Neuroendocrine tumours (NETs) are rare and heterogeneous neoplasms that can present with functional syndromes due to the hypersecretion of peptides. Somatostatin analogues (SSAs) have been used since the 1980s for the treatment of neuroendocrine tumours, with the aim of controlling the symptoms of functioning tumours and improving patients’ quality of life. Data from preclinical studies offer evidence of both direct and indirect mechanisms by which SSAs can exert antitumour effects. The activation of somatostatin receptors by SSAs leads to the activation of phosphotyrosine phosphatases, which control downstream apoptotic and antiproliferation signalling pathways. Also, the suppression of secretion of several growth factors and inhibition of antiangiogenic activity by SSAs indirectly inhibits tumour cell proliferation in vitro. Previous uncontrolled studies had shown tumour shrinkage and disappearance in response to the SSA octreotide. Recent results from the randomised and placebo-controlled PROMID trial have demonstrated that octreotide has antitumour activity in patients with metastatic mid-gut NETs. This article examines recent data providing evidence of the antitumour activity of somatostatin analogues.
Neuroendocrine tumour (NET), somatostatin, antiproliferative activity, octreotide long-acting release (LAR), lanreotide
The authors have no conflicts of interest to declare.
June 26, 2012
Frederico Costa, Oncology Center, Hospital Sírio-Libanês, Adma Jafet Street, 91, São Paulo, SP, 0138-050, Brazil. E: Frederico.firstname.lastname@example.org
The publication of this article was funded by Novartis. The views and opinions expressed are those of the authors and not necessarily those of Novartis.
Neuroendocrine tumours (NETs) are rare neoplasms that arise from neuroendocrine cells which are present throughout the body. NETs may be classified as functioning or non-functioning and are further differentiated based on the site of primary origin, histologic grade (low, intermediate or high) and proliferation rate.1 Functioning NETs are characterised by excessive hormone production and release, and cause hormonal syndromes (outlined in Table 1), while non-functioning NETs are not associated with a distinct hormonal syndrome – although they can secrete hormones and peptides at subclinical levels. Approximately 60–70 % of NET patients are diagnosed with disseminated metastatic disease.2 Even though many patients have indolent disease, some patients present with overtly aggressive tumours. Due to this heterogeneity, treatment is often individualised and may involve several modalities, such as cytoreductive surgery, non-surgical liver-directed therapies, somatostatin analogues, chemotherapy and, more recently, targeted agents.3 These treatments are used with two major objectives: to control the symptoms of hormone hypersecretion and to control tumour growth. The aim of this article is to review the antitumour effects of somatostatin (STS) analogues in the treatment of NETs.
STS is a peptide produced by intestinal paracrine cells and plays a major role in inhibition of gastrointestinal (GI) endocrine secretion.4,5 STS acts as a paracrine, autocrine or neuronal regulatory molecule to inhibit glandular secretion, neurotransmission, smooth muscle contractility and absorption of nutrients, regulating the functioning of activated immune cells.5–7 STS exerts control over several neurophysiological functions, and is a pan-inhibitory agent for all known GI tract hormones.8 In the GI tract, STS promotes reduction of liver and splanchnic blood flow, inhibits GI and pancreatic secretions, inhibits gallbladder contractility and bile flow, slows GI transit, inhibits absorption of glucose and amino acids and inhibits tissue growth and proliferation.5
STS is a cyclic peptide. Its two biological molecular forms are somatostatin-14 (S-14) and somatostatin-28 (S-28), which are both expressed throughout the GI tract. STS is synthesised as part of a large precursor molecule that is cleaved, enzymatically processed and released by endocrine and nerve cells.9 STS binds to five different STS receptor subtypes (numbered 1–5) present at the surface of different endocrine cell types.
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