Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0001430 (adenoma)
 21,222 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanisms of somatostatin (SRIH) action on thyroid-stimulating hormone (TSH) secretion were examined using human TSH-secreting adenoma cells. SRIH (10(-7) M) inhibited TSH secretion through a pertussis toxin-sensitive G protein. SRIH also inhibited forskolin- and 8-bromo-adenosine 3',5'-cyclic monophosphate (8-BrcAMP)-induced TSH secretion. The mechanisms of this inhibition were investigated by measuring intracellular Ca2+ concentration ([Ca2+]i) and by electrophysiological experiments. Application of 10(-7) M SRIH reduced the [Ca2+]i, whereas forskolin and 8-BrcAMP increased the [Ca2+]i. Simultaneous application of SRIH abolished the forskolin-and the 8-BrcAMP-induced [Ca2+]i increase, indicating that the SRIH-induced decrease in [Ca2+]i was independent of the reduction in intracellular cAMP. Under current clamp using the whole cell clamp, 10(-7) M SRIH hyperpolarized the membrane and arrested Ca(2+)-dependent action potentials, which accounted for the SRIH-induced decrease in [Ca2+]i. Voltage clamp experiments revealed that this membrane hyperpolarization resulted from the activation of an inward-rectifying K+ current through a pertussis toxin-sensitive G protein. Intracellular injection of cAMP (100 microM) through the patch pipette did not abolish the SRIH-induced K+ current, indicating that the activation of SRIH-induced K+ channels was independent of intracellular cAMP. From these data, we concluded that SRIH-induced membrane hyperpolarization was responsible for the [Ca2+]i decrease, which in turn inhibited TSH secretion. Application of thyrotropin-releasing hormone (TRH; 10(-7) M) caused an increase in the [Ca2+]i, composed of an initial transient increase followed by a sustained increase. SRIH inhibited the sustained increase in [Ca2+]i. SRIH also inhibited the TRH-induced decrease in the membrane conductance.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mechanisms of action of somatostatin on human TSH-secreting adenoma cells. 773 52

We have previously shown that the somatostatin (SRIH) precursor (pro-SRIH) and SRIH are present in the normal human pituitary, whereas mature SRIH is never detected in GH-secreting adenomas associated with high plasma GH levels, and pro-SRIH is absent in 50% of them. Considering the fact that GHRH is present and released in vitro in higher amounts from GH adenomas than from normal human pituitaries, the possibility of a negative control exerted by GHRH on pituitary SRIH was investigated. When GH-secreting adenomas were incubated for 4 h in the presence of GHRH (10(-8) mol/L), the amount of pro-SRIH, quantified after Sephadex G-50 filtration of the acetic acid extracts, was significantly decreased. The percent inhibition was negatively correlated to the amount of endogenously released GHRH measured in the control incubation medium, suggesting a local negative feedback control exerted by pituitary GHRH on pituitary SRIH. This was further demonstrated when adenomas were incubated with a GHRH antibody. Indeed, the presence of the GHRH antibody resulted in a significant increase in the content of pro-SRIH in the adenoma. Similar results were obtained for in vitro SRIH release; exogenous GHRH induced an inhibition of SRIH release from GH-secreting adenomas, and the GHRH antibody had the opposite effect. Using a perifusion system, we showed the concomitance between the increase in GH release and the decrease in SRIH release after GHRH stimulation. Together, these results show in vitro a negative control exerted by GHRH (both exogenous and locally released) on adenomatous pituitary SRIH. This further amplifies the importance of autocrine or paracrine controls in these tumors.
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PMID:Growth hormone (GH)-releasing hormone tonically inhibits in vitro endogenous somatostatin in human GH-secreting tumors. 774 20

In the present study we investigated the effects of the somatostatin (SS) analogs octreotide, RC-160, and BIM-23014 on GH release by cultured cells of human GH-secreting pituitary tumors, in normal rat anterior pituitary cells, and on gastrin release by cultured cells from a human gastrinoma. In all GH-secreting adenomas and in rat anterior pituitary cells, RC-160 was the most potent compound. RC-160 significantly inhibited GH-, PRL, and/or alpha-subunit release by human GH-secreting pituitary adenoma cells in concentrations as low as 10(-12)-10(-14) M, whereas at the same concentrations, octreotide and BIM-23014 did not inhibit or were significantly less effective in inhibiting GH release (P < 0.01, RC-160 vs. octreotide and BIM-23014). In rat anterior pituitary cell cultures, the IC50 values for inhibition of GH release were, in rank order of potency, 0.1, 5.3, 47, 48, and 99 pM for RC-160, SS-14, BIM-23014, octreotide, and SS-28, respectively. Maximal inhibitory effects by the three analogs were the same in the human GH adenoma cell cultures and the rat anterior pituitary cell cultures (-60%). On the basis of these data, RC-160 appears to be about 500 times more potent than octreotide and BIM-23014 in inhibiting GH release by rat anterior pituitary cells in vitro. Forskolin (100 microM) as well as pretreatment of the cells with pertussis toxin significantly diminished the inhibitory effects of the three SS analogs and those of SS-14 and SS-28 to the same extent. The latter data suggest that octreotide, RC-160, and BIM-23014 act mainly via a pertussis toxin-sensitive G-protein and an adenylyl cyclase-dependent mechanism. In the human gastrinoma culture, RC-160 inhibited gastrin release significantly more than octreotide at 10(-12)- and 10(-14)-M concentrations (P < 0.01). In conclusion, the SS analogs octreotide, RC-160, and BIM-23014 may have significant different potencies of inhibition of hormone release in vitro, with RC-160 being the most potent SS analog and octreotide and BIM-23014 having similar potencies. Depending on the pharmacokinetic properties of these three octapeptide SS analogs, these observations may have consequences for the medical therapy of patients with SS receptor-positive endocrine tumors.
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PMID:Relative potencies of the somatostatin analogs octreotide, BIM-23014, and RC-160 on the inhibition of hormone release by cultured human endocrine tumor cells and normal rat anterior pituitary cells. 790 31

Using a combination of polymerase chain reaction and genomic library screening we have cloned a human gene for a subtype of the somatostatin (SST) receptor (SSTR) termed human SSTR5 (hSSTR5), which is located on chromosome 16. The predicted amino acid sequence of hSSTR5 displays 75% sequence identity with a recently identified rat SSTR [Mol. Pharmacol. 42:939-946 (1992)], suggesting that it is the human homologue of this receptor. hSSTR5 consists of a 363-residue polypeptide exhibiting a putative seven-transmembrane domain topology typical of G protein-coupled receptors. The receptor displays considerable sequence identity to hSSTR1 (42%), hSSTR2 (48%), hSSTR3 (47%), and hSSTR4 (46%). Membranes prepared from COS-7 cells transiently expressing the hSSTR5 gene bound 125I-Leu8,D-Trp22,Tyr25-SST-28 (125I-LTT-SST-28) with high affinity and in a saturable manner. SST-14, SST-28, and various synthetic SST peptide agonists produced dose-dependent inhibition of radioligand binding with the following rank order of potency: LTT-SST-28 > SST-28 > D-Trp8-SST-14 > SST-14 approximately RC-160 approximately BIM 23014 > MK-678 > SMS 201-995. hSSTR5 bound SST-28 with a 12.6-fold greater affinity (Ki = 0.19 nM), compared with SST-14 (Ki = 2.24 nM), indicating that the receptor is SST-28 selective. Addition of GTP, guanosine-5'-O-(3-thio)triphosphate, Na+ ions, or pertusis toxin greatly reduced 125I-LTT-SST-28 binding, thereby indicating that hSSTR5 is coupled to pertussis toxin-sensitive G proteins. Both SST-14 and SST-28 displayed dose-dependent inhibition of forskolin-stimulated cAMP accumulation, consistent with functional coupling of the receptor to adenylyl cyclase inhibition. Northern blot analysis of SSTR5 mRNA revealed a 2.4-kilobase transcript in normal rat pituitary and GH3 rat pituitary tumor cells and a 4.0-kilobase transcript in normal human pituitary. Reverse transcriptase polymerase chain reaction revealed expression of the hSSTR gene in fetal human pituitary and hypothalamus but not in human cerebral cortex. In situ hybridization of the rat pituitary showed that SSTR5 mRNA is selectively localized in the anterior lobe. SSTR5 mRNA was not expressed in four human pituitary tumors (somatotroph adenoma, prolactinoma, and chromophobe adenomas) or in a human insulinoma. Although hSSTR5 displays approximately 75% sequence identity with rat SSTR5, the two receptors display significantly different pharmacological profiles, especially with respect to their binding affinities for the SST analogue SMS 201-995.
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PMID:Molecular cloning, functional characterization, and chromosomal localization of a human somatostatin receptor (somatostatin receptor type 5) with preferential affinity for somatostatin-28. 790 5

Antiproliferative effects of somatostatin (SRIH) analogs were investigated in human thyroid carcinoma cell lines. Membrane preparations from six human thyroid cell lines, including follicular (RO 87-M-1 and RO 82-W-1), papillary (NPA87), and anaplastic (RO 90-D-1) carcinomas, a follicular adenoma, as well as benign and malignant human thyroid tissues, contained high affinity SRIH-binding sites. Ligand-binding studies ([125I]Tyr11-SRIH) demonstrated mean dissociation constants ranging from 114-224 pmol/L, and 20-154 fmol/mg membrane protein mean receptor sites, in cell lines. Four cell lines were grown for 3 days in monolayers with SRIH analogs (octreotide or MK0678) at concentrations from 0.05-100 nmol/L in serum-free medium to assess changes in cell numbers. At the highest dose, MK0678 produced dose-dependent inhibition of growth in RO 87-M-1 and NPA87, each to about 70% of that in control cells. Octreotide produced dose-dependent stimulation of growth in RO 87-M-1 cells, but caused growth inhibition in NPA87 cells, with loss of effect at the highest dose. RO 82-W-1 did not respond to MK0678, yet caused biphasic inhibition with octreotide (75% and 45% of control cell numbers at 0.05 and 100 nmol/L doses, respectively). Anaplastic cells, RO 90-D-1, did not respond to either analog despite similar ligand binding. Addition of epidermal growth factor (100 micrograms/L) or TSH (200 mU/L) increased the sensitivity of RO 87-M-1 cells to growth inhibition by the lowest dose of MK0678, producing biphasic dose-response curves. In conclusion, the present data demonstrate specific SRIH binding to membranes of thyroid carcinoma cells and tissues as well as discordant growth effects of different SRIH analogs on the same cell lines. This may be a result of differential stimulation and regulation of distinct SRIH receptor subtypes.
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PMID:Somatostatin analogs affect proliferation of human thyroid carcinoma cell lines in vitro. 790 17

We report the case of a 62-year-old woman who was admitted to our hospital with diabetic ketoacidosis. Her urinary C-peptide was 3.5 micrograms/day, HLA typing was DR9, and serum was positive for islet cell antibodies. There was no significant increase in the major viral titer. Pancreatic head tumor was suspected, and pancreaticoduodenectomy was performed. The pathology of this tumor was polycystic adenoma. We examined the surgical specimen from around the tumor histologically. The pancreatic islets had decreased in number. The immunohistochemical staining of islets for insulin, glucagon and somatostatin showed that the number of B cells had decreased remarkably, while A and D cells were preserved. Marked lymphocytic infiltration was observed in the islets. The majority of lymphocytes were helper/inducer and suppressor/cytotoxic T cells, which did not express HLA-DR antigen or interleukin-2 receptor. No NK cells were present in the islets. The present case, which was examined histologically in detail, is consistent with the previously proposed hypothesis that autoimmunity might play an important role in the pathogenesis of insulin-dependent diabetes mellitus.
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PMID:Type 1 (insulin-dependent) diabetic patient with remarkable infiltration of lymphocytes to the islets. 795 31

The factors that determine the hormone and volume responses of pituitary adenomas to the somatostatin analog octreotide are poorly understood. We, therefore, studied the correlation between 111indium-pentetreotide somatostatin receptor scintigraphy (SRS) and the clinical and immunohistochemical classification of pituitary adenomas, on the one hand, and hormone and volume responses, on the other hand. Ten patients with GH-secreting (6 females and 4 males; age, 31-67 yr) and 14 patients with clinically nonfunctioning (NF) macroadenomas (5 females and 9 males; age, 22-79 yr) were preoperatively treated with 300 micrograms/day octreotide, which was increased to 600 and 1500 micrograms/day at weekly intervals and then continued for at least 3 months until surgery. SRS was performed before therapy. A sellar magnetic resonance imaging scan was performed before therapy; 1, 2, and 3 weeks and 3 months after start of therapy; and after surgery. Acromegalics also had an 8-h GH profile, insulin-like growth factor-I determination, and a 100-g oral glucose load at these time points. An attempt was made to identify NF adenomas as gonadotroph adenomas using their LH, FSH, and alpha-subunit responses to TRH. In acromegalic patients, octreotide suppressed mean GH (8-h profile) and insulin-like growth factor-I concentrations from 34.9 +/- 9.7 to 8.1 +/- 3.6 micrograms/L and from 2122 +/- 1025 to 701 +/- 208 micrograms/L, respectively, after 3 months. Significant (26-85% decline) tumor shrinkage occurred in 5 of 10 patients, mainly within the first week. Tumor shrinkage and GH suppression were not correlated. Four of 7 patients had increased pituitary 111indium-pentetreotide uptake, but this did not predict GH suppression or tumor shrinkage. Of the NF adenomas, 2 responded with shrinkage (57% and 96% decline). Four of 12 adenomas had increased 111indium-pentetreotide uptake, but this did not correlate with tumor shrinkage (2 adenomas; 1 gonadotroph and 1 null cell adenoma), immunohistochemistry, or clinical classification. We conclude that preoperative octreotide therapy suppresses GH in most patients and reduces tumor volume in up to 50% of acromegalic patients. It also induces shrinkage in some NF adenomas, although less frequently. SRS does not predict shrinkage of either tumor type. Shrinkage does not correlate with clinical classification or immunohistological characteristics. Further studies are needed to identify the factors that determine the hormone and volume responses of pituitary adenomas to octreotide therapy.
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PMID:Preoperative octreotide treatment of growth hormone-secreting and clinically nonfunctioning pituitary macroadenomas: effect on tumor volume and lack of correlation with immunohistochemistry and somatostatin receptor scintigraphy. 796 37

A 40-year-old male patient with a 2 years history of recurring hyperthyroidism is presented with clinical hyperthyroidism and diffuse goiter. Despite thyreostatic treatment and surgical thyroid ablation the hyperthyroidism recurred. The patient had laboratory evidence of hyperthyroidism and his serum TSH was persistently and enormously elevated (T4:214 nmol/l, T3:6.9 nmol/l, TSH:218 mIU/l)> Computed tomography and magnetic resonance imaging confirmed a pituitary mass of 7 cm in a-p diameter, with supra-, parasellar and sphenoidal extension. The pituitary adenoma was partially resected by transsphenoidal surgery, which failed to result in a substantial decrease in the serum thyrotropin level. Pituitary irradiation and a long-term somatostatin analog octreotide treatment (300-600 micrograms/die) combined with bromocriptine therapy resulted in a significant, but still incomplete suppression of thyrotropin secretion (TSH level about 15 mIU/l) and persisting mild hyperthyroidism. The size of the adenoma was unchanged during the two years of highdose octreotide treatment period. According to our best knowledge this is the first reported case of a thyrotropin-secreting pituitary adenoma in Hungary.
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PMID:[Thyroid-stimulating hormone-secreting pituitary adenoma]. 799 Dec 45

Five patients with gonadotropin-secreting pituitary adenomas were studied. The utility of gonadotropin response to TRH stimulation in the diagnosis and follow-up of these tumors was evaluated, as well as the effects of somatostatin analogue SMS 201-995 and bromocriptine on gonadotropin release. Three patients had FSH and LH secreting adenomas while the other two tumors secreted FSH and alpha-subunit. Transsphenoidal resection of the pituitary adenomas were performed in all patients. Following preoperative TRH administration (400 micrograms i.v.), marked increases were observed in FSH levels in two cases, in LH levels in three and in alpha-subunit in one. The FSH and LH responses to t.his stimulus persisted in the same patients after surgery. Following acute bromocriptine administration (5 mg orally), FSH was reduced in all cases by 19% to 46%, LH in three cases by 50-67% and alpha-subunit in one by 33%. In patient no. 5, with persistent high FSH levels in the immediate postoperative period, long-term bromocriptine treatment was administered (15 mg/d orally), resulting in normalization of FSH levels 6 months later, although the size of the tumor was not reduced. After acute SMS 201-995 administration (100 micrograms sc) FSH decreased in two cases by 38% and 76%, LH in three by 30-56% and alpha-subunit in one by 20%. We conclude that gonadotropin response to TRH stimulation is useful in the diagnosis and follow-up of patients with gonadotroph adenoma. Bromocriptine and SMS 201-995 may be effective as coadjuvant treatment following surgery and radiotherapy in these patients, although long-term studies will be necessary to confirm these proposals.
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PMID:Usefulness of thyrotropin-releasing hormone test, SMS 201-995, and bromocriptine in the diagnosis and treatment of gonadotropin-secreting pituitary adenomas. 800 39

The effect of the dopamine agonist bromocriptine and the somatostatin analog SMS 201-995 on growth of 12 human somatotrophic and 13 non-functioning adenoma cell cultures was investigated. When adenoma cells were maintained in medium supplemented with 5% fetal calf serum, cell counts of 10 of 12 somatotrophic cultures increased to 145 +/- 6 and 171 +/- 9% (mean +/- SD) and in 12 of 13 non-functioning cell cultures up to 125 +/- 12 and 217 +/- 15% after 3 days of incubation. In most cases bromocriptine and SMS 201-995 dose dependently (1 nmol/l to 10 mumol/l) inhibited adenoma cell growth but there was only (1, 10 mumol/l) a significant inhibitory effect at high doses of both drugs. A 1 mumol/l concentration of bromocriptine decreased cell counts of 5 of 12 somatotrophic cell cultures (range 84 +/- 3 to 76 +/- 6% vs control = 100%) and in 5 of 13 non-functioning cell cultures (range 85 +/- 4 to 71 +/- 7%). A 10 mumol/l concentration of bromocriptine decreased cell counts in all 12 somatotrophic (range 87 +/- 1 to 61 +/- 8%) and in 12 of 13 non-functioning adenoma cultures (range 87 +/- 6 to 57 +/- 3%). Bromocriptine specifically inhibited growth because its effect could be reversed by the dopamine D2-receptor antagonist haloperidol. Both 1 and 10 mumol/l SMS 201-995 significantly decreased cell counts in three of six somatotrophic (87 +/- 3 to 38 +/- 3%) cell cultures. In two of five cases growth of non-functioning adenoma cultures was suppressed by 1 mumol/l SMS 201-995, and in four of five cases by 10 mumol/l (86 +/- 3 to 74 +/- 4%). The growth inhibitory effect of both bromocriptine and SMS 201-995 was not just due to an effect on growth of fibroblasts contaminating the adenoma cell cultures, because it could be observed also when adenoma cells were maintained in a D-valine-supplemented medium that suppresses fibroblast growth. In summary, both bromocriptine and SMS 201-995 at high doses were able to inhibit cell growth of cultured somatotrophic and non-functioning adenomas in vitro. However, the mechanism of this inhibitory effect is not yet well understood.
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PMID:Effect of bromocriptine and SMS 201-995 on growth of human somatotrophic and non-functioning pituitary adenoma cells in vitro. 812 83


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