Somatostatin agonists for treatment of acromegaly

Ben-Shlomo, Anat; Melmed, Shlomo

doi:10.1016/j.mce.2007.11.024

Cited by 96 publications

(60 citation statements)

References 76 publications

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“…When autonomous GH secretion persists post-operatively, somatostatin analogues (SSA) are the first treatment option (2). The clinically available SSA, Octreotide and Lanreotide respectively, significantly suppress GH secretion in up to 50-70% of acromegalic patients (2,3,4) while strict biochemical control (GH !1 mg/l) is achieved in up to 33% (3). However, these SSA also suppress insulin secretion and thus negatively affect glucose homoeostasis in a significant number of patients (3,5,6,7,8).…”

Section: Introductionmentioning

confidence: 99%

DG3173 (somatoprim), a unique somatostatin receptor subtypes 2-, 4- and 5-selective analogue, effectively reduces GH secretion in human GH-secreting pituitary adenomas even in Octreotide non-responsive tumours

Plöckinger

Hoffmann²,

Geese³

et al. 2012

European Journal of Endocrinology

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Objective: Somatostatin analogues (SSA) reduce autonomous GH secretion by activating somatostatin receptors (sst) 2 and 5 in 50-60% of acromegalic patients. However, by inhibiting insulin secretion these SSA reduce glucose tolerance. DG3173 is a novel SSA with additional binding to sst4 and low insulin-suppressing activity. We investigated the effect of DG3173, including its relation to specific tumour characteristics, on GH secretion in human somatotroph adenoma cell cultures (hSA) in comparison with Octreotide. Methods: Twenty-seven hSA were characterised immunohistochemically for their hormone-and sstexpression, granularity and pre-surgical therapy with SSA. GH was determined in supernatants of hSA treated with DG3173 or Octreotide in time-(nZ6) and dose-response (nZ21) experiments. A positive response was defined as GH suppression to below 80% of baseline. Results: In the dose-response experiments DG3173 suppressed GH secretion in more adenomas than Octreotide (10/21 vs 5/21), including 38% (6/16) of Octreotide non-responders. In responders the extent of GH suppression and IC 50 were comparable for both SSA. The response-rate of both SSA was higher in monohormonal vs bihormonal adenomas, yet GH declined similarly in both groups. Neither pre-surgical SSA (nZ6) nor tumour morphology was related to the GH response. However, semiquantitative analysis indicated a small but significant negative correlation between the GH response to Octreotide and the immunoreactivity scores of sst2 expression. Conclusions: DG3173 equalled Octreotide in suppressing GH secretion in hSA. Since DG3173 suppressed GH in some Octreotide-non-responsive adenomas, its clinical effectiveness will be worth testing. Moreover, its reduced insulin-suppressive potency would make it a valuable alternative to Octreotide.

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Section: Introductionmentioning

confidence: 99%

DG3173 (somatoprim), a unique somatostatin receptor subtypes 2-, 4- and 5-selective analogue, effectively reduces GH secretion in human GH-secreting pituitary adenomas even in Octreotide non-responsive tumours

Plöckinger

Hoffmann²,

Geese³

et al. 2012

European Journal of Endocrinology

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“…The SSAs octreotide and lanreotide bind mainly to SSTR2 and to a lesser extent to SSTR3 and SSTR5, and represent the mainstay of medical therapy of functioning somatotroph and thyrotroph adenomas (Ben-Shlomo & Melmed 2008, Grozinsky-Glasberg et al 2008, Theodoropoulou & Stalla 2013. Treatment of acromegalic patients with these SSAs reduces or normalizes growth hormone and insulin-like growth factor 1 levels and induces tumor shrinkage (Theodoropoulou & Stalla 2013).…”

mentioning

confidence: 99%

“…Pasireotide has a 158-, O30-, and 11-fold higher functional activity than octreotide on SSTR5, SSTR1, and SSTR3 respectively (Schmid & Schoeffter 2004, Theodoropoulou & Stalla 2013. Though not free of side effects, pasireotide has shown promising results in the treatment of acromegalic patients (Ben-Shlomo & Melmed 2008) and, more recently, in the treatment of patients with Cushing's disease (Colao et al 2012, Webb et al 2014. A clinical trial led by Gadelha and colleagues is currently recruiting patients to evaluate the effect of pasireotide on regrowth of clinically non-functioning pituitary adenomas (NFPAs) (www.ClinicalTrials.gov; identifier NCT01620138).…”

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confidence: 99%

SSTR3 is a putative target for the medical treatment of gonadotroph adenomas of the pituitary

Lee¹,

Lupp²,

Mendoza³

et al. 2014

Endocrine-Related Cancer

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Gonadotroph pituitary adenomas (GPAs) often present as invasive macroadenomas not amenable to complete surgical resection. Radiotherapy is the only post-operative option for patients with large invasive or recurrent lesions. No medical treatment is available for these patients. The somatostatin analogs (SSAs) octreotide and lanreotide that preferentially target somatostatin receptor type 2 (SSTR2) have little effect on GPAs. It is widely accepted that the expression of specific SSTR subtypes determines the response to SSAs. Given that previous studies on mRNA and protein expression of SSTRs in GPAs have generated conflicting results, we investigated the expression of SSTR2, SSTR3, and SSTR5 (the main targets of available SSAs) in a clinically and pathologically well-characterized cohort of 108 patients with GPAs. A total of 118 samples were examined by immunohistochemistry using validated and specific MABs. Matched primary and recurrent tissues were available for ten patients. The results obtained were validated in an independent cohort of 27 GPAs. We observed that SSTR3 was significantly more abundant than SSTR2 (P!0.0001) in GPAs, while full-length SSTR5 was only expressed in few tumors. Expression of SSTR3 was similar in primary and recurrent adenomas, was high in potentially aggressive lesions, and did not change significantly in adenomas that recurred after irradiation. In conclusion, low levels of expression of SSTR2 may account for the limited response of GPAs to octreotide and lanreotide. Given the potent anti-proliferative, pro-apoptotic, and anti-angiogenic activities of SSTR3, targeting this receptor with a multireceptor ligand SSA such as pasireotide may be indicated for potentially aggressive GPAs.

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“…Long-acting somatostatin analogs (SSAs) have been widely accepted as the best medical option for the treatment of acromegaly [5]. Nevertheless, at least 35% of patients are considered to be resistant to commercially available SSAs (octreotide LAR and lanreotide autogel) as they do not achieve IGF-I normalization [5,6].…”

mentioning

confidence: 99%

Efficacy of combined octreotide and cabergoline treatment in patients with acromegaly: a retrospective clinical study and review of the literature

et al. 2013

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Somatostatin agonists for treatment of acromegaly

Cited by 96 publications

References 76 publications

DG3173 (somatoprim), a unique somatostatin receptor subtypes 2-, 4- and 5-selective analogue, effectively reduces GH secretion in human GH-secreting pituitary adenomas even in Octreotide non-responsive tumours

DG3173 (somatoprim), a unique somatostatin receptor subtypes 2-, 4- and 5-selective analogue, effectively reduces GH secretion in human GH-secreting pituitary adenomas even in Octreotide non-responsive tumours

SSTR3 is a putative target for the medical treatment of gonadotroph adenomas of the pituitary

Efficacy of combined octreotide and cabergoline treatment in patients with acromegaly: a retrospective clinical study and review of the literature

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