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)

Pancreatic ductal adenocarcinoma was induced in female Syrian golden hamsters by injecting N-nitrosobis(2-oxopropyl)amine (BOP) once a week at a dose of 10 mg per kg of body weight for 18 weeks. Hamsters were then treated with somatostatin analog D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2 (RC-160) or with [6-D-tryptophan]luteinizing hormone-releasing hormone [( D-Trp6]LH-RH) delayed delivery systems. Microcapsules of somatostatin analog RC-160, designed to release a dose of 5 micrograms/day, were injected twice a month and microcapsules of [D-Trp6]LH-RH, calculated to liberate 25 micrograms per day, once a month. After 18 weeks of BOP administration, the hamsters were divided into three groups of 10-20 animals each. Group I consisted of untreated controls, group II was injected with RC-160, and group III was injected with [D-Trp6]LH-RH. A striking decrease in tumor weight and volume was obtained in animals treated with [D-Trp6]LH-RH or with the somatostatin analog RC-160. After 45 days of treatment with either analog, the survival rate was significantly higher in groups II and III (70%), as compared with the control group (35%). The studies, done by light microscopy, high-resolution microscopy, and electron microscopy, showed a decrease in the total number of cancer cells and changes in the epithelium, connective tissue, and cellular organelles in groups II and III treated with the hypothalamic analogs as compared to controls. These results in female hamsters with induced ductal pancreatic tumors confirm and extend our findings, obtained in male animals with transplanted tumors, that [D-Trp6]LH-RH and somatostatin analogs inhibit the growth of pancreatic cancers.
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PMID:Treatment of nitrosamine-induced pancreatic tumors in hamsters with analogs of somatostatin and luteinizing hormone-releasing hormone. 288 Dec 96

Calcitonin (CT) binds to specific receptors in the hypothalamus and has been localized in the pituitary, suggesting a potential neuroendocrine role for this peptide. We and others have previously shown that CT given centrally markedly suppresses pulsatile GH secretion. However, the mechanism mediating this response remains to be elucidated. In the present study, we assessed the involvement of the two hypothalamic GH-regulatory peptides, somatostatin (SRIF) and GH-releasing factor (GRF), using a combination of in vivo and in vitro techniques. Six-hour GH secretory profiles were obtained from eight groups of freely moving rats bearing chronic intracerebroventricular (icv) and intraatrial cannulae. In four groups, salmon (s) CT (250 ng/10 microliters) was administered icv, whereas the remaining four groups received either normal saline (NS) icv or sCT iv. Central injection of sCT caused a severe suppression in amplitude of spontaneous GH pulses compared to NS icv-treated control rats, whereas the same dose of sCT iv had no significant effect. Passive immunization of sCT icv-injected rats with a specific antiserum to SRIF failed to restore the amplitude of GH pulses to normal values. In addition, in vitro basal and 50 mM K+-stimulated SRIF release from incubated hypothalamic fragments was not altered by sCT in doses ranging from 10(-10) to 10(-6) M. The iv administration of a bolus of rat GRF (1-29)NH2 (1 microgram) 1 h after sCT icv injection also failed to augment plasma GH levels compared to sCT iv-treated rats (16.6 +/- 10.0 vs. 326.6 +/- 63.6 ng/ml; P less than 0.001) and NS icv controls (407.2 +/- 145.4 ng/ml; P less than 0.01). Blood calcium levels decreased similarly 1 h after iv and icv sCT administration. These results demonstrate that: sCT inhibits pulsatile GH secretion via a central nervous system site of action, GH suppression induced by sCT is apparently not due solely to increased hypothalamic SRIF release, and centrally administered sCT produces an acute loss of responsiveness of somatotrophs to GRF, which can be dissociated from peripheral blood calcium levels.
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PMID:Mechanisms of calcitonin-induced growth hormone (GH) suppression: roles of somatostatin and GH-releasing factor. 288 73

The cyclic somatostatin analog D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2(CTP) was evaluated for agonist and opioid antagonist actions and receptor selectivity in two bioassays: electrically stimulated guinea pig isolated ileum (GPI) and mouse isolated vas deferens (MVD). CTP (100, 300, 1000 nM) produced concentration-dependent antagonism of the mu agonist [Me-Phe3,D-Pro4]morphiceptin (PL017) in both the GPI and MVD. Schild analysis of the interactions between CTP and PL017 indicated competitive antagonism between these peptides (Schild slope GPI -0.97 +/- 0.16, Schild slope MVD -1.4 +/- 0.4), and also suggested that the mu receptors in the two tissues are not different (pA2 GPI 7.1 +/- 0.17, pA2 MVD 6.9 +/- 0.16). The effects of the delta selective agonist [D-Pen2,D-Pen5]enkephalin in the MVD were not antagonized by CTP. Likewise, in the GPI, CTP did not antagonize the kappa agonist (trans-3-4-dichloro-N-methyl-N-(2-(1-pyrrolidinyl)cyclohexyl)benzenea cetamine (U50, 488H). In comparison, naloxone antagonized both PL017 and U50,488H in the GPI, as well as [D-Pen2,D-Pen5]enkephalin and PL017 in the MVD. In the MVD, CTP also exerted weak somatostatin-like actions (35% maximal inhibition) that could not be demonstrated in somatostatin-tolerant tissues. It also showed inhibitory actions at very high concentrations (3000 and 10,000 nM) that were blocked by both naloxone and the delta antagonist N,N-diallyl-Tyr-AIB-AIB-Phe-Leu-OH (ICI 174,864). ICI 174,864 antagonized [D-Pen2,D-Pen5]enkephalin in the MVD, but did not affect PL017. These results indicate that CTP is a selective mu receptor antagonist in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pharmacologic evaluation of a cyclic somatostatin analog with antagonist activity at mu opioid receptors in vitro. 288 15

We synthesized a series of octapeptide analogs of somatostatin, containing N-terminal tryptophan or another amino acid followed by the hexapeptide sequences Cys-Phe-D-Trp-Lys-Thr-Cys or Cys-Tyr-D-Trp-Lys-Val-Cys and a C-terminal threoninamide or tryptophanamide. After purification by HPLC, the inhibitory activities of these analogs on the release of growth hormone (somatotropin) in rats were determined in vivo. The eight octapeptides with an N-terminal tryptophan residue were found to have a greater inhibitory effect than somatostatin. The most potent of these analogs, D-Trp-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2, was 94.3 times more active than somatostatin. The other analogs, in order of decreasing potency, were Ac-Trp-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2, D-Trp(For)-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2, D-Trp-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2, Ac-Trp(For)-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2, Ac-Trp-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2, D-Trp-Cys-Phe-D-Trp-Lys-Thr-Cys-Trp-NH2, and D-Trp-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2. The growth hormone inhibitory activity of these analogs was from 53.7 to 11.6 times greater than that of somatostatin. The octapeptides containing D- or L-tryptophan at the N-terminus, phenylalanine at position 3, and threonine at position 6 exhibited a greater inhibitory effect on growth hormone release than that of the analogs with tyrosine and valine at positions 3 and 6, respectively. Substitution of D-tryptophan for D-phenylalanine at the N-terminus in the octapeptide containing phenylalanine in the third, threonine in the sixth, and threoninamide in the C-terminal position also increased the growth hormone-release inhibitory activity. Time-course assay showed that D-Trp-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2 (RC-98-I), in a dose of 1 microgram/kg of body weight, inhibited the release of growth hormone for at least 3 hr. In view of their high activity and prolonged duration of action, some of these analogs could be useful clinically.
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PMID:Superactive octapeptide somatostatin analogs containing tryptophan at position 1. 288 20

Antisera of defined regional specificity have been used to measure the concentration of substance P-like immunoreactivity (SP-LI) and neurokinin A-like immunoreactivity (NKA-LI) during a meal-induced flush in 10 patients with metastatic carcinoid tumours. Although all patients flushed, NKA-LI levels in five patients and SP-LI in six patients were not elevated relative to healthy subjects (NKA-LI, less than 3 pg/ml; SP-LI, less than 10 pg/ml) both in the fasted state and after food. In the patients with elevated basal plasma tachykinin levels, increases in NKA-LI and SP-LI after food were erratic and did not correspond to a defined digestive phase or the occurrence of the flush. Chromatographic analysis of plasma demonstrated the presence of neuropeptide K and neurokinin A, and the detection of COOH-terminal fragments of substance P is consistent with the higher levels of circulating SP-LI measured with a COOH-terminally directed antiserum compared with an NH2-terminally directed antiserum. Subcutaneous injection of the somatostatin analogue SMS 201-995 (50 micrograms) alleviated symptoms of flush in two of three patients but only partially suppressed NKA-LI and SP-LI concentrations. It is concluded that circulating tachykinins cannot be solely responsible for the meal-induced carcinoid flush.
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PMID:Circulating tachykinins (substance P, neurokinin A, neuropeptide K) and the carcinoid flush. 288 98

A series of nine closely related somatostatin analogues, containing the hexapeptide H-Cys2-Phe3-D-Trp4-Lys5-Thr6-Cys7-NH2 sequence have been synthesized by Bauer et al. The conformational properties of two of them, showing intermediate activities between those of SMS 201-995 and somatostatin, have been studied by high field n.m.r. spectroscopy in DMSO. Assignments were made using 2D-n.m.r. methods, in particular NOESY experiments and detection of long-range connectivities in aromatic residues. In all the compounds of this series, the biologically active ones as well as the inactive ones, the n.m.r. parameters are in favour of a predominant conformation with a type II' beta turn involving amino acids Phe3 to Thr6. A clearcut correlation exists between the predominant conformation at the cystine bridge side and the activity. The presence of the exocyclic amino acids Phe1 and Thr8 (ol) plays a major role in stabilization of the active conformation.
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PMID:Conformational analysis of two somatostatin analogues by 1H 500 MHz n.m.r. spectroscopy. 288 49

The effect on prolactin (PRL) secretion of acute administration of new octapeptide analogs of somatostatin (SS) with an enhanced and prolonged growth hormone inhibitory activity was investigated in rats under various pretreatment conditions with estrogen and antidopaminergic drugs. Analog D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2 (RC-121), at a dose of 5 micrograms/100 g body wt, did not decrease basal PRL levels in thiopental-anesthetized female rats, untreated or treated with estrogen benzoate (EB) (8 micrograms/rat) for 5 days. When haloperidol was used to elevate PRL level, a single injection of RC-121 inhibited PRL release in EB-pretreated female rats or untreated female and male rats. Analog D-Phe-Cys-Trp-D-Trp-Lys-Val-Cys-Trp-NH2 (RC-160), which has a potency similar to RC-121 in the tests on inhibition of GH, in a dose of 0.2 microgram/100 g body wt, did not lower the elevated PRL level induced by alpha-methyl-p-tyrosine and/or pretreatment with EB (100 micrograms/rat, 3 and 6 days before) in pentobarbital-anesthetized male rats. However, both analogs RC-121 and RC-160, in doses of 0.2 microgram/100 g body wt, decreased the PRL levels elevated by prolonged pretreatment with EB (100 micrograms/rat, twice a week for 3 weeks) in male rats. These results indicate that acute administration of these SS analogs can induce a prolonged inhibition of PRL release when PRL is acutely elevated by haloperidol or chronically elevated by 3 weeks of estrogen administration. Future additional studies are required to investigate the effects of chronic administration of these SS analogs on PRL levels.
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PMID:Inhibitory effects of somatostatin analogs on prolactin secretion in rats pretreated with estrogen or haloperidol. 288 61

The effects of MPTP administered to mice were examined biochemically and pharmacologically. The dopamine level in the striatum of the mice injected with MPTP decreased markedly, but recovered to 50% of the control level 6 weeks later. Amine fluorescence showed a decrease in the amount of amine especially in the lateral part of the striatum. Of the four neuropeptides, only the concentration of somatostatin changed with time. These findings indicate that the time elapsed after MPTP treatment should be taken into consideration when MPTP-treated mice are used as a parkinsonism model. Six weeks after MPTP treatment, the concentration of the striatal muscarinic cholinergic receptor decreased significantly but recovered to the normal level after the administration of L-dopa. Such a change was not detected with the dopamine D2-receptor. The therapeutic efficacy of medication in MPTP-treated mice as examined by the pole test showed that L-threo-3,4-dihydroxyphenylserine (L-threo-DOPS), which is considered to be the precursor of norepinephrine, enhances the effect of L-dopa.
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PMID:MPTP-induced parkinsonian model in mice: biochemistry, pharmacology and behavior. 288 11

A series of psi [CH2NH] pseudopeptide analogues of a potent somatostatin octapeptide analogue, H-D-Phe-Cys-Try-D-Trp-Lys-Val-Cys-Thr-NH2, were synthesized by using a newly developed solid-phase method for direct introduction of the CH2NH peptide bond isostere. Analogues were obtained in normal yields via a combination of sodium cyanoborohydride mediated reductive alkylation of resin-bound peptide amine with a tert-butoxycarbonyl amino acid aldehyde for introduction of a CH2NH bond and normal solid-phase peptide chemistry. A racemization test on a model pseudodipeptide indicated that no more than 6% racemization took place during the aldehyde preparation and alkylation steps. Analogues were examined for their ability to inhibit growth hormone release in vivo in sodium pentobarbital anesthetized rats and in vitro from cultured rat anterior pituitary cells. Analogues modified at the amide carbonyl of Cys2 and Lys5 showed the highest in vivo activity (20 and 8 times more potent than SRIF, respectively) and in vitro activity (0.17 and 0.67 times as active as SRIF). This compared to in vivo and in vitro potencies of 8000% and 100%, respectively, for the parent analogue. Modification of the other cyclic ring amide carbonyls of Tyr3, D-Trp4, and Val6 or the N- or C-terminal amide carbonyl of D-Phe1 or Cys7 gave analogues with considerably lower in vitro or in vivo potencies. The results appear to offer support for a proposed type II beta-turn solution conformation centered on the D-Trp-Lys portion of SRIF octapeptide analogues, resulting in possible hydrogen-bonding interactions between Tyr3 and Val6 and D-Phe1 and Thr8 residues in the parent peptide. These would then be disrupted by methylene replacement of the carbonyl groups with concomitant loss of biological activity as was observed.
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PMID:Solid-phase synthesis and biological properties of psi [CH2NH] pseudopeptide analogues of a highly potent somatostatin octapeptide. 288 17

Analogs of a potent octapeptide analog of somatostatin (SRIF) H-(D)Phe-Cys-Tyr-(D)Trp-Lys-Val-Cys-Thr(NH2) were synthesized. Aromatic substitutions for Tyr resulted in little change in inhibitory potency on growth hormone (GH) secretion in the rat. Substitutions for Val or (D)Trp resulted in analogs with diminished activity. Substitution of (D)Nal for (D)Phe increased duration of GH inhibition. Final weights of subcutaneously implanted prostate tumors (R3327) were 41% lower in rats treated with an N-terminal 4-chloro-(D)phenylalanyl analog as compared to vehicle treated controls. The analog had no effect on testicular weight or final plasma testosterone levels. SRIF analogs may represent an alternative treatment for prostate cancer that would be free of the untoward reproductive effects of other treatments (e.g. LH-RH or castration).
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PMID:Inhibition of rat prostate tumor growth by an octapeptide analog of somatostatin. 288 1


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