively) on pancreas-specific complications after major pancreatectomy in patients without chronic pancreatitis. The use of perioperative analogues that suppress pancreatic exocrine secretion seems not to be warranted as routine treatment.
Topics: Adult; Gastrointestinal Agents; Humans; Pancreas, Exocrine; Pancreatectomy; Pancreatic Fistula; Postoperative Complications; Prospective Studies; Somatostatin
PubMed: 16708293
DOI: 10.1007/s00534-005-1033-9 -
Journal of Endocrinological... 2005At first sight, the title is confusing as it seems to try to merge four unrelated topics into a single presentation. Somatostatin, cortistatin (CST) and ghrelin display... (Review)
Review
At first sight, the title is confusing as it seems to try to merge four unrelated topics into a single presentation. Somatostatin, cortistatin (CST) and ghrelin display broad biological activities, including metabolic effects. However, although apparently unrelated, these peptides entities have more in common than it might be expected and their reciprocal interactions give a new perspective to the hormonal regulation of glucose metabolism. Let's analyze the ghrelin receptor subtype GH secretagogue (GHS)-receptor 1a (R1a). Taking into account the GHS-R1a as receptor of reference, acylated ghrelin is one of its natural ligands. Interestingly, it has been demonstrated that also CST, a neuropeptide, binds with high affinity to the GHS-R1a in human hypothalamus and pituitary tissues. CST is a recently described neuropeptide showing high structural homology with somatostatin that binds to all somatostatin receptor subtypes (SSTRs) with an affinity (1-2 nM). In fact, CST and somatostatin exhibit the same endocrine activities. The existence of specific receptors which selectively bind somatostatin or CST has been hypothesized, based on evidence that CST possesses an action profile different from somatostatin and that CST and somatostatin are often co-expressed in the same neurons but are regulated by different stimuli. Given these findings, the ability of CST to bind the GHS-R1a is of particular relevance because somatostatin and its fragments do not bind the same receptor. Interestingly, the classical synthetic somatostatin analogs, i.e. octreotide, lanreotide and vapreotide bind the GHS-R1a with an affinity lower than that of CST. These findings have generated the hypothesis that CST, because of its ability to bind both SSTRs and GHSRs, would represent the link between ghrelin and "somatostatin/CST" system that had not previously been demonstrated. On the other hand, the GHS-R1a is unlikely to be the only GHS-R. It has been already demonstrated that a GHS-R subtype able to bind non-acylated as well as acylated ghrelin exists and likely mediates biological activities. Another GHS-R subtype likely mediates the influence of unacylated ghrelin on glucose metabolism, since it does not bind nor activates the GHS-R1a. Given this complexity, it is clear that further studies are required to clarify whether ghrelin is the sole ligand or one of a number of ligands activating the GHS-R 1a and whether that receptor used for ghrelin isolation is the sole receptor or one of a group of receptors for such ligands.
Topics: Blood Glucose; Ghrelin; Glucagon; Homeostasis; Humans; Insulin; Kinetics; Ligands; Neuropeptides; Peptide Hormones; Receptors, G-Protein-Coupled; Receptors, Ghrelin; Receptors, Somatostatin; Somatostatin
PubMed: 16625861
DOI: No ID Found