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)

The somatostatin analog SMS 201-995 (2 X 6 or 2 X 20 micrograms daily for 30 days) inhibited the growth of the PRL/ACTH-secreting pituitary tumor 7315a by 36% and 48%, respectively. A biphasic curve of the inhibitory effect of the SMS analog on tumor growth was recognized: the actual tumor growth inhibitory effect occurred during the first 15 days, after which the tumors grew in parallel with the control tumors despite SMS 201-995 treatment. At the end of the 30-day SMS 201-995 treatment, plasma GH and plasma somatomedin-C levels were similar to those in the control tumor-bearing rats. Separate experiments in normal rats showed that tachyphylaxis of the GH-secretion inhibitory effects of three different doses of SMS 201-995 occurred within 6-10 days. No specific somatostatin-14 or SMS 201-995 receptors were present on well grown, untreated 7315a pituitary tumors. However, PRL and ACTH secretion by cultured cells prepared from the 7315a tumor was inhibited by SMS 201-995. Pretreatment of the cultured cells with dexamethasone made PRL secretion by these tumor cells insensitive to SMS 201-995. These studies suggest that several factors played a role in the mechanism of action of the tumor growth-inhibitory actions of SMS 201-995. Twice daily administration of the somatostatin analog rapidly (within 6-10 days) induces tachyphylaxis of the GH-inhibitory effect. From 10 days after implantation the PRL/ACTH-secreting pituitary tumor causes adrenal hyperplasia and increased plasma corticosterone concentrations. Exposure of the 7315a tumor to high glucocorticosteroid levels probably decreases the number of somatostatin receptors, diminishing the possible direct antitumor effect of SMS 201-995.
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PMID:Studies on the mechanism of action of the inhibitory effect of the somatostatin analog SMS 201-995 on the growth of the prolactin/adrenocorticotropin-secreting pituitary tumor 7315a. 287 Sep 15

Twelve patients with active acromegaly, six of whom had not responded to previous combined surgery, radiotherapy, and bromocriptine administration, were treated with an octapeptide long-acting somatostatin analogue, SMS 201-995, given subcutaneously for up to 1 year. Growth hormone (GH) levels decreased by 50% to 90% after a single 25-micrograms SMS 201-995 injection in all patients, including two who were resistant to bromocriptine therapy. After GH values reached a nadir, they returned to preinjection values over a 12-hour period and no rebound was seen. Assessment of the GH-lowering effect of the drug at weekly intervals for the first 6 weeks and monthly thereafter disclosed no tachyphylaxis. Gradual increase of the dose from 50 to 150 micrograms daily led to a significant increase in clinical improvement. Shrinkage of the size of the pituitary tumor was documented in three of nine evaluated cases. Abdominal cramps of a transient nature not associated with diarrhea were noted in two patients but there were no other side effects. Hematological and biochemical blood and urine tests, including serum thyroxine and cortisol levels, did not reveal any abnormality during chronic treatment. This study demonstrates the safety and efficacy of SMS 201-995 in the short-term treatment of acromegaly.
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PMID:Therapeutic efficacy of a somatostatin analogue (SMS 201-995) in active acromegaly. 287 84

The beneficial effect of the long-acting analogue of somatostatin SMS 201-995 in the treatment of acromegaly is described in three cases, and current published experience is reviewed. A total of 64 patients from 10 series have received the drug from one to 25 months, usually in doses of 50-150 micrograms every eight hours by subcutaneous injection. Clinical and chemical improvement was observed in the majority of subjects but normal 24-hour serum growth hormone levels were achieved in no more than 35 percent of this group and possibly less. We have found that higher doses, up to 1,500 micrograms per day, which have generally been free of side effects, are sometimes required to normalize growth hormone secretion. A reduction of up to 33 percent in pituitary tumor size has been reported in more than half of the 27 cases studied from four groups. Clinically important side effects are infrequent, but diarrhea, usually transient, occurred in about 13 percent, with frank steatorrhea in 2 to 6 percent of cases. Alteration in carbohydrate metabolism, such as transient glucose intolerance at the start of therapy in non-diabetic acromegalic patients, and increased sensitivity to insulin or oral hypoglycemic agents in diabetic acromegalic patients, is common. Overall, SMS 201-995 appears to be a valuable new agent for the treatment of acromegaly, but long-term safety needs to be established.
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PMID:Role of a long-acting somatostatin analogue (SMS 201-995) in the treatment of acromegaly. 287 53

Corticotropin-releasing factor (CRF) and both human pancreatic growth hormone-releasing factor (hp-GRF) and rat hypothalamic GRF (rh-GRF) stimulated ACTH release from neoplastic AtT-20 mouse pituitary tumor cells in a dose-dependent fashion, with CRF inducing a 10-fold increase and GRF a maximal increment of approximately one-half that of CRF. Neither rh-GRF nor hp-GRF induced ACTH release in normal anterior pituitary cells. Pretreatment with either dexamethasone or somatostatin prior to the addition of rh-GRF inhibited the increase in ACTH release. Both ovine CRF and rh-GRF stimulated adenosine 3,5-monophosphate production in AtT-20 cells. The weak but clearly discernible effect of GRF on ACTH release from AtT-20 cells may be due to an abnormality in the AtT-20 cell receptor.
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PMID:Growth hormone-releasing factor releases ACTH from an AtT-20 mouse pituitary tumor cell line but not from normal pituitary cells. 288 43

Ten acromegalic patients, four previously untreated, were studied before and at regular intervals during treatment with the long-acting somatostatin analog SMS 201-995 (200-300 micrograms daily for 2 or 3 sc injections for 16-108 weeks). All patients had rapid clinical improvement, with disappearance of excessive perspiration, paresthesias, and headache within the first 6 weeks of therapy. The mean 24-h serum GH concentrations fell from 44.0 +/- 7.8 (+/-SE) micrograms/L before to 5.9 +/- 1.0 microgram/L at the end of therapy. The GH levels from 2-6 h after the acute administration of 50 micrograms SMS 201-995 before the start of therapy correlated significantly with the mean 24-h GH concentrations after 16-108 weeks of treatment (P less than 0.05). The initially increased serum somatomedin-C (Sm-C) levels normalized in 5 of these 10 patients; the mean values were 7.3 +/- 0.9 U/mL before and 2.9 +/- 0.7 U/mL at the end of therapy. The Sm-C and mean GH levels continuously decreased during long term therapy; the concentrations after 1.5-2 yr of therapy were significantly lower than those after 6-12 months of therapy (P less than 0.01 and P less than 0.01, respectively). A slight decrease in the size of the pituitary tumor was noted by computed tomography in three of six patients. Transient clinically detectable steatorrhea occurred in two patients. Postprandial hyperglycemia occurred during therapy in eight patients, while in two patients with type 2 diabetes mellitus carbohydrate tolerance improved in one and deteriorated in the other. SMS 201-995 is a highly effective medical treatment for acromegaly. Clinically improvement occurs rapidly, and the inhibition of serum GH and Sm-C levels persisted even after more than 1 yr of therapy. No important subjective side-effects were noted. SMS 201-995 is an excellent drug in patients in whom acromegaly persists after surgery and for interim treatment to shorten the period of clinical activity after irradiation.
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PMID:SMS 201-995 induces a continuous decline in circulating growth hormone and somatomedin-C levels during therapy of acromegalic patients for over two years. 288 85

A patient with a mixed pituitary tumor secreting TSH and GH was treated, starting 3 months after partial adenomectomy, with the somatostatin analog SMS 201-995 for 8 months. Somatostatin itself inhibited TSH, GH, and alpha-subunit release by the tumor both in vivo and in vitro. Long term treatment with twice daily sc injections of SMS 201-995 resulted in decreased TSH secretion and lower serum thyroid hormone levels. However, euthyroidism was achieved only when the patient was treated with three daily 200-micrograms injections of SMS 201-995. After 30 weeks of SMS 201-995 therapy, TSH secretion increased, while GH secretion remained suppressed. After withdrawal for 6 months, SMS 201-995 (100 micrograms, sc, twice daily) again completely inhibited TSH secretion. SMS 201-995 did not alter the volume of the residual adenomatous tissue. We conclude that SMS 201-995 may be a valuable therapeutic agent for the management of patients with a thyrotroph adenoma. However, desensitization may occur during long term treatment.
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PMID:Long term treatment with the somatostatin analog SMS 201-995 in a patient with a thyrotropin- and growth hormone-secreting pituitary adenoma. 289 19

The role of GTP on somatostatin-induced K+ current increase was examined in dissociated human pituitary tumor cells obtained from three acromegalic patients. Pituitary cells in culture were voltage-clamped by using the patch clamp technique in the whole-cell configuration. Somatostatin (100 nM) increased the membrane permeability to K+ ions and inhibited hormone secretion. A current-voltage relation of the somatostatin-induced K+ current showed an inward rectification when the concentration of extracellular K+ ions was increased. The amplitude of the somatostatin-induced K+ current decreased during recording when the patch pipette solution did not contain GTP; addition of 100 microM GTP to the patch pipette solution prevented this reduction. Intracellular application of 100 microM guanosine 5'-[gamma-thio]triphosphate (GTP[gamma S] evoked an inward rectifying K+ conductance in the absence of somatostatin. After the GTP[gamma S]-induced K+ conductance reached a steady level, application of somatostatin did not further increase the K+ conductance. In pertussis toxin-treated cells GTP[gamma S] did not evoke K+ conductance. It was concluded that somatostatin-induced K+ channels were regulated by a GTP-binding protein.
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PMID:Requirement of GTP on somatostatin-induced K+ current in human pituitary tumor cells. 289 85

Ten acromegalics received daily doses of 200-300 micrograms of a long-acting somatostatin analog, SMS 201-995 (Sandostatin, SMS), for an average of 64 weeks. Basal mean GH values of 44 +/- (SE) 7.8 ng/ml had fallen into the normal range at the end of the observation period (mean 64 weeks). This effect was accompanied by a substantial drop in somatomedin-C values. Reduction of pituitary tumor size could be documented in 3 of 6 patients. Whereas SMS did not affect high plasma PRL in 4 microprolactinoma patients, lactotrophs turned sensitive to this agent in mixed GH/PRL tumors. In a comparative study between SMS and bromocriptine, the former normalized circulating GH in 10 of 17 acromegalics in an acute trial, whereas bromocriptine was effective in only 5. A combination of both substances was effective in 2 of 3 patients who were insensitive to single drug administration. Cultures of GH-secreting tumor cells showed a statistically significant hormone decrease in the medium when exposed to SMS. However, in some instances, a diminution of the GH contents of the tumor cells was also observed, presumably as the basis for intracellular breakdown and clinical tumor shrinkage.
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PMID:Somatostatin analog treatment of acromegaly: new aspects. 290 Jan 90

The effects of pertussis toxin treatment on the characteristics of somatostatin receptors in the anterior pituitary tumor cell line AtT-20 were examined. Pertussis toxin selectively catalyzed the ADP ribosylation of the alpha subunits of the inhibitory GTP binding proteins in AtT-20 cells. Toxin treatment abolished somatostatin inhibition of forskolin-stimulated adenylyl cyclase activity and somatostatin stimulation of GTPase activity. To examine the effects of pertussis toxin treatment on the characteristics of the somatostatin receptor, the receptor was labeled by the somatostatin analog [125I]CGP 23996. [125I]CGP 23996 binding to AtT-20 cell membranes was saturable and within a limited concentration range was to a single high affinity site. Pertussis toxin treatment reduced the apparent density of the high affinity [125I]CGP 23996 binding sites in AtT-20 cell membranes. Inhibition of [125I]CGP 23996 binding by a wide concentration range of CGP 23996 revealed the presence of two binding sites. GTP predominantly reduced the level of high affinity sites in control membranes. Pertussis toxin treatment also diminished the amount of high affinity sites. GTP did not affect [125I]CGP 23996 binding in the pertussis toxin-treated membranes. The high affinity somatostatin receptors were covalently labeled with [125I] CGP 23996 and the photoactivated crosslinking agent n-hydroxysuccinimidyl-4-azidobenzoate. No high affinity somatostatin receptors, covalently bound to [125I]CGP 23996, were detected in the pertussis toxin-treated membranes. These results are most consistent with pertussis toxin uncoupling the inhibitory G proteins from the somatostatin receptor thereby converting the receptor from a mixed population of high and low affinity sites to only low affinity receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pertussis toxin modifies the characteristics of both the inhibitory GTP binding proteins and the somatostatin receptor in anterior pituitary tumor cells. 290 Mar 31

The molecular mechanisms of somatostatin (SRIF) desensitization were investigated in the anterior pituitary tumor cell line AtT-20. Previous studies have shown that pretreatment of AtT-20 cells with SRIF analogs desensitizes the cells to SRIF inhibition of hormone release, cyclic AMP formation and calcium influx. This desensitization may involve a change in the properties of the SRIF receptors. Pretreatment of AtT-20 cells with Trp8-SRIF reduced the binding of the SRIF analog [125I]CGP 23996 (des-Alal, Gly2-[desamino-Cys3, Tyr11]-3, 14-dicarbasomatostatin) to AtT-20 cell membranes. The loss of [125I]CGP 23996 binding was dependent on the time of Trp8-SRIF treatment and was reversible. The ability of GTP analogs to inhibit [125I]CGP 23996 binding was reduced after Trp8-SRIF treatment, suggesting that the SRIF receptor and the inhibitory G proteins become uncoupled during desensitization. This is indicated further by the decrease in SRIF stimulation of GTPase activity and SRIF inhibition of forskolin-stimulated adenylyl cyclase activity in desensitized membranes. The reduction and recovery of SRIF inhibition of adenylyl cyclase activity after Trp8-SRIF pretreatment has a similar time course as the changes in [125I]CGP 23996 binding. GTP inhibition of forskolin-stimulated adenylyl cyclase activity is also reduced in SRIF-desensitized membranes. The loss of the GTP effect occurs rapidly and does not fully recover after Trp8-SRIF pretreatment. The levels of ADP-ribosylation of inhibitory GTP binding protein, the relative quantity of the alpha subunits of the inhibitory G proteins and their electrophoretic mobility after 2-dimensional gel electrophoretic analysis, are not altered in SRIF-desensitized membranes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characteristics of somatostatin desensitization in the pituitary tumor cell line AtT-20. 290 14


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