Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0007095 (carcinoid)
 6,990 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The SRIF analog octreotide (SMS 201-995) has been in clinical use for over 6 yr in the treatment of acromegaly and metastatic endocrine pancreatic and carcinoid tumors. The use of the analog in the treatment of acromegaly and TSH-secreting tumors is beyond the scope of this clinical review. Patient acceptance of the analog, given chronically by the sc route, has been excellent and side effects have been few with the exception of the development of gallstones. In endocrine pancreatic and carcinoid tumors the hypersecretion of hormones such as VIP, glucagon, and gastrin and the secretory products of carcinoid tumors (e.g. 5-hydroxytryptamine and tachykinins) and their clinical effects may be successfully blocked. This allows excellent palliation of such tumors and often enables the patients to return home and lead normal social lives. Initial hopes that long-term octreotide therapy would be an effective antitumor drug, reducing tumor growth, based on experimental animal models and human tumor cell lines, have not been born out in clinical practice. A reduction in gut tumor bulk due to octreotide, rarely or never occurs as a sustained phenomenon. Eventually a decrease in, and finally an absence of, clinical effectiveness occurs despite the reintroduction of other treatment modalities.
 ...
PMID:Clinical review 23: The use of the long-acting somatostatin analog octreotide in the treatment of gut neuroendocrine tumors. 164 13

Somatostatin (SS) receptor status was investigated in the tumor tissues from 62 patients with carcinoid tumors and 15 patients with islet cell carcinomas using receptor autoradiography techniques with two different iodinated somatostatin analogues as radioligands, a [Leu8, DTrp22, Tyr25]somatostatin-28 and a somatostatin octapeptide, Tyr3-octreotide. The carcinoid tumors were either primaries (n = 32) or metastases (n = 43), sampled as surgical specimens or as small needle liver biopsies. Fifty-four of 62 carcinoid patients had SS receptor-positive tumors (87%). All 15 islet cell carcinoma patients had positive tumors (4 primaries, 11 metastases), i.e., 3 vipomas, 3 insulinomas, 2 glucagonomas, 1 gastrinoma, 2 polyfunctional tumors, and 4 nonfunctioning tumors. Saturation and competition experiments on tissue sections revealed saturable, high affinity binding sites pharmacologically specific for bioactive SS analogues. In a majority of the tumors, the receptors were densely distributed and were always homogeneously found in the whole tumor. All except two tumors were labeled with both radioligands. Multiple liver metastases (n = 16) from three different patients were all shown to contain a comparable amount of receptors. SS receptors could be demonstrated even in very small tissue samples of liver metastases obtained by percutaneous liver biopsies (mean weight, 6.8 mg). The majority of the eight SS receptor-negative carcinoids were mainly bronchial carcinoids (n = 5), usually poorly differentiated. On the contrary, SS receptor-positive cases were never found to be anaplastic. All tumors except one from patients pretreated with octreotide (3 days to 3.8 years) were SS receptor positive. In the majority of carcinoids or islet cell carcinomas, the SS receptor status correlated with the in vivo biochemical response (hormone inhibition) to octreotide. These data demonstrate (a) the high prevalence of SS receptors in the primary tumors of both carcinoids and islet cell carcinomas, (b) their presence in metastases as well, (c) their continuous expression even during long term octreotide therapy, (d) the possibility of measuring SS receptors in percutaneous needle liver biopsies, and (e) the evidence of their functionality. This study therefore suggests that tumoral SS receptors may be the likely molecular basis for octreotide action and may be an important parameter for predicting the therapeutic efficacy of SS analogues in carcinoids and islet cell carcinomas.
 ...
PMID:Detection of somatostatin receptors in surgical and percutaneous needle biopsy samples of carcinoids and islet cell carcinomas. 216 86

The rectal mucosa is richly endowed with a constellation of amine and polypeptide hormone-producing endocrine cell types which may be identified by silver staining and immunohistochemical methods. In order to study the relationships of rectal carcinoid tumors to the normal hindgut endocrine cells, rectal carcinoids and normal rectal mucosa were compared for the presence of argentaffinity and argyrophilia and for the distribution of a battery of polypeptide hormones. Normal rectal mucosa contained frequent cells which stained for bovine pancreatic polypeptide (PP), human PP, and glucagon-like immunoreactivity (GLI. Somatostatin (SRIF) was present in a smaller proportion of rectal endocrine cells. Both argentaffin and argyrophil cells were encountered frequently in normal rectal mucosa. In the series of 13 rectal carcinoids examined, two cases were focally argentaffin-positive, while eight tumors revealed varying degrees of argyrophilia. Eight tumors contained immunoreactive bovine PP, and four of these tumors which were tested for human PP were also positively stained. SRIF was present in five cases, while GLI was identified in two tumors. Four of the tumors were multihormonal. Rectal carcinoids have a rich polypeptide hormone content which parallels that of the normal rectal mucosa. The distinctive hormonal profile and silver staining properties may prove to be of value as specific markers for carcinoid tumors of rectal or hindgut origin.
 ...
PMID:Rectal carcinoids as tumors of the hindgut endocrine cells: a morphological and immunohistochemical analysis. 617 28

Small ACTH-secreting carcinoid tumors responsible for Cushing's syndrome are often difficult to localize using available radiological investigations. Somatostatin receptors have been found in about 90% of carcinoid tumors studied, leading to a new approach for the localization of tumors or metastasis by using radiolabeled somatostatin analogs. We report a case of Cushing's syndrome due to an ACTH-secreting bronchial carcinoid tumor, completely suppressible with octreotide treatment and evidenced by body scintigraphy with 111In-labeled pentreotide. After removal, which led to patient recovery, the tumor was studied in vitro. In situ hybridization, using a complementary DNA probe, revealed POMC messenger ribonucleic acid in a subpopulation of tumor cells. These cells were labeled by immunochemistry using an antiserum directed against ACTH. Confocal laser scanning microscopy analysis showed that the ACTH-immunoreactive peptide was sequestered in secretory granules. Autoradiographic labeling using [125I-Tyrzero,D-Trp8]somatostatin-14 demonstrated the presence of somatostatin-binding sites in the whole tumor tissue. The relative affinities of various selective somatostatin analogs and the ability of GTP to inhibit radioligand binding suggested that the receptor expressed in the tumor cells belonged to the SSTR-2 subtype.
 ...
PMID:Characterization of the somatostatin receptor subtype in a bronchial carcinoid tumor responsible for Cushing's syndrome. 771 18

Somatostatin receptors were detected in peritumoral veins of various human cancer tissue specimens. Vascular and neoplastic tissue from 14 colonic adenocarcinomas, 13 carcinoids, 6 renal-cell carcinomas and 7 malignant lymphomas were analyzed for somatostatin receptors by use of quantitative receptor autoradiography. In colonic carcinoma specimens, the peritumoral vessels expressed a high density of somatostatin receptors, whereas the neoplastic tissue itself was receptor-negative in many cases. In contrast, the incidence and density of somatostatin receptors in peritumoral vessels was low in well-differentiated gastrointestinal and bronchial carcinoids, in contrast to the high density of such receptors in the carcinoid tumor tissue. Autochthonous vessels surrounding other tumors such as renal-cell carcinomas or malignant lymphomas also frequently expressed somatostatin receptors. In all cases, the somatostatin receptors were localized in veins, particularly in the smooth-muscle cell layer. They exhibited specific and high-affinity binding of somatostatin-14, somatostatin-28 and octreotide, suggesting a preferential expression of the SSTR2 receptor subtype. Since the vessels of normal non-neoplastic human tissues, e.g. of intestine or lymphatic organs, have few somatostatin receptors, the increased somatostatin receptor expression in peritumoral vessels observed in this study may be linked to the neoplastic process itself. The results suggest that somatostatin and somatostatin receptors may play a regulatory role for hemodynamic tumor-host interactions, possibly involving tumor stroma generation, tumor environment, angiogenesis and, particularly, vascular drainage of poorly differentiated neoplasms.
 ...
PMID:High density of somatostatin receptors in veins surrounding human cancer tissue: role in tumor-host interaction? 831 45

Gastric carcinoids are the sequel of enterochromaffin-like (ECL) cell hyperplasia, and are usually associated with a low-acid state and hypergastrinaemia. The somatostatin (SRIF) analogue octreotide has been noted to decrease both plasma gastrin levels and ECL cell hyperplasia/neoplasia in human and rodent experimental models. The African rodent, mastomys, exhibits a genetic propensity to gastric carcinoid formation which can be significantly accelerated by acid-inhibition-induced hypergastrinaemia. Thus a low-acid state induced by either irreversible H2 blockade or proton pump inhibition shortens the natural 2-year induction time to 4 months. In vivo studies of this model demonstrate that, similar to the human situation, octreotide decreases plasma gastrin levels and inhibits low-acid-induced gastric carcinoid formation. In vitro, using isolated ECL cells, SRIF inhibits both gastrin-stimulated ECL cell histamine secretion and DNA synthesis. This mechanism appears to function via the SRIF receptor (SSTR) subtype 2, which we have identified in both naive and transformed ECL cells. Thus the direct effect of SRIF regulation of ECL cell function is mediated by at least a SSTR2 subtype. It is possible that the alteration of the SSTR2 during ECL cell transformation may contribute to the genetic susceptibility of the mastomys to carcinoid tumour formation. The precise anti-proliferative mechanism of SRIF and its role in neuroendocrine cell transformation remain to be defined. Pharmacological manipulation of the SSTR2 may provide a viable therapeutic and diagnostic target in the management not only of ECL cell neoplasia but also other types of neuroendocrine cell tumour.
 ...
PMID:Somatostatin receptor regulation of gastric carcinoid tumours. 881 59

SRIF receptor scintigraphy (SRS) has been proposed for the localization of ectopic ACTH-secreting tumors responsible for Cushing's syndrome. However, in most cases reported, the tumors were also visible using conventional imaging. Therefore, the usefulness of SRS in localizing truly occult ectopic ACTH-secreting tumors remains unknown. We report the results of SRS in 12 patients with ectopic ACTH syndrome (EAS) and in whom the source of ACTH was occult at presentation despite carefully performed conventional imaging. The diagnosis of EAS was made by identification of an ACTH-secreting tumor during follow-up in 5 patients or given a pituitary-to-peripheral ACTH ratio of 1.9 or less during petrosal sinus sampling combined with CRH injection and a negative pituitary magnetic resonance imaging (MRI). Whole-body planar SRS, using (111)In-pentetreotide, was performed 19 times in the 12 patients during initial workup and/or follow-up. Axial tomography imaging (single-photon emission-computed tomography) was performed in 7 of these. Conventional imaging was performed within a month of SRS, allowing comparison of the two approaches for the localization of the ACTH-secreting tumors. In addition, the response of plasma cortisol, after a single injection of 200 microg octreotide, was studied in 6 patients. Five patients had negative SRS and conventional imaging studies. The source of ACTH secretion remains occult despite 10-55 months of follow-up in four of these, whereas a 2-cm ileal carcinoid tumor, with liver micrometastases, was found at laparotomy in one patient, 14 months after presentation. SRS was positive in 4 of 12 patients. It was false-positive in 1 patient with follicular thyroid adenoma. Nineteen months after presentation, SRS identified liver metastasis that was also visible using MRI in one patient, but the primary tumor remains occult. SRS identified a 10-mm pancreatic tumor that became detectable, using computed tomography (CT) scanning 9 months later, in 1 patient; and 2 mediastinal lymph nodes of 10 mm, previously ignored by MRI, in another patient, whereas no tumor was detectable within the parenchymal lung. SRS had little influence on therapeutic options in these 2 patients, in whom no final diagnosis could be made. Repetition of SRS during the follow-up of patients with previously negative scintiscans was useless. Conventional imaging was positive in 6 of 12 patients. In the 2 patients with pancreatic tumor and isolated mediastinal lymph nodes, conventional imaging studies were interpreted as positive only after the results of SRS. One patient had liver metastasis that was also visible using SRS. Thin-section CT scanning visualized ACTH-secreting bronchial tumors and metastatic mediastinal lymph nodes of 10-15 mm in diameter in 3 patients after 14-72 months of follow-up, whereas SRS was negative. There was no evident relationship between the endocrine status (hyper- or eucortisolism) and the results of SRS. The in vivo response of plasma cortisol to octreotide correlated to the results of SRS in 4 of 6 cases. In conclusion, both imaging procedures had a low diagnostic yield in this series. However, the sensitivity of SRS for the detection of bronchial carcinoids was lower than that of thin-section CT scanning. We therefore advocate the use of conventional imaging, including thin-section CT scanning of the chest, analyzed by experienced radiologists, as the first-line investigation in patients with occult EAS. SRS should not be repeated during the follow-up in patients with a previously negative scintigram.
 ...
PMID:Usefulness of somatostatin receptor scintigraphy in patients with occult ectopic adrenocorticotropin syndrome. 1048 18

Somatostatin, also known as somatotropin release-inhibiting factor (SRIF), is a natural cyclic peptide inhibitor of pituitary, pancreatic, and gastrointestinal secretion. Its long-acting analogs are in clinical use for treatment of various endocrine syndromes and gastrointestinal anomalies. These analogs are more potent inhibitors of the endocrine release of GH, glucagon, and insulin than the native SRIF; hence, they do not display considerable physiological selectivity. Our goal was to design effective and physiologically selective SRIF analogs with potential therapeutic value. We employed an integrated approach consisting of screening of backbone cyclic peptide libraries constructed on the basis of molecular modeling of known SRIF agonists and of high throughput receptor binding assays with each of the five cloned human SRIF receptors (hsst1-5). By using this approach, we identified a novel, high affinity, enzymatically stable, and long-acting SRIF analog, PTR-3173, which binds with nanomolar affinity to human SRIF receptors hsst2, hsst4, and hsst5. The hsst5 and the rat sst5 (rsst5) forms have the same nanomolar affinity for this analog. In the human carcinoid-derived cell line BON-1, PTR-3173 inhibits forskolin-stimulated cAMP accumulation as efficiently as the drug octreotide, indicating its agonistic effect in this human cell system. In hormone secretion studies with rats, we found that PTR-3173 is 1000-fold and more than 10,000-fold more potent in inhibiting GH release than glucagon and insulin release, respectively. These results suggest that PTR-3173 is the first highly selective somatostatinergic analog for the in vivo inhibition of GH secretion, with minimal or no effect on glucagon and insulin release, respectively.
 ...
PMID:Novel long-acting somatostatin analog with endocrine selectivity: potent suppression of growth hormone but not of insulin. 1114 12

5-Hydroxytryptamine (5-HT) released from enterochromaffin cells activates secretory and peristaltic reflexes necessary for lubrication and propulsion of intestinal luminal contents. The aim of this study was to identify mechanosensitive intracellular signaling pathways that regulate 5-HT release. Human carcinoid BON cells displayed 5-HT immunoreactivity associated with granules dispersed throughout the cells or at the borders. Mechanical stimulation by rotational shaking released 5-HT from BON cells or from guinea pig jejunum during neural blockade with tetrodotoxin. In streptolysin O-permeabilized cells, guanosine 5'-O- (2-thiodiphosphate) (GDP-beta-S) and a synthetic peptide derived from the COOH terminus of Galphaq abolished mechanically evoked 5-HT release, while the NH(2)-terminal peptide did not. An antisense phosphorothioated oligonucleotide targeted to a unique sequence of Galphaq abolished mechanically evoked 5-HT release and reduced Galphaq protein levels without affecting the expression of Galpha(11). Depletion and chelation of extracellular calcium did not alter mechanically evoked 5-HT release, whereas depletion of intracellular calcium stores by thapsigargin and chelation of intracellular calcium by 1,2-bis (o-Aminophenoxy) ethane-N,N,N',N'-tetraacetic acid tetra (acetoxymethyl) ester (BAPTA-AM) reduced 5-HT release. Mechanically evoked 5-HT release was inhibited by somatostatin-14 in a concentration-dependent manner. The results suggest that mechanical stimulation of enterochromaffin-derived BON cells directly or indirectly stimulates a G protein-coupled receptor that activates Galphaq, mobilizes intracellular calcium, and causes 5-HT release.
 ...
PMID:Mechanical stimulation activates Galphaq signaling pathways and 5-hydroxytryptamine release from human carcinoid BON cells. 1158 6

Five somatostatin receptor (sst) subtype genes, sst(1), sst(2), sst(3), sst(4) and sst(5), have been cloned and characterised. The five sst subtypes all bind natural somatostatin-14 and somatostatin-28 with high affinity. Endocrine pancreatic and endocrine digestive tract tumours also express multiple sst subtypes, but sst(2) predominance is generally found. However, there is considerable variation in sst subtype expression between the different tumour types and among tumours of the same type. The predominant expression of sst(2) receptors on pancreatic endocrine or carcinoid tumours is essential for the control of hormonal hypersecretion by the octapeptide somatostatin analogues such as octreotide and lanreotide. Somatostatin and its octapeptide analogues are also able to inhibit proliferation of normal and tumour cells. The high density of sst(2) or sst(5) on pancreatic endocrine or carcinoid tumours further allows the use of radiolabelled somatostatin analogues for in vivo visualisation. The predominant expression of sst(2) receptors in these tumours and the efficiency of sst(2) receptors to undergo agonist-induced internalisation is also essential for the application of radiolabelled octapeptide somatostatin analogues. Currently, [(111)In-DTPA(0)]octreotide, [(90)Y-DOTA(0),Tyr(3)]octreotide, [(177)Lu-DOTA(0)Tyr(3)]octreotate, [(111)In-DOTA(0)]lanreotide and [(90)Y-DOTA(0)]lanreotide can be used for this purpose.
 ...
PMID:Somatostatin receptors in gastroentero-pancreatic neuroendocrine tumours. 1471 57


1 2 Next >>