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)

Somatostatin (SRIF) exerts its diverse biological effects through a family of membrane receptors. In addition to inhibiting GH secretion, SRIF has antiproliferative effects and has been used clinically in the treatment of pituitary tumors. SRIF receptor (SSTR) expression has recently been identified in pituitary adenomas, and it is unknown whether differential expression of SSTR subtypes predicts clinical responses to SRIF analogs. We therefore determined which SSTR subtype messenger RNAs (mRNAs) are expressed in pituitary adenoma phenotypes and in normal human pituitary tissue using reverse transcriptase-polymerase chain reaction and tested whether expression of specific SSTR subtype mRNA is necessary for SRIF inhibition of GH secretion in human somatotroph adenomas in vitro. Expression of SSTR subtypes 1, 2, and 5 mRNA was identified in all pituitary adenoma types and normal pituitary tissue. In contrast, SSTR3 mRNA was detected in only one somatotroph adenoma as well as in control insulinoma tissue, a tissue known to express SSTR3 mRNA, and was not detected in normal pituitary tissue. SSTR4 mRNA was not detected in any human pituitary tissue. To determine whether specific SSTR subtype mRNA expression is required for SRIF inhibition of GH secretion, five somatotroph adenomas were treated with 10(-7) mol/L SRIF in vitro, and significant inhibition of GH release occurred in all adenomas. All five tumors expressed SSTR2 mRNA and SSTR5 mRNA, and three expressed SSTR1 mRNA. The absence of SSTR1 mRNA expression did not affect the ability of SRIF to suppress GH secretion. We conclude that: 1) human pituitary adenomas and normal pituitary express multiple SSTR gene transcripts; 2) SSTR5 mRNA, which has not been reported in other human endocrine tumor types, is expressed in neoplastic and normal pituitary tissue; and 3) SSTR2 mRNA, SSTR5 mRNA, and variable SSTR1 mRNA are expressed in GH-secreting tumors, which are responsive to SRIF in vitro. Further understanding of SSTR gene expression in pituitary adenomas will facilitate our understanding of the pathogenetic mechanisms of tumorigenesis and may provide a rationale for the use of specific SRIF analogs for clinical application.
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PMID:Somatostatin receptor subtype gene expression in pituitary adenomas. 771 15

The rodent SSTR2 mRNA has been reported to be alternatively spliced to generate long (SSTR2A) and short (SSTR2B) receptor isoforms which differ in sequence at their C-terminal regulatory domains. By extending the 3' nucleotide sequence of the human gene (hSSTR2) we show highly conserved intron/exon boundaries suggesting that hSSTR2 is also capable of generating spliced variants. mRNA blots of rat tissues reveal 2 transcripts of 2.8 and 2.3 kb that are differentially expressed in brain regions and multiple peripheral organs. The 2.3 kb mRNA is preferentially expressed in pituitary tumor cells (AtT-20 mouse, GH3 rat, human prolactinoma, human somatotroph adenoma), but not in rat or human insulinoma cells. This transcript shows 4 fold induction by forskolin in AtT-20 cells suggesting cAMP dependent control of SSTR2 gene expression. The abundant expression of SSTR2 gene, the occurrence of 2 isoforms and evidence of extensive regulation at both gene and peptide levels, suggests that SSTR2 is the principal SST-14 selective subtype.
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PMID:Multiple gene transcripts of the somatostatin receptor SSTR2: tissue selective distribution and cAMP regulation. 838 8

The expression of somatostatin receptor (SSTR) subtypes and relative abundance of SSTR2 mRNA were examined in 18 pituitary adenomas using the reverse transcription-polymerase chain reaction (RT-PCR) method. SSTR1 and SSTR2 were expressed in all pituitary adenomas examined. Six of 9 somatotroph adenomas, 1 of 4 lactotroph adenomas and 1 of 2 thyrotroph adenomas also expressed SSTR5. SSTR3 and SSTR4 mRNAs were detected in 1 and 2 cases of somatotroph adenoma, respectively. SSTR2 mRNA expression was quantified by comparison with the PCR cycle-dependent amplification of beta-actin or cyclophilin. The relative abundance of SSTR2 mRNA varied greatly among adenomas with more than a 1000-fold difference. SSTR2 mRNAs in lactotroph adenomas were less abundant (P < 0.01) than those in somatotroph adenomas. No significant correlation was found between the relative abundance of SSTR2 mRNA levels and GH sensitivity to octreotide administration. However, one of the thyrotroph adenomas exhibited marked shrinkage in tumor size after octreotide therapy, in which SSTR2 mRNA was the most abundant among the adenomas examined. GH sensitivity to octreotide was not significantly different between SSTR5 mRNA positive and negative adenomas. In conclusion, SSTR2 mRNA levels varied greatly among pituitary adenomas but were not correlated with GH sensitivity to octreotide. Further investigations of functional SSTR subtype proteins and of postreceptor signal transductions are required to clarify the molecular mechanisms of octreotide action.
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PMID:Expression of somatostatin receptor (SSTR) subtypes in pituitary adenomas: quantitative analysis of SSTR2 mRNA by reverse transcription-polymerase chain reaction. 886 48

Somatostatin (SRIH) analogs can suppress the proliferation of human differentiated thyroid carcinoma cell lines that express SRIH receptors (SSTRs) demonstrated by radioligand binding analysis. Five distinct human SSTR subtypes (hSSTR1-5) that bind native SRIH exhibit diverse affinities to a wide range of SRIH analogs. Reverse transcriptase-PCR amplification of ribonucleic acids (RNAs) obtained from normal thyroid tissues and nine human thyroid carcinoma cell lines, grown as monolayer cultures and xenograft tumors in nude mice, were used to discriminate expression of SSTR subtype messenger RNAs (mRNAs). The cell lines were derived from a follicular adenoma (KAK-1), two follicular carcinomas (MRO-87 and WRO-82), two papillary carcinomas (NPA87 and KAT-10), and four anaplastic thyroid carcinomas (DRO-90, ARO-81, KAT-4, and KAT-18). Most thyroid cancer cell line monolayers and xenografts expressed SSTR3 and SSTR5 mRNAs. SSTR1 expression was more varied between monolayers and xenografts, whereas SSTR2 mRNA was only faintly detectable at the most extreme resolution. SSTR4 mRNA was faintly positive in only one anaplastic carcinoma xenograft. Normal thyroid also expressed SSTR3 and SSTR5 mRNAs, with only faint expression of SSTR1 and SSTR2 mRNAs (in one of five and three of five samples, respectively). SSTR mRNA expression was dependent upon in vitro culture conditions, as xenograft SSTR mRNA expression tended to decrease compared to that in each respective monolayer culture. Characterization of SSTR subtype expression in human thyroid carcinomas may permit targeting of specific SRIH analogs to inhibit proliferation of differentiated and anaplastic thyroid carcinomas in patients.
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PMID:Somatostatin receptor subtype expression in human thyroid and thyroid carcinoma cell lines. 917 96

This new generation of SRIF analogs offer exciting opportunities to improve hormone hypersecretion in patients with GH- and TSH-secreting pituitary adenomas and possibly even in patients harboring prolactinomas and non-functioning tumors. Future development of novel analogs with improved affinity for both SSTR2 and SSTR5 may have even greater potency to suppress pituitary hormone hypersecretion and block adenoma growth.
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PMID:Structure and function of somatostatin receptors in growth hormone control. 938 89

Previously, we have shown somatostatin receptor (SSTR) subtype-specific regulation of growth hormone (GH), thyroid-stimulating hormone, and prolactin (PRL) secretion in human fetal pituitary cultures, where GH and thyroid-stimulating hormone are mediated by both SSTR2 and SSTR5, whereas SSTR2 preferentially mediates PRL secretion. We now tested SSTR subtype-selective analogues in primary human GH- and PRL-secreting pituitary adenoma cultures. Analogue affinities determined by membrane radioligand binding in cells stably expressing human SSTR forms were either SSTR2 or SSTR5-selective. Analogues preferential either for SSTR2, including octreotide, lanreotide, and novel compounds with improved affinity for SSTR2, or new SSTR5-selective compounds suppressed GH in tumor cell cultures (up to 44% of control; P < 0.0005). However, novel analogues from both groups were 30-40% more potent than octreotide and lanreotide in suppressing GH (P < 0.05). Heterologous analogue combinations containing both SSTR2- and SSTR5-selective compounds were more potent in decreasing GH than analogues used alone (P < 0.05), or than combinations of compounds specific for the same receptor subtype (P < 0.005). In contrast, SSTR2-selective analogues did not suppress PRL release from six cultured prolactinomas studied. However, new SSTR5-selective analogues suppressed in vitro PRL secretion (30-40%; P < 0.05) in four of six prolactinomas. These results suggest that both SSTR2 and SSTR5 are involved in GH regulation in somatotroph adenoma cells, whereas SSTR5 exclusively regulates PRL secretion from prolactinoma cells. Thus, somatostatin analogues with improved selective binding affinity for these receptor subtypes may be effective in the treatment of either GH- or PRL-secreting adenomas.
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PMID:Somatostatin receptor (SSTR) subtype-selective analogues differentially suppress in vitro growth hormone and prolactin in human pituitary adenomas. Novel potential therapy for functional pituitary tumors. 941 Sep 19

As cotreatment of somatostatin (SRIF) and dopamine (DA) agonists reduces GH in acromegaly more effectively than either agonist alone, SRIF and DA receptors (SSTR and DAR) may interact with enhanced functional activity. The selective SSTR2 agonist, BIM-23023 (50% effective dose, 0.42), and the DAR2 agonist, BIM-53097 (50% effective dose, 22.1), dose- dependently inhibited GH secretion in cultured primary rat and human fetal as well as in human pituitary tumor cells derived from GH-secreting adenomas. The combination of individual SSTR2 and DAR2 agonists was additive for suppressing GH secretion in both rat and human pituitary cells. BIM-23A387 is a chimeric compound that contains structural elements of both SRIF and DA in a single molecule and retains potent, selective binding to DAR2 and SSTR2. BIM-23A387 (50% effective dose, 0.16 for SSTR2 and 24.5 for DAR2), displayed similar efficacy in suppressing GH secretion from rat pituitary cells as the combination of the two individual agonists. In contrast, the chimeric molecule was more potent than individual selective analogs in suppressing GH secretion by human fetal pituitary and GH-secreting adenoma cells (P < 0.05). Although the DAR2 antagonist, sulpiride, reversed BIM-23A387-induced GH suppression, blockade of SSTR2 by the selective SSTR antagonist, BIM-23454, did not block BIM-23A387-suppressed GH secretion. These results indicate that mechanisms by which the chimeric molecule suppresses pituitary GH secretion may not be mediated by individual SSTR2 or DAR2 signaling, respectively. Functional interaction of the two receptors may explain the clinical observation that more effective GH suppression is achieved when DAR2 and SSTR2 agonists are administered in combination. The SRIF/DA chimeric molecule, BIM-23A387, represents a novel tool for effective drug treatment of acromegaly and for prolactinomas otherwise resistant to dopaminergic therapy.
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PMID:Suppression of rat and human growth hormone and prolactin secretion by a novel somatostatin/dopaminergic chimeric ligand. 1460 82

Since the cloning and characterization of the five human somatostatin receptor (SSTR) subtypes, our understanding of the expression and functional role of the five SSTR subtypes in human (neuro-)endocrine tumors has increased significantly. The majority of human (neuro-)endocrine tumors express multiple SSTR. GH-secreting pituitary adenomas preferentially express SSTR2 and SSTR5, prolactinomas SSTR1 and SSTR5, and corticotroph adenomas express SSTR2 (low number) and predominantly SSTR5s. In addition, gastroenteropancreatic (GEP) neuroendocrine tumors frequently express multiple SSTR as well, with SSTR2 being expressed at the highest level. Treatment with the current generation of octapeptide somatostatin-analogs, e.g. octreotide and lanreotide, normalizes circulating GH- and IGF-I levels in approximately 60-70% of acromegalic patients, thereby remaining about one-third of patients uncontrolled. In patients with GEP neuroendocrine tumors, both somatostatin-analogs effectively suppress the production of bioactive peptides and hormones by the tumor cells, resulting in an important improvement of the related clinical symptomatology. However, a considerable proportion of patients experience an escape from treatment within months to several years. Altogether, the current generation of somatostatin analogs are effective medical tools in the treatment of acromegalic patients and of patients with neuroendocrine GEP tumors, but there is certainly a need for novel somatostatin analogs. In recent years, a significant number of novel somatostatin-ligands has been developed. These ligands include SSTR selective-, bi-specific, universal, as well as chimeric dopamine (DA)-somatostatin ligands. In vitro studies using human pituitary adenoma cells demonstrate a more profound inhibition of GH, PRL and ACTH secretion by somatostatin-analogs targeting both SSTR2s and SSTR5s, compared with SSTR2-preferential somatostatin-analogs. This likely reflects the SSTR subtype expression pattern in the adenoma cells. A first proof-of-concept trial with the more universal somatostatin-ligand SOM230 in 12 acromegalic patients shows that a single dose of SOM230 is effective in suppressing circulating GH concentrations in a significant larger number of patients compared with octreotide. In animal models, SOM230 has a better effect on GH and IGF-I level with less signs of tachyphylaxis compared with octreotide. Depending on the SSTR expression pattern on neuroendocrine GEP tumors, somatostatin-analogs targeting multiple SSTRs may play a future role in the more long-term control of patients with neuroendocrine GEP tumors. The first clinical trial comparing octreotide and SOM230 is ongoing. However, every advantage has its disadvantage. Targeting multiple SSTR potentially induces more adverse effects as well. Especially, glucose homeostasis might induce new problems in the long-term use of universal ligands.
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PMID:Pre-clinical and clinical experiences with novel somatostatin ligands: advantages, disadvantages and new prospects. 1662 43

Clinically "non-functioning" human pituitary adenomas (NFPA) constitute about 35% of pituitary adenomas. Somatostatin receptors (SSTR) expression in these adenomas has previously been described both in vitro and in vivo, without evidence for a correlation with tumor volume or the therapeutic efficacy of somatostatin analogs. This study was performed on 13 surgically removed pituitary macroadenomas, diagnosed before surgery as "non-functioning". In addition, 3 growth hormone (GH)-secreting adenomas served as controls. A specimen from each tumor was dispersed and digested to isolate and culture the tumor cells, and the in vitro effects of SSTR2 and SSTR5 selective analogs and Cortistatin (CST) (100nM) on cell viability were studied. The quantity of viable cells was estimated using the XTT method. RNA purification of tumor samples and subsequent RT-PCR studies for SSTR2 and SSTR5 expression were performed. Somatostatin analog with high affinity for SSTR2 reduced cell viability by 20-80% in 8 of 13 NFPAs studied, all expressing the SSTR2. The inhibitory effect on cell viability of SSTR5-selective analog was 15-80% in 10 of 13 NFPAs studied, all but three expressing the SSTR5. CST, however, effectively reduced cell viability in only 6 NFPAs. Cell viability was inhibited by all peptides studied in 2 out of 3 GH-secreting adenomas, expressing both receptors. The third adenoma responded to SSTR2 analog and expressed only SSTR2. These results suggest the involvement of SSTR2 and SSTR5 in the anti-proliferative effects of somatostatin; however, CST is less potent in reducing cell viability in these tumors.
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PMID:Effects of selective somatostatin analogs and cortistatin on cell viability in cultured human non-functioning pituitary adenomas. 1827 67

Somatostatin analogs and dopamine agonists are clinically used for medical therapy of functioning pituitary tumors, such as growth hormone- and prolactin-secreting tumors, however, their effects on ACTH-secreting tumors are controversial. This study was aimed to determine whether somatostatin receptor (SSTR) subtype (1-5) and dopamine receptor type 2 (D2R) are differentially expressed in pituitary tumors causing Cushing's disease (CD), silent corticotroph adenoma (SCA), and non-functioning pituitary tumor (NFT). Tissue specimens were obtained from 35 pituitary tumors during transsphenoidal surgery. The steady-state mRNA levels of SSTR1-5 and D2R genes were determined by real-time reverse-transcription polymerase chain reaction. Both SSTR1 and 2 mRNA levels in SCA were greater than CD, while SSTR1 mRNA levels, but not SSTR2, in SCA were also greater than NFT. SSTR5 mRNA levels in CD were greater than SCA, but did not differ between NFT and SCA. SSTR4 mRNA expression was undetectable. D2R mRNA levels were markedly lower in CD and SCA than in NFT. The present study suggests that somatostatin analogs more selective for SSTR5 and for SSTR1 and/or 2may have the therapeutic potential for medical treatment of CD and SCA, respectively, whereas clinical application of dopamine agonists selective for D2R is very limited in either CD or SCA.
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PMID:Differential expression of somatostatin and dopamine receptor subtype genes in adrenocorticotropin (ACTH)-secreting pituitary tumors and silent corticotroph adenomas. 1931 29


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