Inhibitory effect of pasireotide and octreotide on lymphocyte activation

Lattuada, D.; Casnici, Claudia; Crotta, Katia; Mastrotto, Cristina; Franco, Paola; Schmid, Herbert; Marelli, O

doi:10.1016/j.jneuroim.2006.10.007

Cited by 35 publications

(28 citation statements)

References 30 publications

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“…Recently, the antiproliferative effect of octreotide LAR was demonstrated in the randomized, doubleblind, placebo-controlled PROMID study in patients with advanced, intestinal (midgut) NETs , in which octreotide LAR 30 mg/28 days led to a significant increase in time to tumor progression compared with placebo (14.3 vs 6.0 months; PZ0.000072), regardless of whether patients had a functioning or nonfunctioning tumor (Arnold et al 2009). In line with the antitumor effects of octreotide, pasireotide has been shown to have direct and indirect antitumor effects in vitro, including sst receptor-mediated apoptosis and inhibition of cell proliferation (Adams et al 2004, Lattuada et al 2007, Ono et al 2007). In the current study, pasireotide treatment resulted in stable disease in more than half of the patients, which is a clinically relevant achievement in patients with functioning NETs refractory or resistant to octreotide LAR.…”

Section: Discussionmentioning

confidence: 99%

Pasireotide (SOM230) shows efficacy and tolerability in the treatment of patients with advanced neuroendocrine tumors refractory or resistant to octreotide LAR: results from a phase II study

Kvols¹,

Öberg²,

O'Dorisio³

et al. 2012

Endocrine-Related Cancer

173

116

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Pasireotide (SOM230) is a novel multireceptor-targeted somatostatin (sst) analog with high binding affinity for sst receptor subtype 1, 2, 3 (sst 1,2,3 ) and sst 5 . Because of this binding profile, pasireotide may offer symptom control in patients with neuroendocrine tumors (NETs) and carcinoid syndrome no longer responsive to octreotide LAR. This was a phase II, open-label, multicenter study of pasireotide in patients with advanced NET whose symptoms of carcinoid syndrome (diarrhea/flushing) were inadequately controlled by octreotide LAR. Patients received s.c. pasireotide 150 mg twice daily (bid), escalated to a maximum dose of 1200 mg bid until a clinical response was achieved. Forty-four patients were evaluated for efficacy and 45 for tolerability. Pasireotide 600-900 mg s.c. bid effectively controlled the symptoms of diarrhea and flushing in 27% of patients. Evaluation of tumor response in 23 patients showed 13 with stable disease and ten with progressive disease at study end. The most common drug-related adverse events were nausea (27%), abdominal pain (20%), weight loss (20%), and hyperglycemia (16%) and most were of mild or moderate severity. Pasireotide 600-900 mg s.c. bid was effective and generally well tolerated in controlling the symptoms of carcinoid syndrome in 27% of patients with advanced NET refractory or resistant to octreotide LAR therapy.

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Section: Discussionmentioning

confidence: 99%

Pasireotide (SOM230) shows efficacy and tolerability in the treatment of patients with advanced neuroendocrine tumors refractory or resistant to octreotide LAR: results from a phase II study

Kvols¹,

Öberg²,

O'Dorisio³

et al. 2012

Endocrine-Related Cancer

173

116

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“…Local application of SRIF-14 into the inflamed knee joint in rabbits was shown to prevent joint swelling and edema (34)(35)(36). SRIF and its analogs also inhibit the production and release of proinflammatory mediators, such as TNF␣, IFN␥, and interleukin-6 in a number of inflammatory disorders (3,4,37,38). In RA patients, somatostatin receptors have been detected in the synovial tissue of affected joints (39,40).…”

Section: Discussionmentioning

confidence: 99%

Differential antiinflammatory and antinociceptive effects of the somatostatin analogs octreotide and pasireotide in a mouse model of immune‐mediated arthritis

Imhof¹,

Glück²,

Gajda³

et al. 2011

Arthritis & Rheumatism

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Objective. Clinical and preclinical evidence suggests that somatostatin exhibits potent antiinflammatory and antinociceptive properties. However, it is not known which of the 5 somatostatin receptor subtypes (SSTRs 1-5) is involved in these actions. The purpose of this study was to assess the effects of the stable somatostatin analogs octreotide and pasireotide (SOM230) in a mouse model of antigen-induced arthritis (AIA). Methods. Studies were performed in SSTR2-deficient mice (SSTR2 -/-) and their wild-type littermates (SSTR2 ؉/؉). The expression of SSTR1, SSTR2A, SSTR3, and SSTR5 in dorsal root ganglia was examined by immunohistochemistry.Results. Untreated SSTR2 -/-mice with AIA displayed joint swelling and mechanical hyperalgesia similar to that seen in SSTR2 ؉/؉ mice. In wild-type mice, both octreotide and pasireotide significantly attenuated knee joint swelling and histopathologic manifestations of arthritis to an extent comparable to that of dexamethasone. In SSTR2 -/-mice, the antiinflammatory effects of both octreotide and pasireotide were completely abrogated. Prolonged administration of pasireotide also inhibited joint swelling and protected against joint destruction during AIA flare reactions. In addition, both octreotide and pasireotide reduced inflammatory hyperalgesia. The antinociceptive actions of octreotide were abolished in SSTR2 -/-mice, but those of pasireotide were retained. In dorsal root ganglia of naive wild-type mice, only SSTR1 and SSTR2A, but not SSTR3 or SSTR5, were detected in a subset of small-and mediumdiameter neurons.Conclusion. Our findings indicate that the antinociceptive and antiinflammatory actions of octreotide and pasireotide are largely mediated via the SSTR2 receptor. In addition, we identified the SSTR1 receptor as a novel pharmacologic target for somatostatinmediated peripheral analgesia in inflammatory pain.

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“…Multiple SSTRs are expressed in a wide variety of both endocrine-related and nonneuroendocrine tumors [33]. The stimulation of somatostatin receptors produces antiproliferative effects by inducing G₀-G 1 cell cycle arrest (typically through SSTR2 and SSTR5) or G 2 -M apoptosis (through SSTR2, SSTR3, and inhibition of IGF-1) [32,33,35]. In human lymphocytes, apoptosis induced by octreotide appears to be at least partially mediated through SSTR2, whereas pasireotide-induced apoptosis is primarily mediated through SSTR3, although an apoptotic effect caused by the heterodimerization of SSTR2/SSTR3 cannot be ruled out with either SRL [35].…”

Section: Preclinical Studies: Antiproliferative Effectsmentioning

confidence: 99%

Pasireotide in Acromegaly: An Overview of Current Mechanistic and Clinical Data

Samson¹

2015

Neuroendocrinology

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Background: Acromegaly is an insidious neuroendocrine disorder caused by hypersecretion of growth hormone (GH) by a somatotroph adenoma. Somatostatin receptor ligands (SRLs) are recommended as first-line medical therapy in patients for whom surgery has failed or is contraindicated. There are 5 known somatostatin receptor subtypes (SSTRs), 2 of which, i.e. SSTR2 and SSTR5, are expressed by a majority of somatotroph adenomas. The currently available SRLs, i.e. octreotide and lanreotide, primarily bind to SSTR2. Pasireotide (SOM230) is a new multireceptor-targeted SRL which has a broader binding profile and an increased affinity for SSTR1, 2, 3, and 5. Methods: PubMed searches were performed to identify all of the available published English language data on pasireotide with regard to the mechanism of action, in vitro effects, and clinical data. Results: Preclinical studies have demonstrated that pasireotide has a broader range of functional activity than octreotide. Recently, the efficacy of pasireotide in attenuating GH and insulin-like growth factor 1 (IGF-1) levels in patients with acromegaly has been evaluated in phase III clinical trials. Pasireotide demonstrated superiority over octreotide in achieving biochemical control (i.e. GH ≤2.5 µg/l and age- and sex-matched IGF-1 normalization) in patients with acromegaly, as well as significant efficacy in treating patients who were previously inadequately controlled on the maximum allowed doses of octreotide and lanreotide. Pasireotide-induced hyperglycemia was the most concerning adverse event but was reversible upon discontinuation of pasireotide. Conclusion: The clinical data support pasireotide as a promising new therapy for the treatment of acromegaly, and the long-acting formulation was recently approved in the US and Europe for the treatment of acromegaly.

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Inhibitory effect of pasireotide and octreotide on lymphocyte activation

Cited by 35 publications

References 30 publications

Pasireotide (SOM230) shows efficacy and tolerability in the treatment of patients with advanced neuroendocrine tumors refractory or resistant to octreotide LAR: results from a phase II study

Pasireotide (SOM230) shows efficacy and tolerability in the treatment of patients with advanced neuroendocrine tumors refractory or resistant to octreotide LAR: results from a phase II study

Differential antiinflammatory and antinociceptive effects of the somatostatin analogs octreotide and pasireotide in a mouse model of immune‐mediated arthritis

Pasireotide in Acromegaly: An Overview of Current Mechanistic and Clinical Data

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