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Octreotide and Lanreotide are the two SSAs adminsitered somatostatin receptor subtypes in 80-90% of GEP-NETs
by injection. Octreotide was the first SSA for the treatment according to autoradiographic or scintigraphic studies. [30,31]
of hormone-producing pituitary, pancreatic and intestinal The biological effects of SSAs occur in relation to receptor
neuroendocrine tumors (NETs). Lanreotide has a similar subtype interaction. Inhibition of secretion appears to be
[16]
mechanism of action, also displays high-affinity binding for largely mediated via the effects of the sst2 subtype, and
types 2 and 5, has low affinity for types 1 and 4 and medium all commercially available SSAs have appreciable affinity
affinity for type 3. [17] for sst2. However, proliferation in endocrine tissue may
be mediated via other receptor subtypes. In patients with
Several chemotherapy agents have been employed, well-differentiated, slow-growing tumours, SSAs may be
either as single-agent or in combination for advanced- considered the first-line treatment with relatively good
stage disease in poorly differenctiated NENs, [18,19] but objective response rates and an excellent safety profile.
also in well- and moderately differentiated tumors in The most used formulations of SSAs are long-acting-
advanced disease. [20-22] These agents are streptozotocin, release (LAR) Octreotide (10-20-30 mg) and Lanreotide
doxorubicin, 5-fluorouracil, cisplatin, etoposide, and autogel (60-90-120 mg). These drugs are very effective
dacarbazine. Recently, some new chemotherapeutic agents at controlling tumor-related symptoms in the so called
have come available, such as temozolomide, oxaliplatin, “functioning tumors” (symptomatic responses occur
capecitabine, irinotecan, and gemcitabine. Also a new in 60-100% of patients). Furthermore, they are able
[32]
way of chemotherapy administration is metronomic to significantly decrease specific tumor markers (i.e.
chemotherapy. [23,24] This overview details the evolution of urinary 5-hydroxy indole acetic acid and circulating
SSAs and various chemotherapy combinations and their Chromogranin A) in greater than 50% of patients. They
application to the management of NENs. are well-tolerated and safe, with a high tolerability rate
even through a long period of treatment. Side effects,
SOMATOSTATIN ANALOGS which occur in 20-50% of cases, are usually mild and do
not require drug discontinuation. The most frequent side
In 1972, at the Salk Institute in La Jolla, California, a effects are the development of gallstones, pain at the site of
growth hormone (GH)-releasing antagonist (SST) was application, abdominal pain, flatulance, nausea, asthenia,
incidentally identified in the sheep hypothalamus during and glucose intolerance. First-line systemic therapy for
[32]
the search for a GH releasing hormone. [25,26] Crude NETs often consists of SSAs such as octreotide acetate
extracts of sheep hypothalamus added to in vitro anterior (Sandostatin ; Novartis Pharmaceutical Company, East
®
pituitary cells caused an inhibition of GH secretion. After Hanover, NJ, United States) or lanreotide (Somatuline ;
®
purification, a single compound accounting for all the GH- Ipsen Pharmaceuticals, Paris, France). These drugs,
release inhibiting acitivity of the crude extract was isolated, initially developed to palliate the symptoms of Carcinoid
and its primary structure, a 14-amino acid peptide, was Syndrome, have an inhibitory effect on secretion of
identified. The SST neuropeptide family (also known gastrointestinal hormones (i.e. serotonin). Accumulating
[26]
as somatostatin release-inhibiting factors) comprises data indicate that SSAs are also capable of inhibiting NET
peptides that originate from different post-translational growth [33,34] and have been demonstrated in numerous
processing of a 116 amino acid precursor (pre-proSST), studies to represent the best available agents to induce
which is encoded by a single gene located in humans on symptomatic relief in patients with somatostatin receptors
chromosome 3q28. Pre-proSSA is processed to pro-SST (sstr)-positive, hormone-producing NETs. The symptoms
(96 amino acids), which is further cleaved to produce two they control differ depending on tumour location and
bioactive proteins, the predominant, but functionally less which amines/peptides are produced, but include sweating,
active SST molecule consisting of 14 amino acids (SST- flushing, diarrhea, and bronchospasm. There has been a
14), and a larger more potent molecular form, SST-28. controversy regarding the relative efficacy of octreotide
[27]
Twenty years after the discovery of SST in 1972, molecular and lanreotide. Most studies include both primary and
cloning lead to the identification of its receptor structure. secondary treatment with no stratification of the cohort
[28]
Subsequently, it became apparent that in mammals, before analysis. Although it is generally considered that the
SST mediates its inhibitory effects through binding to available SST analogs have a similar efficacy in treating
at least five high-affinity G-protein-coupled membrane hormone induced NET symptoms, some differences in
receptors. Somatostatin (SST) and its analogs (SSAs) response may exist. [3]
[29]
inhibit multiple cellular functions, including secretion,
motility and proliferation and its action is mediated by OCTREOTIDE
somatostatin receptors sst1-5. These five receptors bind
the natural peptide with high affinity, but only sst2, sst3 Octreotide (SMS201-995) was the first available SSAs and
and sst5 bind the short synthetic analogues used to the treat was introduced into clinical practice in 1983 for treatment
neuroendocrine tumours (NET). SSAs have been used of hormone-producing pituitary, pancreatic, and intestinal
successfully to treat functional gastro-entero-pancreatic NETs. As octreotide is incompletely absorbed after oral
[16]
(GEP) NETs for more than a quarter of a century. The administration, its efficacy relied upon intravenous or
[3]
main reason of the use of SSAs is the expression of subcutaneous injection. The standard dose of octreotide
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Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ August 31, 2016 ¦