The somatostatin analogue SOM230, compared with octreotide, induces differential effects in several metabolic pathways in acromegalic patients

Hoek, Joost van der; Lelij, Aart-Jan van der; Feelders, Richard A; Herder, Wouter W. de; Uitterlinden, Piet; Poon, Kwai W.; Boerlin, Viktor; Lewis, Ian; Krahnke, Tillmann; Hofland, Leo J.; Lamberts, Steven W. J.

doi:10.1111/j.1365-2265.2005.02322.x

Cited by 56 publications

(29 citation statements)

References 52 publications

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“…As such, the combination of single-receptor ligands such as dopamine agonists (DAs) and SSAs, and also somatostatin-dopamine (SS-DA) chimeric compounds, could have synergistic effects by targeting these coexpressed receptors in GEP-NETs. Beneficial effects of chimeric compounds and multiligand SSAs were already shown in a subgroup of patients with NETs and growth hormone/prolactin-secreting pituitary adenomas [19,20,21,22]. In one study, antiproliferative effects were observed in the small intestinal NET (siNET) cell line KRJ-I after incubation with multiligand SSAs but not with SS-DA, because KRJ-I cells lack D2R expression [23].…”

Section: Introductionmentioning

confidence: 99%

Effects of Somatostatin Analogs and Dopamine Agonists on Insulin-Like Growth Factor 2-Induced Insulin Receptor Isoform A Activation by Gastroenteropancreatic Neuroendocrine Tumor Cells

Adrichem¹,

Herder²,

Kamp³

et al. 2016

Neuroendocrinology

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Background: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) express insulin-like growth factor (IGF)-related factors [IGF1, IGF2; insulin receptor (IR)-A, IR-B; IGF-binding protein (IGFBP) 1-3] as well as somatostatin (SSTRs) and dopamine D₂ receptors (D2Rs). Objectives: To (1) compare mRNA expression of IGF-related factors in human pancreatic NET (panNET) cell lines with that in human GEP-NETs to evaluate the usefulness of these cells as a model for studying the IGF system in GEP-NETs, (2) determine whether panNET cells produce growth factors that activate IR-A, and (3) investigate whether somatostatin analogs (SSAs) and/or dopamine agonists (DAs) influence the production of these growth factors. Methods: In panNET cells (BON-1 and QGP-1) and GEP-NETs, mRNA expression of IGF-related factors was measured by quantitative real-time PCR. Effects of the SSAs octreotide and pasireotide (PAS), the DA cabergoline (CAB), and the dopastatin BIM-23A760 (all 100 nM) were evaluated at the IGF2 mRNA and protein level (by ELISA) and regarding IR-A bioactivity (by kinase receptor activation assay) in panNET cells. Results: panNET cells and GEP-NETs had comparable expression profiles of IGF-related factors. Especially in BON-1 cells, IGF2 and IR-A were most highly expressed. PAS + CAB inhibited IGF2 (-29.5 ± 4.9%, p < 0.01) and IGFBP3 (-20.0 ± 4.0%, p < 0.01) mRNA expression in BON-1 cells. In BON-1 cells, IGF2 protein secretion was significantly inhibited with BIM-23A760 (-23.7 ± 3.8%). BON-1- but not QGP-1- conditioned medium stimulated IR-A bioactivity. In BON-1 cells, IR-A bioactivity was inhibited by BIM-23A760 and PAS + CAB (-37.8 ± 2.1% and -30.9 ± 4.1%, respectively, p < 0.0001). Conclusions: (1) The BON-1 cell line is a representative model for studying the IGF system in GEP-NETs, (2) BON-1 cells produce growth factors (IGF2) activating IR-A, and (3) combined SSTR and D2R targeting with PAS + CAB and BIM-23A760 suppresses IGF2-induced IR-A activation.

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Section: Introductionmentioning

confidence: 99%

Effects of Somatostatin Analogs and Dopamine Agonists on Insulin-Like Growth Factor 2-Induced Insulin Receptor Isoform A Activation by Gastroenteropancreatic Neuroendocrine Tumor Cells

Adrichem¹,

Herder²,

Kamp³

et al. 2016

Neuroendocrinology

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“…In vivo, SOM-230 differs from SMS 201-995 in that its terminal elimination half-life is increased, resulting in a longer duration of action, as shown by the suppression of GH release 6 h after drug application [4]. SOM-230 has been reported to exhibit a GH release inhibitory effect less susceptible to desensitization compared with the effect of octreotide [6]. SOM-230 is currently evaluated versus octreotide, in a head to head clinical trial [7].…”

Section: Somatostatin Analogs: Selectivity and Pharmacokinetic Profilesmentioning

confidence: 99%

Medical Treatment of Acromegaly: Comorbidities and Their Reversibility by Somatostatin Analogs

et al. 2006

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Relief of symptoms can be achieved following surgery for growth hormone (GH)-secreting adenomas, as well as after pharmacological therapy with somatostatin analogs. Recently, long-acting somatostatin analog depot formulations, octreotide LAR and lanreotide SR have become available. Somatostatin analogs control GH/insulin-like growth factor (IGF)-1 excess, induce tumor shrinkage in a high proportion of patients, improve symptoms of acromegaly with relatively limited side effects and are successfully administered in patients not suitable for surgery. Furthermore, preoperative somatostatin analogs have been suggested to improve outcome for tumors with limited invasiveness, while surgical tumor debulking in cases that are, at least partially, somatostatin resistant, increases the achievement of normal IGF-1 levels by postoperative somatostatin analog treatment. Effective control of hypertension, as well as diabetes, is mandatory in order to reduce the increased vascular morbidity/mortality. Control of GH/IGF-1 excess generally improves glucose metabolism. Somatostatin analogs improve insulin sensitivity, exerting, however, a concomitant direct inhibitory effect on insulin secretion, with a net balance leaning towards a deterioration in glucose homeostasis. As a result, oral insulin secretagogues (and/or insulin) should probably be preferred to insulin sensitizers in acromegalic patients developing diabetes while on somatostatin analogs. Nevertheless, glucose tolerance remains normal in most of the nondiabetic acromegalic patients, while diabetic acromegalic patients on insulin are at risk for hypoglycemia during initiation of somatostatin analog therapy. Although successful management of acromegaly has been associated with improvement in morphological and functional parameters of cardiomyopathy, limited and conflicting information is available regarding the effect on blood pressure control. Contradictory results have also been reported regarding sleep hypopnea or apnea in treated acromegalic patients. As acromegalic skeletal abnormalities are rather irreversible, apneic episodes may persist after normalization of hormonal levels. Aggressive therapy, including surgery, pharmacological treatment and, in some cases, pituitary irradiation, aiming at normalization of IGF-1 levels, is required for arthropathy management. Some improvement in pain, crepitus and range of motion has been observed after treatment with somatostatin analogs. Information on the impact of disease control, either by surgery or somatostatin analog treatment, on gonadal function is limited. Finally, the link between the hormonal/biochemical and the psychiatric/psychological features of acromegaly, as well as a potential basis for positive effects of somatostatin analog therapy remain unclear.

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“…Octreotide and lanreotide, the stable somatostatin analogs currently available for clinical use, bind only to sst2 with high affinity and to sst3 and sst5 with moderate affinity (1). Compounds displaying high selectivity for distinct somatostatin receptor subtypes and multi-ligand somatostatin analogs, like SOM230 and BIM-23244, displaying high affinity for multiple receptor subtypes have been tested in preclinical studies (8)(9)(10)(11)(12).…”

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Novel insights in somatostatin receptor physiology

Tulipano

Schulz

2007

eur j endocrinol

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The experimental data reviewed in the present paper deal with the molecular events underlying the agonist-dependent regulation of the distinct somatostatin receptor subtypes and may suggest important clues about the clinical use of somatostatin analogs with different pattern of receptor specificity for the in vivo targeting of tumoral somatostatin receptors. Somatostatin receptor subtypes are characterized by differential b-arrestin trafficking and endosomal sorting upon agonist binding due, at least in part, to the differences in their C-terminal tails. Moreover, the subcellular expression pattern of somatostatin receptor subtypes and their activity in response to agonist treatment are affected by intracellular complements, such as proteins involved in intracellular vesicle trafficking. Different somatostatin analogs may induce distinct conformations of the receptor/ligand complex, preferentially coupled to either receptor signaling or receptor endocytosis.European Journal of Endocrinology 156 S3-S11

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The somatostatin analogue SOM230, compared with octreotide, induces differential effects in several metabolic pathways in acromegalic patients

Cited by 56 publications

References 52 publications

Effects of Somatostatin Analogs and Dopamine Agonists on Insulin-Like Growth Factor 2-Induced Insulin Receptor Isoform A Activation by Gastroenteropancreatic Neuroendocrine Tumor Cells

Effects of Somatostatin Analogs and Dopamine Agonists on Insulin-Like Growth Factor 2-Induced Insulin Receptor Isoform A Activation by Gastroenteropancreatic Neuroendocrine Tumor Cells

Medical Treatment of Acromegaly: Comorbidities and Their Reversibility by Somatostatin Analogs

Novel insights in somatostatin receptor physiology

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