Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P61278 (somatostatin)
 22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bombesin is a tetradecapeptide which stimulates prolactin secretion in rats and man and in cultures of GH4C1 cells, a clonal strain of rat pituitary tumor cells. We have utilized [125I-Tyr4]bombesin to identify and characterize specific high affinity receptors in GH4C1 cells. Scatchard analysis of equilibrium binding data at 4 degrees C indicated the presence of a single class of non-interacting binding sites for bombesin (RT = 3600 +/- 500 sites/cell). The value for the equilibrium dissociation constant (Kd = 1.2 +/- 0.4 nM) agreed closely with the ED50 (0.5 nM) for bombesin stimulation of prolactin release. [125I-Tyr4]Bombesin binding at steady state at 37 degrees C was inhibited by increasing concentrations of unlabeled bombesin in a dose-dependent manner, with an ID50 = 1.4 +/- 0.2 nM. However, binding of [125I-Tyr4] bombesin was not inhibited by 100 nM thyrotropin-releasing hormone, vasoactive intestinal peptide, epidermal growth factor, or somatostatin. Therefore, [125I-Tyr4]bombesin binds to a receptor distinct from the receptors for other peptides which regulate hormone secretion by GH4C1 cells. The analog specificity for high affinity binding showed that the receptors for bombesin recognize the COOH-terminal octapeptide sequence in the molecule. Among five pituitary cell strains tested, two which contained saturable binding sites for [125I-Tyr4]bombesin (GH4C1 and GH3) had previously been shown to respond to bombesin with increased hormone secretion, whereas three which lacked receptors (GC, F4C1, and AtT20/D16v) were unresponsive. Therefore, the [125I-Tyr4]bombesin binding sites appear to be necessary for the biological actions of bombesin. Examination of the processing and metabolism of receptor-bound peptide demonstrated that at 4 degrees C [125I-Tyr4]bombesin binds to receptors on the surface of GH4C1 cells. At 37 degrees C, receptor-bound peptide is rapidly internalized and subsequently degraded in lysosomes. In summary, we have characterized for the first time specific, high affinity pituitary bombesin receptors which are necessary for the biological action of bombesin.
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PMID:Characterization of bombesin receptors in a rat pituitary cell line. 630 45

The MtTW15 pituitary tumor secretes growth hormone and prolactin. Perfusion of these dispersed MtTW15 tumor cells with 10 nM growth hormone releasing factor (GRF) increases growth hormone release without affecting prolactin release. This effect is dose-dependent between 0.001 and 0.1 nM and is blocked by 100 nM somatostatin. These findings suggest that this tumor and clones derived from it may be valuable tools in studying the cellular mechanisms of action of GRF and somatostatin.
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PMID:Growth hormone releasing factor increases growth hormone release from MtTW15 pituitary tumors. 643 47

The expression of three somatostatin receptor subtypes, SSTR3, SSTR4, and SSTR5, was evaluated in 33 pituitary tumor specimens. SSTR3 expression was studied by reverse transcription coupled to polymerase chain reaction, whereas SSTR4 and SSTR5 expression was determined by ribonuclease protection assay. SSTR3 was expressed in 6 of 7 GH-secreting tumors, all 8 clinically nonfunctioning tumors, all 3 prolactinomas, and 1 of 2 ACTH-secreting tumors tested. Eight nonfunctioning adenomas had undetectable messenger ribonucleic acid levels of SSTR4, and only 1 of them expressed SSTR5. SSTR4 expression was also undetectable in 11 GH-secreting tumors, 3 prolactinomas, and 1 ACTH-secreting tumor tested. In contrast, SSTR5 was highly expressed in 10 of 11 GH-secreting adenomas and 1 prolactinoma. Two prolactinomas and 1 ACTH-secreting tumor had low levels of expression of SSTR5. The widespread pituitary adenoma expression of SSTR3, regardless of hormonal secretory type, suggests that SSTR3 might be involved in a somatostatin action(s) other than GH or TSH regulation. SSTR5 is expressed predominantly in mammosomatotroph-derived tumors, suggesting that this receptor subtype may be an important determinant of GH secretion in acromegaly.
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PMID:Expression of three somatostatin receptor subtypes in pituitary adenomas: evidence for preferential SSTR5 expression in the mammosomatotroph lineage. 752 50

The lack of inhibition of Growth Hormone (GH) levels after glucose load is considered a marker of inappropriate GH secretion in acromegaly. In order to investigate the physiopathology of this phenomenon, we have studied the GH variations after an oral glucose load (0.75 g/kg BW per os, OGTT) or intravenous glucose bolus (25 g i.v., IVGTT), in a group of 12 acromegalic patients, aged 20 +/- 69 yr (mean 48), 5 males and 7 females, with basal GH levels ranging from 11 to 76.2 ng/ml. The results indicate that only a group of acromegalic patients (group 1) had a partial GH inhibition after OGTT (mean decrease: 56.4 +/- 4.2%), but in no patients GH levels were influenced by intravenous administration of glucose. It is possible that in group 1 patients, the gastroenteric response could partially influence the GH secretion by the pituitary tumor, probably due to an increased peripheral somatostatin release. The dissociation of the GH response to OGTT and IVTT could indicate a supersensitivity to peripheral somatostatin, related to a deficiency in central somatostatinergic tone and therefore represent a more unfavourable prognostic sign.
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PMID:GH response to oral and intravenous glucose load in acromegalic patients. 759 Jun 15

Octreotide (Sandostatin) is a synthetic analog of somatostatin, an endogenous GH inhibitory peptide that has been used as an adjunct to surgery and radiotherapy in the treatment of acromegaly. When given sc in divided daily doses, it lowers serum GH to less than 5 micrograms/L in approximately 50% of cases. Data suggest that continuous infusions of somatostatin analogs may be more effective in lowering GH. We have evaluated Sandostatin-LAR, a new long-acting preparation of Sandostatin, in eight patients with acromegaly. After an initial pharmacokinetic study, patients received a minimum of 10 im injections of Sandostatin-LAR (20, 30, or 40 mg) at 28- or 42-day intervals. Serum GH levels decreased from 10.7 +/- 2.8 micrograms/L (mean +/- SE) at baseline to a nadir of 2.6 +/- 0.4 micrograms/L after the tenth injection, and to less than 5 micrograms/L in every patient. Serum insulin-like growth factor-I decreased from 927 +/- 108 ng/mL at baseline to 472 +/- 59 ng/mL at the end of the sixth injection and returned to normal (< 500 ng/mL) in seven of the eight patients. This was associated with significant improvements in headache, arthralgia, and sweating. There was no evidence of octreotide accumulation, and the drug was well tolerated. To date, no gallstones have occurred, and serial pituitary imaging has revealed no increase in the size of the initial pituitary tumor. In particular, two previously untreated patients have shown complete regression of the initial microadenoma and have serum GH values of less than 2.5 micrograms/L. Sandostatin-LAR is an effective and well-tolerated treatment for patients with acromegaly. Undoubtedly the initial indication for Sandostatin-LAR will be in the patient who is not cured after surgery and radiotherapy, but our experience suggests that it may be used as a primary treatment in some acromegalics.
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PMID:Depot long-acting somatostatin analog (Sandostatin-LAR) is an effective treatment for acromegaly. 759 36

Recently, we developed a technique that allows the in vivo visualization in man of somatostatin receptor-positive neuroendocrine tumors after i.v. injection of [125I-Tyr3]octreotide or [111In-DTPA-D-Phe1]octreotide. Radiotherapy of such tumors using somatostatin analogs coupled to alpha- or beta-emitting radionuclides has been proposed as an application for radiolabeled somatostatin analogs. To develop this concept further, it is of importance to know whether the above-mentioned radiolabeled somatostatin analogs are internalized by the tumor cells, and whether it might be possible to manipulate the degree of internalization. In the present study we investigated the internalization of a stable somatostatin analog, [125I-Tyr3]octreotide, by mouse AtT20/D16V pituitary tumor cells and primary cultures of human GH-secreting pituitary tumor cells. Treatment of the cells with low pH was used to distinguish between membrane-bound (acid-releasable) and internalize (acid-resistant) radioligand. [125I-Tyr3]octreotide showed a time-dependent increasing accumulation in AtT20 cells; after 4 h of incubation, values up to 6-8% of the dose of radioligand added were obtained. Binding and internalization of [125I-Tyr3]octreotide were temperature dependent and inhibited by pertussis toxin. Inhibitors of lysosomal degradation did not increase the amount of internalized radioligand. After 4 h of incubation, 88% of the radioactivity present in the cells was still peptide bound, suggesting a low intracellular breakdown of this radioligand. Six of seven human GH-secreting adenoma cell cultures also internalized [125I-Tyr3]octreotide (variation between 0.24-4.98% of the dose radioligand added). Displacement of binding and internalization of [125I-Tyr3]octreotide by unlabeled octreotide showed a bell-shaped curve in AtT20 cells. At low concentrations (0.1 and 1 nM), binding and internalization were increased, whereas at higher concentrations, saturation occurred. In contrast to this, binding of [125I-Tyr3]octreotide to a broken cell preparation of AtT20 cells was displaced in a dose-dependent manner by unlabeled octreotide, with an IC50 of 0.1 nM. Similar observations were made in the human GH-secreting adenoma cell cultures. In conclusion, a high amount of [125I-Tyr3]octreotide is internalized in a specific-, time-, temperature-, and pertussis toxin-sensitive GTP-binding protein-dependent manner by mouse AtT20 and human GH-secreting pituitary tumor cells. In the presence of a low concentration of unlabeled octreotide, a rapid increase in the amount of [125I-Tyr3]octreotide internalized by AtT20 cells and by the majority of the human GH-secreting adenoma cell cultures was found.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Internalization of the radioiodinated somatostatin analog [125I-Tyr3]octreotide by mouse and human pituitary tumor cells: increase by unlabeled octreotide. 764 74

Somatostatin (SRIF) and its analogs exert potent inhibitory effects on hormonal hypersecretion. In addition, they have been demonstrated to inhibit the proliferation of various cell lines as well as the growth of some endocrine tumors in vivo. To evaluate the action of SRIF and its analog octreotide on the proliferation and cell cycle kinetics of endocrine cells, we investigated their effect on GH3 rat pituitary tumor cells, a GH-producing cell line. Using flow cytometric DNA analysis with propidium iodide staining, we found that octreotide inhibits the proliferation of synchronized GH3 cells, achieving a maximal reduction, compared to controls, of 19.4 +/- 5.3% and 22.4 +/- 5.1% with 100 ng/ml and 1000 ng/ml octreotide, respectively (P < 0.05). This effect was demonstrated to be due to a block in progression from the G0/G1 phase to the S phase of the cell cycle. This was most evident after 24 h of exposure to 100 ng/ml octreotide, at which time there was a 7.1 +/- 1.4% increase in cells in G0/G1 (P < 0.01) and a 6.6 +/- 1.3% decrease in cells in S phase (P < 0.01). However, unless octreotide was replenished, this effect was transient and overcome by 36-48 h. No apoptosis was seen, and trypan blue studies confirmed that cell death by necrosis did not occur. A single exposure to native SRIF-14 had little effect, but a G0/G1 cell cycle block and inhibition of proliferation were seen if SRIF was regularly replenished. We conclude that SRIF and octreotide exert a cytostatic effect on GH3 cells by causing a partial G0/G1 cell cycle block. These findings suggest that the actions of SRIF and octreotide occur through signal transduction pathways that act predominantly on downstream regulators.
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PMID:Somatostatin-14 and its analog octreotide exert a cytostatic effect on GH3 rat pituitary tumor cell proliferation via a transient G0/G1 cell cycle block. 766 34

The peptide galanin is synthesized within and secreted from specific cell types of the rat anterior pituitary gland. The small size of the rat anterior pituitary gland is somewhat limiting for studying the regulation of galanin gene expression and peptide synthesis/secretion. We examined the mammotropic rat pituitary tumor MtTW-10 as a possible model system to study galanin. The objectives of this study were to 1) determine if galanin is secreted from MtTW-10 cells in vitro in a regulated manner, 2) characterize the molecular forms of immunoreactive galanin secreted by MtTW-10 cells, and 3) assess whether galanin gene expression in MtTW-10 tumors is regulated by estradiol. MtTW-10 pituitary tumors were transplanted to female Wistar-Furth rats that were implanted with estradiol-filled capsules. Cells were harvested from the MtTW-10 tumors and cultured for 4 days. When examined by electron microscopy, the MtTW-10 cells maintained in culture were irregular in shape with microvilli on their surface and contained numerous large secretory granules. Immunoreactive galanin, PRL, and GH were secreted from the cells in a time-dependent fashion during static incubations. LH, ACTH, and TSH were undetectable in the culture medium. Somatostatin (10 and 100 nM) inhibited galanin, PRL, and GH release in a dose-dependent manner. In contrast, dopamine, TRH, LH-releasing hormone, CRH, and GH-releasing hormone at concentrations of 10-100 nM failed to alter hormone secretion. Only high concentrations of dopamine (1 microM) inhibited the secretion of galanin, PRL, and GH. HPLC fractionation of peptides secreted by MtTW-10 cells cultures showed that approximately 84% of the galanin immunoreactivity coeluted with synthetic rat galanin. In tumor-bearing rats, plasma levels of immunoreactive galanin were 10-fold higher after estradiol treatment than levels in ovariectomized controls. Galanin mRNA levels were increased 20-fold by estradiol in MtTW-10 tumors, as determined by solution hybridization, and peptide levels were elevated nearly 100-fold. We conclude that 1) galanin is secreted from MtTW-10 cells in vitro, and its secretion is inhibited by somatostatin; and 2) estradiol increases galanin gene expression and peptide secretion in MtTW-10 tumors in vivo. These data show that MtTW-10 tumors may be useful to study the regulation of pituitary galanin gene expression, peptide synthesis, and secretion.
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PMID:MtTW-10 pituitary tumor cells: galanin gene expression and peptide secretion. 769 42

Somatostatin (SS) and its analogs exert direct antiproliferative effects in a variety of tumor cells not only by inhibiting the mitogenic signalling of growth factor receptor kinases, but also by inducing apoptosis. In this study, the apoptotic effect of the octreotide SS analog, SMS 201-995, was investigated in phase synchronized AtT-20 mouse pituitary tumor cells. SMS 201-995 added to cells synchronized in G1 or in G2 phases induces apoptosis which is manifested in the subsequent cell cycle. No evidence of apoptosis was seen in cells subjected to cell cycle arrest in G1 by lovastatin or in G2 with 160 nM staurosporine. SMS 201-995 did not induce detectable apoptosis in unsynchronized cells which remained predominantly in G1 phase. These findings provide the first documentation that SS peptides regulate cell growth in G2 to induce apoptosis.
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PMID:Cell cycle dependent induction of apoptosis by somatostatin analog SMS 201-995 in AtT-20 mouse pituitary cells. 773 6

This review evaluates the efficacy, tolerability, and safety of continuous subcutaneous infusion (CSI) relative to intermittent subcutaneous injection (ISI) of the somatostatin analog, octreotide in the treatment of acromegaly. Data was extracted from five clinical series using CSI octreotide in acromegaly, six reports comparing CSI to ISI, and three studies comparing pulsatile subcutaneous infusion (PSI) to ISI. Effects of each drug regimen on the control of growth hormone (GH), insulin-like growth factor (IGF-1), clinical symptomatology, pituitary tumor size, and adverse effects were evaluated. Normalization of serum GH or IGF-1 levels, as well as improvement in clinical symptoms was reported in the majority of the patients studied. Cases in which pituitary adenomas decreased in size were also documented during the study period. When the effects of CSI were compared with ISI, a more pronounced control of GH and IGF-1 was observed. In addition, diurnal GH fluctuation during CSI was significantly reduced relative to ISI in two reports. Moreover, in two patients, CSI achieved similar clinical and biochemical effects at lower doses than when the drug was given by ISI. Finally, adverse effects with CSI may be less severe than with ISI. Continuous subcutaneous infusion of octreotide produced biochemical improvement in 67 of the 88 patients reviewed. When compared with ISI, CSI induced more pronounced biochemical control, often with less fluctuation in GH and IGF-1 levels. Because of a lack of data, definite conclusions regarding the differences between regimens on clinical symptomatology and tolerability could not be discerned. A large prospective, long-term randomized crossover study is recommended to make these determinations.
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PMID:Continuous versus intermittent subcutaneous infusion of octreotide in the treatment of acromegaly. 775 14


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