ANNIVERSARY REVIEW: Octreotide, 40 years later

in European Journal of Endocrinology
Correspondence should be addressed to S W J Lamberts; Email: s.w.j.lamberts@erasmusmc.nl

Octreotide remains 40 years after its development a drug, which is commonly used in the treatment of acromegaly and GEP-NETs. Very little innovation that competes with this drug occurred over this period. This review discusses several aspects of 40 years of clinical use of octreotide, including the application of radiolabeled forms of the peptide.

Abstract

Octreotide remains 40 years after its development a drug, which is commonly used in the treatment of acromegaly and GEP-NETs. Very little innovation that competes with this drug occurred over this period. This review discusses several aspects of 40 years of clinical use of octreotide, including the application of radiolabeled forms of the peptide.

Introduction

A peptide inhibiting the release of growth hormone (GH) was accidentally detected in the hypothalamus of rats during studies of the distribution of GH-releasing factor (1). This peptide, called somatostatin, is a peptide hormone that plays an inhibitory role in the regulation of multiple physiological functions, including pituitary, pancreatic and gastrointestinal hormone secretion (2, 3).Somatostatin exerts its biological effects by interaction with specific somatostatin receptors (SSTs) expressed on target tissues. Five human receptor subtypes have been detected (SST 1-5), each mediating a distinct signaling pathway (4, 5). In clinical applications, only SST2 and SST5 play an important role so far (6).

Somatostatin acts in different organ systems as a neurohormone, a neurotransmitter or as local factor acting via autocrine or paracrine mechanisms. In his Nobel lecture, Guillemin summarized a number of potential problems with regard to the clinical application of somatostatin (7): in view of its ability to inhibit such a variety of physiological processes, he predicted that somatostatin might be of therapeutic value in clinical conditions involving hyperfunction of the organ systems mentioned above. However, the multiple simultaneous effects of pharmacological concentrations of somatostatin in different organs, the need for intravenous administration, its short half-life in the circulation, and the post-infusion hypersecretion of hormones considerably hampered the initial enthusiasm for its clinical use. From 1978 on, a number of drug companies started programs to synthesize long-acting somatostatin analogs.

Octreotide (SMS 201-995) was one of the first biologically stable somatostatin analogs to be synthesized (8): it has a much longer half-life in the human circulation than somatostatin and binds with a high affinity to SST2 (9). The structure of natural somatostatin and octreotide is shown in Fig. 1. In patients with acromegaly subcutaneously administered octreotide suppressed GH secretion without a rebound hypersecretion (10). A long-acting repeatable formulation (Octreotide-LAR) was introduced for intramusculair administration later.

Figure 1
Figure 1

The structure of natural somatostatin-14 and octreotide.

Citation: European Journal of Endocrinology 181, 5; 10.1530/EJE-19-0074

Lanreotide, another metabolically stable somatostatin analog with a similar high SST2 binding profile (11), was introduced shortly after octreotide. Lanreotide is now available in a subcutaneously administered sustained-release formulation (Lanreotide-Autogel). Octreotide and lanreotide have very similar characteristics both with regard to tolerability and efficacy (vide infra).

Adverse effects

Common adverse effects of octreotide treatment include nausea, abdominal cramps, diarrhea, flatulence and fat malabsorption (12). These symptoms start within hours after injection of the drug, their severity is dose dependent, and they resolve spontaneously within 7–14 days, despite continuous treatment. The occurrence of these adverse effects is readily understood from the physiological actions of somatostatin in the gastroenterological tract and exocrine pancreas (2, 3). The spontaneous resolution of these symptoms suggests rapid adaptation/desensitization/tachyphylaxis of the effects of octreotide on the function of the gastrointestinal tract and pancreas. Indeed, after 7 days of octreotide administration in healthy volunteers the initial dose-dependent inhibitory effects on the secretion of gastric acid, amylase, trypsin and lipase diminish and subsequently disappear completely (13, 14). Octreotide therapy can lead to changes in bile composition and gall bladder contractility (15). Up to one-third of patients with acromegaly develop biliary sludge or gallstones, but symptomatic gallbladder disease occurs in only 1% of patients per treatment year (12).Octreotide inhibits GH, insulin and glucagon secretion in normal individuals, while it delays the absorption of carbohydrates. In the first days of octreotide administration reduced glucose tolerance is observed. However, after 1 week adaptation develops, and during long-term administration, octreotide does not change glucose homeostasis in normal individuals, while also GH secretion and IGF-I levels remain unchanged. An example of the rapid adaptation of the initial suppressive effect of octreotide on normal GH secretion in rats is shown in Fig. 2.

Figure 2
Figure 2

The effect of twice daily subcutaneous administration of octreotide (SMS 201-995) or placebo for 4 (left panel), 6 (middle panel) or 10 days (right panel) on circulating GH levels in normal female rats. Blood was collected 30 min after the last injection; n = 8 animals per group; values represent mean ± s.e.m. Adapted from Ref. (52).

Citation: European Journal of Endocrinology 181, 5; 10.1530/EJE-19-0074

The rapid adaptation of these initial effects of octreotide on a number of physiological functions in different organ systems eventually resulted in disappointment concerning its potential clinical use for a number of gastrointestinal and pancreatic diseases and diabetes. The transient suppression by octreotide of pancreatic enzyme suppression turned out to be too short-lived to improve the outcome of elective pancreatic surgery or of pancreatic fistulas. Also in secretory diarrhea, intestinal fistulas, the metabolic control and the prevention of chronic complications of diabetes, in (neonatal) hypoglycemia, nesidioblastosis and in the prevention of tall stature, long-term therapy with octreotide failed or demonstrated only short (days) transient beneficial effects (12, 16).

Only in the initial treatment of acute variceal bleeding octreotide transiently lowers blood pressure in the abdominal vessels, improving the outcome in a subset of patients (17).

Acromegaly

The introduction of octreotide in the medical treatment of acromegaly has been of paramount benefit for the majority of patients: a marked relief of symptoms occurs rapidly after the start of therapy, for example headaches, excessive perspiration, paresthesias and carpal syndrome improve together with the allover quality of life (12, 18, 19). Also disease- associated co-morbidities including cardiac and respiratory disorders (snoring, sleep apnea) improve during long-term therapy.

There is evidence that an early diagnosis and normalization of GH/IGF-I levels improves the excess mortality risk associated with acromegaly (20, 21). However, it remains unknown to which extent medical therapy contributes to this.

The initially available subcutaneous form of octreotide reduced GH and IGF-I levels in most patients (18, 19, 22), but the monthly Octreotide-LAR preparation subsequently caused a similar or even better control (23). Interestingly, Octreotide-LAR and Lanreotide-Autogel elicited similar response rates (24, 25). From these studies, it became evident that GH was controlled in 57%, and IGF-I normalized in 67% of patients.

However, these biochemical response rates showed considerable variation between studies. Colao et al. (26) observed response rates varying between 17 and 86% for Octreotide-LAR. A multitude of factors might contribute to these variations: difference in patient populations with regard to tumor size, age, inclusion of treatment responders and pretreatment with medical therapy are potential confounders. Another problem is that biochemical targets vary between studies, that the standardization of GH and IGF-I assays is often lacking, but most important that over the past years biochemical endpoints have become more strict in their requirement of age-adjusted normalization of both mean GH and IGF-I levels (27). In prospective studies using stringent composite biochemical endpoints to evaluate treatment-naive patients not preselected for responsiveness to prior somatostatin therapy, response rates are ranging from 17 to 37%.

Other effects of somatostatin analog therapy in acromegaly are also of clinical importance: tumor shrinkage occurs in two-third of patients (27). Tumor volume reduction is observed typically within 3 months, reaching its maximal after 6–12 months, and lasts throughout therapy. During treatment (remnant) anterior and posterior pituitary function remains intact.

Escapes from octreotide therapy are extremely rare: once the GH-secreting pituitary adenoma initially responds with a decrease in GH release and tumor shrinkage one can rely on the maintenance of this effect in the long-term follow-up. Stopping octreotide therapy results in most instances in a slow reversal of GH release, symptomatology and tumor size. This reversal can take many months. In a limited number of patients a biochemical ‘cure’ has been observed in the long-term follow-up after stopping somatostatin analog treatment. The mechanism of this phenomenon remains unclear. Spontaneous hemorrhage within the tumor tissue might have happened somewhere in the course of the disease.

Pathophysiological explanation of the effects of octreotide came mostly from in vitro studies with tumor tissue removed from acromegalic patients during transsphenoidal surgery (9, 28): the number of SST2 on the GH-secreting pituitary adenoma cells are closely related to the in vivo response of GH and IGF-I levels to octreotide (29, 30). Low SST2-expressing tumors exhibit a poor response (Fig. 3). SST2 receptor expression appears not the only determinant in the response to octreotide treatment. Other factors, including cellular E-cadherin, beta-arrestin 1 and filamin-A, have been associated with response to treatment with octreotide and lanreotide (31, 32, 33). The mechanism of action of octreotide on these pituitary adenomas involves not only an acute suppressive effect on GH secretion, but eventually hormone synthesis may decrease. Somatostatin does not seem to have an inhibitory effect on GH mRNA expression in primary cultures of human GH-secreting pituitary adenomas (34). On the other hand, GH mRNA levels are significantly lower in adenomas of acromegalic patients treated with octreotide, compared to adenomas of octreotide-naïve patients (35). Moreover, inhibition of GH release in somatotroph adenomas by octreotide is associated with accumulation of lysosomes, which suggests that octreotide induces increased lysosomal degradation of stored hormone (36). Altogether, this results into shrinkage of the GH-synthesizing and storing capacity and of related intracellular components. This shrinking effect does probably not include an important anti-tumor effect, as reflected in rebound GH secretion and reversal of tumor size after stopping octreotide administration. The mechanism which ascertains the long-term effect of octreotide on GH secretion and tumor size without an escape/adaptation/desensitization/tachyphylaxis could involve a difference in the internalization and reappearance of the peptide receptor complex on the cell membrane and/or a difference in intracellular mechanisms involved in desensitization processes, between the adenoma cell and SST2 on normal target organs (9).

Figure 3
Figure 3

Patients that achieved IGF-1 normalization after adjuvant treatment with long-acting octreotide (Octreotide-LAR) showed significantly higher SST2A immunoreactivity (as quantified by an immunoreactivity score (IRS)) compared with the non-normalized group (P = 0.002; n = 18). Adapted from Ref. (29).

Citation: European Journal of Endocrinology 181, 5; 10.1530/EJE-19-0074

TSH-secreting pituitary adenomas

Most TSH-secreting pituitary adenomas express SST2 and respond to octreotide with suppression of hormone release and control of tumor growth, as well as clinical improvement (37, 38).

Gastro-entero and pancreatic neuroendocrine tumors

Gastro-entero and pancreatic neuroendocrine tumors (GEP-NETs) have retained many characteristics of the neuroendocrine cells in the gut and endocrine pancreas from which they originate: more than 80% of these tumors express SST2 (39, 40). Most are slow-growing malignant tumors, which have metastasized at diagnosis. Their clinical manifestations are often related to hormonal hypersecretion.

Octreotide controls diarrhea and flushing attacks caused by an overproduction of serotonin and tachykinins in 70–90% of carcinoid patients (41), while it ameliorates dehydration, hypokalemic alkalosis, diarrhea, peptic ulceration, hypoglycemic attacks and necrolytic skin lesions in 50–80% of patients with endocrine pancreatic tumors secreting vasoactive intestinal polypeptide, gastrin, insulin and glucagon, respectively (12, 42). The immediate clinical effects of somatostatin analog therapy on quality of life are in most cases striking.

From early on after the clinical introduction of octreotide in the mid-eighties there have been suggestions that this medical treatment might prolong survival of patients with GEP-NETS. Such an effect might be attributed on the one hand to the clinical improvement in many of these patients during control of hormonal hypersecretion. On the other hand, there were many experimental studies, mainly from Schally’s group suggesting direct anti-tumor effects by somatostatin analog administration (43, 44).

Two large clinical trials indeed demonstrated a direct anti-tumor effect of Octreotide-LAR (PROMID study) and Lanreotide-Autogel (Clarinet study) in patients with well-differentiated metastatic GEP-NETs (45, 46): in the first study octreotide administration delayed tumor progression from 6 to 14.3 months, while in the other study lanreotide induced after 2 years a median progression-free survival of 65.1 vs 33.0% in the placebo group. In these studies, progression of tumor growth was measured, while potential shrinkage in a subset of patients was not reported.

The molecular basis of the anti-proliferative effect of octreotide/lanreotide in GEP-NETs suggests that their interaction with SST2 on the tumor cells is coupled to intracellular signaling pathways that directly or indirectly influence cell cycling (47), apoptosis (48) and/or angiogenesis (49).

The immediate clinical improvement together with the proven anti-tumor effects of somatostatin analog therapy in metastatic, inoperable GEP-NETs make these patients, if SST2 are present on these tumors (vide infra), candidates for long-term primary treatment with octreotide/lanreotide.

A major problem of somatostatin analog therapy in these patients is, however, that eventually a decrease/loss of the control of hormonal secretion and of tumor growth develops (50, 51). It can initially be reversed by increase of the dose of octreotide/lanreotide. Escape from therapy seems not related to transient downregulation of SST2 on the tumor cells, because sensitivity is not restored after a drug holiday (52). This loss of sensitivity seems initially be related to a loss of connection between the peptide receptor complex and its intracellular messenger system, but eventually tumor cell clones appear that lack SST2 (9).

In vivo visualization of SST2 receptors

The presence of a high density of SST2 receptors on human neuroendocrine tumors, as demonstrated by in vitro autoradiography using 125I-Tyr3-octreotide (39, 40), as well as the inhibitory effect of octreotide on hormone secretion by these tumors, suggested the feasibility to visualize such tumors in vivo in patients after the administration of Tyr3-octreotide coupled to 123I (53). [123I-Tyr3]octreotide scanning revealed the localization of the primary tumors and their metastases in 38 of 42 patients with carcinoids, islet cell tumors and paragangliomas (54). The surgically removed tumors of a number of these patients were subsequently investigated in vitro, while also preoperative hormonal studies with octreotide had been carried out. There was a close parallel relationship between the presence of SST2 on these tumors in vitro, the hormonal response pre-operatively, and the in vivo visualization of these tumors (55).Because of logistical and practical drawbacks of the use of 123I, an alternative was created by coupling a spacer (DTPA (diethylenetriaminepentaacetic acid)) to octreotide, resulting in a compound which efficiently binds to 111Indium (56).

The introduction of 111In-DTPA-octreotide scintigraphy in patients with GEP-NETs has revolutionized their diagnostic and therapeutic approach (53, 54, 55, 57, 58): 80–100% of GEP-NETs express at diagnosis SST2, allowing the visualization of the primary tumor, as well as previously unknown metastases. SST imaging has greater sensitivity than conventional imaging studies in 60–90% of patients. Whole body imaging at one time for the detection of distant metastases resulted in management changes in 25–50% of cases. SST scintigraphy allows visualization of GEP-NET lesions smaller than 1 cm in 50% of cases, but results heavily depend on the degree of differentiation, because poorly differentiated tumors frequently either do not express SST2 or do so in low densities. A positive SST scan predicts whether the patient is a candidate for SST2-targeted radiotherapy (vide infra). Recently with the introduction of PET imaging molecular imaging with 68Ga-labeled somatostatin analogs has been developed; this new compound allows an even greater spatial resolution than 111In-DTPA-octreotide (59).

The clinical introduction of SST scintigraphy has provided many new insights in the distribution of SSTR in human diseases (52, 54, 57). Apart from most GEP-NETS many other neuroendocrine tumors express enough SST to allow visualization of their primary location as well as their metastases: these include paragangliomas, pheochromocytomas, medullary thyroid cancers and small-cell lung cancers. A number of adenocarcinomas originating from the breast, kidney, colon, ovary and other organs, which contain dispersed neuroendocrine cells express SST2 at a variable degree, allowing their in vivo visualization. Tumors originating from other tissues that normally express SSTR like the leptomeninx (meningiomas), glia (well-differentiated astrocytomas), lymphocytes (malignant lymphomas) can be visualized as well. Finally, it was demonstrated that clusters of activated immune cells in granulomas (in sarcoidosis and tuberculosis and rheumatoid arthritis) can be visualized in vivo (52, 54, 57). Today, there is limited knowledge concerning the pathophysiological role of SST2 expression.

The visualization of SST on such a variety of disease processes was unexpected. It was proven that the sensitivity and specificity of SST imaging is extremely high: indeed in all conditions mentioned above the presence of SST on the visualized tissues was ascertained in vitro. However, one should realize that the specificity of SST imaging for GEP-NETS is not high: in a given patient one should remain alert whether a SST2-positive location indeed represents a GEP-NET, rather than for example a previously unknown meningioma, sarcoidosis or rheumatoid arthritis.

SST-targeted radiotherapy

Early studies demonstrated that exposure of cultured SST2-positive human tumor cells to [125I-Tyr3]octreotide resulted in a dose- and time-dependent specific uptake and retention of radioactivity within these tumor cells (Fig. 4) (60, 61). Also, in animal studies involving rats bearing SST2 expressing tumors, it was demonstrated that such internalization and retention occurs in vivo, while the unbound somatostatin ligand is rapidly cleared via the kidneys: this results in a high gradient between radioactivity in the blood and the tumor tissue (56).

Figure 4
Figure 4

Time-dependent increased uptake of [125I-Tyr3]octreotide by cells of a human carcinoid. Values represent the amount of uptake, expressed as the percentage of the added dose of [125I-Tyr3]octreotide, in the absence and in the presence of excess (1 μM) unlabeled octreotide, to determine non-specific internalization. Adapted from Ref. (60).

Citation: European Journal of Endocrinology 181, 5; 10.1530/EJE-19-0074

The use of radiolabeled somatostatin analog therapy for the therapy of advanced well-differentiated GEP-NETs has been developed step by step over the past 25 years (62).Initially, efficacy results were based on the use of very high doses of 111In-DTPA octreotide. More promising results were subsequently found with 90Y-DOTA Tyr3-octreotide and 177Lu-DOTA-Tyr3-octreotide. Eventually 177Lu-DOTA-Tyr3-octreotate was found to be the compound with the highest affinity to SST2. Lutetium-177 is a beta- and gamma-emitting radionuclide with a maximum particle range of 2 mm, and a half-life of 160 h. In a multinational, multicenter study in 229 patients with well-differentiated metastatic midgut neuroendocrine tumors 113 patients received Octreotide-LAR alone (60 mg/month), and 116 patients received the same dose of Octreotide-LAR once a month together with four infusions of [177Lu-DOTA-Tyr3]octreotate (7.4 GBq with intervals of 8 weeks). Treatment with the 177Lu compound resulted in a longer progression-free survival: at 20 months 65 vs 10.8% in the high dose Octreotide-LAR only group, while there was also an increased overall survival (14 vs 26 deaths). Toxicity and adverse effects were limited (63). [177Lu-DOTA, Tyr3]octreotate therapy for NET patients recently received EMA and FDA approval.

Somatostatin receptor subtype 5 (SST5)

SST5 is distributed throughout the human body in several organs, including the anterior pituitary, the endocrine cells lining the gut and of the pancreas. In human pathology SST5 expression is found to be of clinical importance in both GH- and ACTH-secreting pituitary adenomas (64, 65), while their presence is low in GEP-NETS (65).

Pasireotide is a multireceptor-targeted somatostatin analog with an in comparison to octreotide slightly lower affinity to SST2, but a nearly 40 times higher affinity to SST5 (66). Corticotropinomas predominantly express SST5 (67, 68) and ACTH secretion by cultured tumor cells obtained at transsphenoidal operation is suppressed by pasireotide in nanomolar concentrations in 60% of cases (69). In a multicenter study pasireotide (600 μg (82 patients) or 900 μg (80 patients) twice daily) normalized urinary free cortisol concentrations in 15 and 25% of patients with Cushing’s disease, respectively (70).

In early studies from Melmed’s laboratory, it was demonstrated that SST5 expressed on GH-producing tumor cells were functional: several new chimeric compounds which bound with high affinity to both SST2 and SST5 suppressed GH more than SST2-specific compounds alone (6, 71).

Van der Hoek et al. (72) compared the effects of nanomolar concentrations of octreotide and pasireotide: in a number of acromegalic tumors a higher expression of SST 5 mRNA expression was accompanied by a significantly higher suppression of GH by pasireotide (Fig. 5). Indeed, as expected, a comparison between the effect of long-term treatment of Octreotide-LAR and pasireotide-LAR in acromegalic patients demonstrated that more patients were biochemically cured with pasireotide (73).

Figure 5
Figure 5

In vitro data of two acromegalic patients, demonstrating a preferential inhibition of GH secretion in vitro by pasireotide in cultured cells with high SST5 expression, compared to SST2 expression (patient 12). Relative SST2 and SST5 expression in GH-secreting pituitary adenoma tissue of patient 6 (lower left) and patient 12 (lower right). Effects of octreotide (10 nM) and pasireotide (10 nM) on GH secretion by cultured pituitary adenoma cells from patient 6 (upper left) and patient 12 (upper right). Adapted from Ref. (72).

Citation: European Journal of Endocrinology 181, 5; 10.1530/EJE-19-0074

From pre-clinical data, it had become evident that pasireotide administration in young rats completely stops body growth, while IGF-I levels remain lowered during long-term follow-up (74). Also in a study by Feelders et al. (75) in patients with Cushing’s disease, IGF-I levels decreased over time during pasireotide administration, with a level below the lower limit of normal range in 9 of 17 patients after 80 days (75).

In all clinical studies reported so far pasireotide caused from the very first injection on a deterioration of glucose metabolism, which did not improve during continued administration of the drug. In about 40% of patients with Cushing’s disease hyperglycemia was diagnosed during pasireotide treatment, while 18% developed diabetes, despite the expected improvement of glucose tolerance in response to the control of ACTH/cortisol hypersecretion (70). Pasireotide induces glucose intolerance and diabetes in about half of acromegalic patients; there are no guidelines so far concerning the question what the place of this drug is in comparison with octreotide/lanreotide alone or in combination with a GH receptor antagonist.

Octreotide after 40 years

Octreotide remains 40 years after its development a drug, which is commonly used in the treatment of acromegaly and GEP-NETs. Very little innovation that competes with this drug occurred over this period. As mentioned earlier octreotide and lanreotide have a similar efficacy and safety profile. The long-acting depot preparations of both drugs can be interchanged in the clinic. Only an oral formulation of octreotide is on the horizon for clinical introduction (76). The rapid adaptation of SST2 on normal organs makes the drug very safe and well tolerated. In acromegaly octreotide rapidly improves symptomatology and quality of life, it shrinks pituitary tumor size in two-third of cases without growth during long-term follow-up; also pituitary function remains intact, while no escape from therapy occurs. The number of patients in which octreotide eventually induces a biochemical cure depends on how strict composite endpoints are defined. Addition of once daily or weekly injections of a GH receptor antagonist is successful in most cases (77). For patients with GEP-NETs the introduction of octreotide meant an enormous improvement in their quality of life. Apart from control of hormonal hypersecretion somatostatin analogs were proven to have anti-proliferative effects as well, as demonstrated by delay in tumor growth progression, as well as survival.Although not reported in detail, a number of acromegalic patients are currently treated for more than 25 years with continuing efficacy and without notable adverse effects.

SST2 visualization and SST2-targeted radiotherapy revolutionized diagnosis and treatment of GEP-NET patients: the scan indicates the localization of the primary tumor, as well as their often previously unknown metastases, while a positive scan predicts sensitivity of the tumor tissue to octreotide: this applies both to the treatment with ‘cold’ somatostatin analogs (hormonal hypersecretion and control of tumor growth), as to the use of SST2-targeted radiotherapy (proven shrinkage and prolonged survival as well).The central problem to be solved in patients with GEP-NETs is how to optimally use the window of opportunity of SST2 expression on the tumors: during long-term therapy with octreotide eventually loss of sensitivity occurs with an escape from treatment. This escape is related to loss of tumor differentiation and eventually loss of SST2 expression. It is crucial to define in a given patient the optimal moment for SST2-targeted radiotherapy. Moreover, depending on the tumor type, 10–50% of NET patients have tumors that do not express sufficient SST to make them eligible for SST2-targeted radiotherapy (78). Preliminary studies suggest that pharmacologically driven transient upregulation of SST2 to enhance the effect of targeted radiotherapy will be a feasible option in some patients (79). SST-targeted radiotherapy is an innovative viable development in clinical medicine. Based on this development a new research field, called theranostics (80), is developing in Nuclear Medicine, with 177LU-PSMA (prostate-specific membrane antigen) administration as an innovative successful treatment for androgen-receptor-resistant prostate cancer patients (81). SST5 physiology turned out to be different from SST2: pasireotide, a compound with a 40 times higher affinity for SST5 than octreotide causes in normal individuals GH/IGF-I deficiency, as well as clinically significant impairment of glucose metabolism. In contrast to SST2, SST5 activation in normal organs appears not to adapt/desensitize. These adverse effects limit its use in acromegaly and in Cushing’s disease considerably. Guillemin (7) commented in his Nobel lecture on the limitations of the clinical use of somatostatin: he was right with regard to SST5: the adverse effects on normal organs limit the use of SST5-specific analogs. However, SST2 desensitization on normal organs, which develops within several days, opened the opportunity for octreotide to be administered for a prolonged time without important adverse effects.

Declaration of interest

L H has received investigator-initiated research support from Ipsen and Novartis Pharma. S W J L has nothing to disclose.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

References

  • 1

    BrazeauPValeWBurgusRLingNButcherMRivierJGuilleminR. Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone. Science 1973 7779. (https://doi.org/10.1126/science.179.4068.77)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    ReichlinS. Somatostatin (second of two parts). New England Journal of Medicine 1983 15561563. (https://doi.org/10.1056/NEJM198312223092506)

    • Search Google Scholar
    • Export Citation
  • 3

    ReichlinS. Somatostatin. New England Journal of Medicine 1983 14951501. (https://doi.org/10.1056/NEJM198312153092406)

  • 4

    PatelYCSrikantCB. Subtype selectivity of peptide analogs for all five cloned human somatostatin receptors (hsstr 1–5). Endocrinology 1994 28142817. (https://doi.org/10.1210/endo.135.6.7988476)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    GuntherTTulipanoGDournaudPBousquetCCsabaZKreienkampHJLuppAKorbonitsMCastanoJPWesterHJ et al. International Union of Basic and Clinical Pharmacology. CV. Somatostatin receptors: structure, function, ligands, and new nomenclature. Pharmacological Reviews 2018 763835. (https://doi.org/10.1124/pr.117.015388)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    ShimonITaylorJEDongJZBitonteRAKimSMorganBCoyDHCullerMDMelmedS. Somatostatin receptor subtype specificity in human fetal pituitary cultures. Differential role of SSTR2 and SSTR5 for growth hormone, thyroid-stimulating hormone, and prolactin regulation. Journal of Clinical Investigation 1997 789798. (https://doi.org/10.1172/JCI119225)

    • Search Google Scholar
    • Export Citation
  • 7

    GuilleminR. Peptides in the brain: the new endocrinology of the neuron. Science 1978 390402. (https://doi.org/10.1126/science.212832)

  • 8

    BauerWBrinerUDoepfnerWHallerRHugueninRMarbachPPetcherTJPless. SMS 201–995: a very potent and selective octapeptide analogue of somatostatin with prolonged action. Life Sciences 1982 11331140. (https://doi.org/10.1016/0024-3205(82)90087-x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    HoflandLJLambertsSW. The pathophysiological consequences of somatostatin receptor internalization and resistance. Endocrine Reviews 2003 2847. (https://doi.org/10.1210/er.2000-0001)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    LambertsSWOosteromRNeufeldMdel PozoE. The somatostatin analog SMS 201–995 induces long-acting inhibition of growth hormone secretion without rebound hypersecretion in acromegalic patients. Journal of Clinical Endocrinology and Metabolism 1985 11611165. (https://doi.org/10.1210/jcem-60-6-1161)

    • Search Google Scholar
    • Export Citation
  • 11

    HoflandLJvan KoetsveldPMWaaijersMZuyderwijkJLambertsSW. Relative potencies of the somatostatin analogs octreotide, BIM-23014, and RC-160 on the inhibition of hormone release by cultured human endocrine tumor cells and normal rat anterior pituitary cells. Endocrinology 1994 301306. (https://doi.org/10.1210/endo.134.1.7903931)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    LambertsSWvan der LelyAJde HerderWWHoflandLJ. Octreotide. New England Journal of Medicine 1996 246254. (https://doi.org/10.1056/NEJM199601253340408)

    • Search Google Scholar
    • Export Citation
  • 13

    CreutzfeldtWLembckeBFolschURSchleserSKoopI. Effect of somatostatin analogue (SMS 201–995, Sandostatin) on pancreatic secretion in humans. American Journal of Medicine 1987 4954. (https://doi.org/10.1016/0002-9343(87)90426-8)

    • Search Google Scholar
    • Export Citation
  • 14

    LondongWAngererMKutzKLandgrafRLondongV. Diminishing efficacy of octreotide (SMS 201–995) on gastric functions of healthy subjects during one-week administration. Gastroenterology 1989 713722.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    MoschettaAStolkMFRehfeldJFPortincasaPSleePHKoppeschaarHPVan ErpecumKJVanberge-HenegouwenGP. Severe impairment of postprandial cholecystokinin release and gall-bladder emptying and high risk of gallstone formation in acromegalic patients during Sandostatin LAR. Alimentary Pharmacology and Therapeutics 2001 181185. (https://doi.org/10.1046/j.1365-2036.2001.00924.x)

    • Search Google Scholar
    • Export Citation
  • 16

    HarrisAGO’DorisioTMWolteringEAAnthonyLBBurtonFRGellerRBGrendellJHLevinBRedfernJS. Consensus statement: octreotide dose titration in secretory diarrhea. Diarrhea Management Consensus Development Panel. Digestive Diseases and Sciences 1995 14641473. (https://doi.org/10.1007/bf02285194)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    BurroughsAKMcCormickPAHughesMDSprengersDD’HeygereFMcIntyreN. Randomized, double-blind, placebo-controlled trial of somatostatin for variceal bleeding. Emergency control and prevention of early variceal rebleeding. Gastroenterology 1990 13881395. (https://doi.org/10.1016/0016-5085(90)91166-4)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    VanceMLHarrisAG. Long-term treatment of 189 acromegalic patients with the somatostatin analog octreotide. Results of the International Multicenter Acromegaly Study Group. Archives of Internal Medicine 1991 15731578. (https://doi.org/10.1001/archinte.151.8.1573)

    • Search Google Scholar
    • Export Citation
  • 19

    EzzatSSnyderPJYoungWFBoyajyLDNewmanCKlibanskiAMolitchMEBoydAESheelerLCookDM. Octreotide treatment of acromegaly. A randomized, multicenter study. Annals of Internal Medicine 1992 711718. (https://doi.org/10.7326/0003-4819-117-9-711)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    SwearingenBBarkerFG2ndKatznelsonLBillerBMGrinspoonSKlibanskiAMoayeriNBlackPMZervasNT. Long-term mortality after transsphenoidal surgery and adjunctive therapy for acromegaly. Journal of Clinical Endocrinology and Metabolism 1998 34193426. (https://doi.org/10.1210/jcem.83.10.5222)

    • Search Google Scholar
    • Export Citation
  • 21

    HoldawayIMBollandMJGambleGD. A meta-analysis of the effect of lowering serum levels of GH and IGF-I on mortality in acromegaly. European Journal of Endocrinology 2008 8995. (https://doi.org/10.1530/EJE-08-0267)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    LambertsSWUitterlindenPVerschoorLvan DongenKJdel PozoE. Long-term treatment of acromegaly with the somatostatin analogue SMS 201–995. New England Journal of Medicine 1985 15761580. (https://doi.org/10.1056/NEJM198512193132504)

    • Search Google Scholar
    • Export Citation
  • 23

    FredaPUKatznelsonLvan der LelyAJReyesCMZhaoSRabinowitzD. Long-acting somatostatin analog therapy of acromegaly: a meta-analysis. Journal of Clinical Endocrinology and Metabolism 2005 44654473. (https://doi.org/10.1210/jc.2005-0260)

    • Search Google Scholar
    • Export Citation
  • 24

    MurrayRDMelmedS. A critical analysis of clinically available somatostatin analog formulations for therapy of acromegaly. Journal of Clinical Endocrinology and Metabolism 2008 29572968. (https://doi.org/10.1210/jc.2008-0027)

    • Search Google Scholar
    • Export Citation
  • 25

    CarmichaelJDBonertVSNunoMLyDMelmedS. Acromegaly clinical trial methodology impact on reported biochemical efficacy rates of somatostatin receptor ligand treatments: a meta-analysis. Journal of Clinical Endocrinology and Metabolism 2014 18251833. (https://doi.org/10.1210/jc.2013-3757)

    • Search Google Scholar
    • Export Citation
  • 26

    ColaoAAuriemmaRSPivonelloRKasukiLGadelhaMR. Interpreting biochemical control response rates with first-generation somatostatin analogues in acromegaly. Pituitary 2016 235247. (https://doi.org/10.1007/s11102-015-0684-z)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    MelmedSBronsteinMDChansonPKlibanskiACasanuevaFFWassJAHStrasburgerCJLugerAClemmonsDRGiustinaA. A Consensus Statement on acromegaly therapeutic outcomes. Nature Reviews: Endocrinology 2018 552561. (https://doi.org/10.1038/s41574-018-0058-5)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    LambertsSW. The role of somatostatin in the regulation of anterior pituitary hormone secretion and the use of its analogs in the treatment of human pituitary tumors. Endocrine Reviews 1988 417436. (https://doi.org/10.1210/edrv-9-4-417)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    GattoFFeeldersRAvan der PasRKrosJMWaaijersMSprij-MooijDNeggersSJvan der LelijAJMinutoFLambertsSW et al. Immunoreactivity score using an anti-sst2A receptor monoclonal antibody strongly predicts the biochemical response to adjuvant treatment with somatostatin analogs in acromegaly. Journal of Clinical Endocrinology and Metabolism 2013 E66E71. (https://doi.org/10.1210/jc.2012-2609)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30

    TaboadaGFLuqueRMNetoLVMachado EdeEde OSbaffiBCDominguesRCMarcondesJBChimelliLMFontesRNiemeyerP et al. Quantitative analysis of somatostatin receptor subtypes (1–5) gene expression levels in somatotropinomas and correlation to in vivo hormonal and tumor volume responses to treatment with octreotide LAR. European Journal of Endocrinology 2008 295303. (https://doi.org/10.1530/EJE-07-0562)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    FougnerSLLekvaTBorotaOCHaldJKBollerslevJBergJP. The expression of E-cadherin in somatotroph pituitary adenomas is related to tumor size, invasiveness, and somatostatin analog response. Journal of Clinical Endocrinology and Metabolism 2010 23342342. (https://doi.org/10.1210/jc.2009-2197)

    • Search Google Scholar
    • Export Citation
  • 32

    GattoFBiermaszNRFeeldersRAKrosJMDoganFvan der LelyAJNeggersSJLambertsSWPereiraAMFeroneD et al. Low beta-arrestin expression correlates with the responsiveness to long-term somatostatin analog treatment in acromegaly. European Journal of Endocrinology 2016 651662. (https://doi.org/10.1530/EJE-15-0391)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    PeverelliEGiardinoETreppiediDVitaliECambiaghiVLocatelliMLasioGBSpadaALaniaAGMantovaniG. Filamin A (FLNA) plays an essential role in somatostatin receptor 2 (SST2) signaling and stabilization after agonist stimulation in human and rat somatotroph tumor cells. Endocrinology 2014 29322941. (https://doi.org/10.1210/en.2014-1063)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    DavisJRWilsonEMVidalMEJohnsonAPLynchSSSheppardMC. Regulation of growth hormone secretion and messenger ribonucleic acid accumulation in human somatotropinoma cells in vitro. Journal of Clinical Endocrinology and Metabolism 1989 704708. (https://doi.org/10.1210/jcem-69-4-704)

    • Search Google Scholar
    • Export Citation
  • 35

    TsukamotoNNagayaTKuwayamaATakanoKShizumeKSugitaKSeoH. Octreotide treatment results in the inhibition of GH gene expression in the adenoma of the patients with acromegaly. Endocrine Journal 1994 437444. (https://doi.org/10.1507/endocrj.41.437)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36

    AsaSLFelixIKovacsKRamyarL. Effects of somatostatin on somatotroph adenomas of the human pituitary: an in vitro functional and morphological study. Endocrine Pathology 1990 228235. (https://doi.org/10.1007/BF02915416)

    • Search Google Scholar
    • Export Citation
  • 37

    ChansonPWeintraubBDHarrisAG. Octreotide therapy for thyroid-stimulating hormone-secreting pituitary adenomas. A follow-up of 52 patients. Annals of Internal Medicine 1993 236240. (https://doi.org/10.7326/0003-4819-119-3-199308010-00010)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38

    TjornstrandANystromHF. DIAGNOSIS of ENDOCRINE DISEASE: Diagnostic approach to TSH-producing pituitary adenoma. European Journal of Endocrinology 2017 R183R197. (https://doi.org/10.1530/EJE-16-1029)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 39

    ReubiJCKrenningELambertsSWKvolsL. Somatostatin receptors in malignant tissues. Journal of Steroid Biochemistry and Molecular Biology 1990 10731077. (https://doi.org/10.1016/0960-0760(90)90468-Z)

    • Search Google Scholar
    • Export Citation
  • 40

    ReubiJCKvolsLKrenningELambertsSW. Distribution of somatostatin receptors in normal and tumor tissue. Metabolism: Clinical and Experimental 1990 7881. (https://doi.org/10.1016/0026-0495(90)90217-z)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41

    KvolsLKMoertelCGO’ConnellMJSchuttAJRubinJHahnRG. Treatment of the malignant carcinoid syndrome. Evaluation of a long-acting somatostatin analogue. New England Journal of Medicine 1986 663666. (https://doi.org/10.1056/NEJM198609113151102)

    • Search Google Scholar
    • Export Citation
  • 42

    KvolsLKBuckMMoertelCGSchuttAJRubinJO’ConnellMJHahnRG. Treatment of metastatic islet cell carcinoma with a somatostatin analogue (SMS 201–995). Annals of Internal Medicine 1987 162168. (https://doi.org/10.7326/0003-4819-107-2-162)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43

    SchallyAV. Oncological applications of somatostatin analogues. Cancer Research 1988 69776985.

  • 44

    LiebowCLeeMTSchallyA. Antitumor effects of somatostatin mediated by the stimulation of tyrosine phosphatase. Metabolism: Clinical and Experimental 1990 163166. (https://doi.org/10.1016/0026-0495(90)90237-7)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45

    RinkeAMullerHHSchade-BrittingerCKloseKJBarthPWiedMMayerCAminossadatiBPapeUFBlakerM et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. Journal of Clinical Oncology 2009 46564663. (https://doi.org/10.1200/JCO.2009.22.8510)

    • Search Google Scholar
    • Export Citation
  • 46

    CaplinMEPavelMCwiklaJBPhanATRadererMSedlackovaECadiotGWolinEMCapdevilaJWallL et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. New England Journal of Medicine 2014 224233. (https://doi.org/10.1056/NEJMoa1316158)

    • Search Google Scholar
    • Export Citation
  • 47

    PagesPBenaliNSaint-LaurentNEsteveJPSchallyAVTkaczukJVaysseNSusiniCBuscailL. sst2 somatostatin receptor mediates cell cycle arrest and induction of p27(Kip1). Evidence for the role of SHP-1. Journal of Biological Chemistry 1999 1518615193. (https://doi.org/10.1074/jbc.274.21.15186)

    • Search Google Scholar
    • Export Citation
  • 48

    FerranteEPellegriniCBondioniSPeverelliELocatelliMGelminiPLucianiPPeriAMantovaniGBosariS et al. Octreotide promotes apoptosis in human somatotroph tumor cells by activating somatostatin receptor type 2. Endocrine-Related Cancer 2006 955962. (https://doi.org/10.1677/erc.1.01191)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 49

    Garcia de la TorreNWassJATurnerHE. Antiangiogenic effects of somatostatin analogues. Clinical Endocrinology 2002 425441. (https://doi.org/10.1046/j.1365-2265.2002.01619.x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 50

    LambertsSWPietersGFMetselaarHJOngGLTanHSReubiJC. Development of resistance to a long-acting somatostatin analogue during treatment of two patients with metastatic endocrine pancreatic tumours. Acta Endocrinologica 1988 561566. (https://doi.org/10.1530/acta.0.1190561)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 51

    WynickDAndersonJVWilliamsSJBloomSR. Resistance of metastatic pancreatic endocrine tumours after long-term treatment with the somatostatin analogue octreotide (SMS 201–995). Clinical Endocrinology 1989 385388. (https://doi.org/10.1111/j.1365-2265.1989.tb00436.x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 52

    LambertsSWKrenningEPReubiJC. The role of somatostatin and its analogs in the diagnosis and treatment of tumors. Endocrine Reviews 1991 450482. (https://doi.org/10.1210/edrv-12-4-450)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 53

    KrenningEPBakkerWHBreemanWAKoperJWKooijPPAusemaLLamerisJSReubiJCLambertsSW. Localisation of endocrine-related tumours with radioiodinated analogue of somatostatin. Lancet 1989 242244. (https://doi.org/10.1016/s0140-6736(89)91258-0)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 54

    LambertsSWBakkerWHReubiJCKrenningEP. Somatostatin-receptor imaging in the localization of endocrine tumors. New England Journal of Medicine 1990 12461249. (https://doi.org/10.1056/NEJM199011013231805)

    • Search Google Scholar
    • Export Citation
  • 55

    LambertsSWHoflandLJvan KoetsveldPMReubiJCBruiningHABakkerWHKrenningEP. Parallel in vivo and in vitro detection of functional somatostatin receptors in human endocrine pancreatic tumors: consequences with regard to diagnosis, localization, and therapy. Journal of Clinical Endocrinology and Metabolism 1990 566574. (https://doi.org/10.1210/jcem-71-3-566)

    • Search Google Scholar
    • Export Citation
  • 56

    BakkerWHKrenningEPReubiJCBreemanWASetyono-HanBde JongMKooijPPBrunsCvan HagenPMMarbachP. In vivo application of [111In-DTPA-D-Phe1]-octreotide for detection of somatostatin receptor-positive tumors in rats. Life Sciences 1991 15931601. (https://doi.org/10.1016/0024-3205(91)90053-e)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 57

    KrenningEPKwekkeboomDJBakkerWHBreemanWAKooijPPOeiHYvan HagenMPostemaPTde JongMReubiJC. Somatostatin receptor scintigraphy with [111In-DTPA-D-Phe1]- and [123I-Tyr3]-octreotide: the Rotterdam experience with more than 1000 patients. European Journal of Nuclear Medicine 1993 716731. (https://doi.org/10.1007/BF00181765)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 58

    ItoTLeeLJensenRT. Treatment of symptomatic neuroendocrine tumor syndromes: recent advances and controversies. Expert Opinion on Pharmacotherapy 2016 21912205. (https://doi.org/10.1080/14656566.2016.1236916)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 59

    DeppenSABlumeJBobbeyAJShahCGrahamMMLeePDelbekeDWalkerRC. 68Ga-DOTATATE compared with 111In-DTPA-Octreotide and conventional imaging for pulmonary and gastroenteropancreatic neuroendocrine tumors: a systematic review and meta-analysis. Journal of Nuclear Medicine 2016 872878. (https://doi.org/10.2967/jnumed.115.165803)

    • Search Google Scholar
    • Export Citation
  • 60

    LambertsSWJde HerderWWvan KoetsveldPMKoperJWvan der LelyAJVisser-WisselaarHAHoflandLJ. Somatostatin receptors: clinical implications for endocrinology and oncology. In Somatostatin and Its Receptors. Eds ChadwickD & CardewG. Chichester, West Suusex, UK: John Wiley & Sons1995.

    • Search Google Scholar
    • Export Citation
  • 61

    HoflandLJvan KoetsveldPMWaaijersMZuyderwijkJBreemanWALambertsSW. Internalization of the radioiodinated somatostatin analog [125I-Tyr3]octreotide by mouse and human pituitary tumor cells: increase by unlabeled octreotide. Endocrinology 1995 36983706. (https://doi.org/10.1210/endo.136.9.7649075)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 62

    KwekkeboomDJKrenningEP. Peptide receptor radionuclide therapy in the treatment of neuroendocrine tumors. Hematology/Oncology Clinics of North America 2016 179191. (https://doi.org/10.1016/j.hoc.2015.09.009)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 63

    StrosbergJEl-HaddadGWolinEHendifarAYaoJChasenBMittraEKunzPLKulkeMHJaceneH et al. Phase 3 trial of (177)Lu-Dotatate for midgut neuroendocrine tumors. New England Journal of Medicine 2017 125135. (https://doi.org/10.1056/NEJMoa1607427)

    • Search Google Scholar
    • Export Citation
  • 64

    MelmedS. Medical progress: acromegaly. New England Journal of Medicine 2006 25582573. (https://doi.org/10.1056/NEJMra062453)

  • 65

    de HerderWWHoflandLJvan der LelyAJLambertsSW. Somatostatin receptors in gastroentero-pancreatic neuroendocrine tumours. Endocrine-Related Cancer 2003 451458. (https://doi.org/10.1677/erc.0.0100451)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 66

    SchmidHASchoeffterP. Functional activity of the multiligand analog SOM230 at human recombinant somatostatin receptor subtypes supports its usefulness in neuroendocrine tumors. Neuroendocrinology 2004 (Supplement 1) 4750. (https://doi.org/10.1159/000080741)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 67

    de BruinCPereiraAMFeeldersRARomijnJARoelfsemaFSprij-MooijDMvan AkenMOvan der LelijAJde HerderWWLambertsSW et al. Coexpression of dopamine and somatostatin receptor subtypes in corticotroph adenomas. Journal of Clinical Endocrinology and Metabolism 2009 11181124. (https://doi.org/10.1210/jc.2008-2101)

    • Search Google Scholar
    • Export Citation
  • 68

    KornerMWaserBChristEBeckJReubiJC. A critical evaluation of sst3 and sst5 immunohistochemistry in human pituitary adenomas. Neuroendocrinology 2018 116127. (https://doi.org/10.1159/000472563)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 69

    HoflandLJvan der HoekJFeeldersRvan AkenMOvan KoetsveldPMWaaijersMSprij-MooijDBrunsCWeckbeckerGde HerderWW et al. The multi-ligand somatostatin analogue SOM230 inhibits ACTH secretion by cultured human corticotroph adenomas via somatostatin receptor type 5. European Journal of Endocrinology 2005 645654. (https://doi.org/10.1530/eje.1.01876)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 70

    ColaoAPetersennSNewell-PriceJFindlingJWGuFMaldonadoMSchoenherrUMillsDSalgadoLRBillerBM et al. A 12-month phase 3 study of pasireotide in Cushing’s disease. New England Journal of Medicine 2012 914924. (https://doi.org/10.1056/NEJMoa1105743)

    • Search Google Scholar
    • Export Citation
  • 71

    ShimonIYanXTaylorJEWeissMHCullerMDMelmedS. Somatostatin receptor (sstr) subtype-selective analogues differentially suppress in vitro growth hormone and prolactin in human pituitary adenomas. Novel potential therapy for functional pituitary tumors. Journal of Clinical Investigation 1997 23862392. (https://doi.org/10.1172/JCI119779)

    • Search Google Scholar
    • Export Citation
  • 72

    van der HoekJde HerderWWFeeldersRAvan der LelyAJUitterlindenPBoerlinVBrunsCPoonKWLewisIWeckbeckerG et al. A single-dose comparison of the acute effects between the new somatostatin analog SOM230 and octreotide in acromegalic patients. Journal of Clinical Endocrinology and Metabolism 2004 638645. (https://doi.org/10.1210/jc.2003-031052)

    • Search Google Scholar
    • Export Citation
  • 73

    ColaoABronsteinMDFredaPGuFShenCCGadelhaMFleseriuMvan der LelyAJFarrallAJHermosillo ResendizK et al. Pasireotide versus octreotide in acromegaly: a head-to-head superiority study. Journal of Clinical Endocrinology and Metabolism 2014 791799. (https://doi.org/10.1210/jc.2013-2480)

    • Search Google Scholar
    • Export Citation
  • 74

    WeckbeckerGBrinerULewisIBrunsC. SOM230: a new somatostatin peptidomimetic with potent inhibitory effects on the growth hormone/insulin-like growth factor-I axis in rats, primates, and dogs. Endocrinology 2002 41234130. (https://doi.org/10.1210/en.2002-220219)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 75

    FeeldersRAde BruinCPereiraAMRomijnJANetea-MaierRTHermusARZelissenPMvan HeerebeekRde JongFHvan der LelyAJ et al. Pasireotide alone or with cabergoline and ketoconazole in Cushing’s disease. New England Journal of Medicine 2010 18461848. (https://doi.org/10.1056/NEJMc1000094)

    • Search Google Scholar
    • Export Citation
  • 76

    MelmedSPopovicVBidlingmaierMMercadoMvan der LelyAJBiermaszNBolanowskiMCoculescuMSchopohlJRaczK et al. Safety and efficacy of oral octreotide in acromegaly: results of a multicenter phase III trial. Journal of Clinical Endocrinology and Metabolism 2015 16991708. (https://doi.org/10.1210/jc.2014-4113)

    • Search Google Scholar
    • Export Citation
  • 77

    NeggersSJFranckSEde RooijFWDallengaAHPoublonRMFeeldersRAJanssenJABuchfelderMHoflandLJJorgensenJO et al. Long-term efficacy and safety of pegvisomant in combination with long-acting somatostatin analogs in acromegaly. Journal of Clinical Endocrinology and Metabolism 2014 36443652. (https://doi.org/10.1210/jc.2014-2032)

    • Search Google Scholar
    • Export Citation
  • 78

    SundinAArnoldRBaudinECwiklaJBErikssonBFantiSFazioNGiammarileFHicksRJKjaerA et al. Enets consensus guidelines for the standards of care in neuroendocrine tumors: radiological, nuclear medicine and hybrid imaging. Neuroendocrinology 2017 212244. (https://doi.org/10.1159/000471879)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 79

    VeenstraMJvan KoetsveldPMDoganFFarrellWEFeeldersRALambertsSWJde HerderWWVitaleGHoflandLJ. Epidrug-induced upregulation of functional somatostatin type 2 receptors in human pancreatic neuroendocrine tumor cells. Oncotarget 2018 1479114802. (https://doi.org/10.18632/oncotarget.9462)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 80

    FaniMPeitlPKVelikyanI. Current status of radiopharmaceuticals for the theranostics of neuroendocrine neoplasms. Pharmaceuticals 2017 E30. (https://doi.org/10.3390/ph10010030)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 81

    RahbarKAhmadzadehfarHKratochwilCHaberkornUSchafersMEsslerMBaumRPKulkarniHRSchmidtMDrzezgaA et al. German multicenter study investigating 177Lu-PSMA-617 radioligand therapy in advanced prostate cancer patients. Journal of Nuclear Medicine 2017 8590. (https://doi.org/10.2967/jnumed.116.183194)

    • Search Google Scholar
    • Export Citation

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Figures

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    The structure of natural somatostatin-14 and octreotide.

  • View in gallery

    The effect of twice daily subcutaneous administration of octreotide (SMS 201-995) or placebo for 4 (left panel), 6 (middle panel) or 10 days (right panel) on circulating GH levels in normal female rats. Blood was collected 30 min after the last injection; n = 8 animals per group; values represent mean ± s.e.m. Adapted from Ref. (52).

  • View in gallery

    Patients that achieved IGF-1 normalization after adjuvant treatment with long-acting octreotide (Octreotide-LAR) showed significantly higher SST2A immunoreactivity (as quantified by an immunoreactivity score (IRS)) compared with the non-normalized group (P = 0.002; n = 18). Adapted from Ref. (29).

  • View in gallery

    Time-dependent increased uptake of [125I-Tyr3]octreotide by cells of a human carcinoid. Values represent the amount of uptake, expressed as the percentage of the added dose of [125I-Tyr3]octreotide, in the absence and in the presence of excess (1 μM) unlabeled octreotide, to determine non-specific internalization. Adapted from Ref. (60).

  • View in gallery

    In vitro data of two acromegalic patients, demonstrating a preferential inhibition of GH secretion in vitro by pasireotide in cultured cells with high SST5 expression, compared to SST2 expression (patient 12). Relative SST2 and SST5 expression in GH-secreting pituitary adenoma tissue of patient 6 (lower left) and patient 12 (lower right). Effects of octreotide (10 nM) and pasireotide (10 nM) on GH secretion by cultured pituitary adenoma cells from patient 6 (upper left) and patient 12 (upper right). Adapted from Ref. (72).

References

  • 1

    BrazeauPValeWBurgusRLingNButcherMRivierJGuilleminR. Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone. Science 1973 7779. (https://doi.org/10.1126/science.179.4068.77)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    ReichlinS. Somatostatin (second of two parts). New England Journal of Medicine 1983 15561563. (https://doi.org/10.1056/NEJM198312223092506)

    • Search Google Scholar
    • Export Citation
  • 3

    ReichlinS. Somatostatin. New England Journal of Medicine 1983 14951501. (https://doi.org/10.1056/NEJM198312153092406)

  • 4

    PatelYCSrikantCB. Subtype selectivity of peptide analogs for all five cloned human somatostatin receptors (hsstr 1–5). Endocrinology 1994 28142817. (https://doi.org/10.1210/endo.135.6.7988476)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    GuntherTTulipanoGDournaudPBousquetCCsabaZKreienkampHJLuppAKorbonitsMCastanoJPWesterHJ et al. International Union of Basic and Clinical Pharmacology. CV. Somatostatin receptors: structure, function, ligands, and new nomenclature. Pharmacological Reviews 2018 763835. (https://doi.org/10.1124/pr.117.015388)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    ShimonITaylorJEDongJZBitonteRAKimSMorganBCoyDHCullerMDMelmedS. Somatostatin receptor subtype specificity in human fetal pituitary cultures. Differential role of SSTR2 and SSTR5 for growth hormone, thyroid-stimulating hormone, and prolactin regulation. Journal of Clinical Investigation 1997 789798. (https://doi.org/10.1172/JCI119225)

    • Search Google Scholar
    • Export Citation
  • 7

    GuilleminR. Peptides in the brain: the new endocrinology of the neuron. Science 1978 390402. (https://doi.org/10.1126/science.212832)

  • 8

    BauerWBrinerUDoepfnerWHallerRHugueninRMarbachPPetcherTJPless. SMS 201–995: a very potent and selective octapeptide analogue of somatostatin with prolonged action. Life Sciences 1982 11331140. (https://doi.org/10.1016/0024-3205(82)90087-x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    HoflandLJLambertsSW. The pathophysiological consequences of somatostatin receptor internalization and resistance. Endocrine Reviews 2003 2847. (https://doi.org/10.1210/er.2000-0001)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    LambertsSWOosteromRNeufeldMdel PozoE. The somatostatin analog SMS 201–995 induces long-acting inhibition of growth hormone secretion without rebound hypersecretion in acromegalic patients. Journal of Clinical Endocrinology and Metabolism 1985 11611165. (https://doi.org/10.1210/jcem-60-6-1161)

    • Search Google Scholar
    • Export Citation
  • 11

    HoflandLJvan KoetsveldPMWaaijersMZuyderwijkJLambertsSW. Relative potencies of the somatostatin analogs octreotide, BIM-23014, and RC-160 on the inhibition of hormone release by cultured human endocrine tumor cells and normal rat anterior pituitary cells. Endocrinology 1994 301306. (https://doi.org/10.1210/endo.134.1.7903931)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    LambertsSWvan der LelyAJde HerderWWHoflandLJ. Octreotide. New England Journal of Medicine 1996 246254. (https://doi.org/10.1056/NEJM199601253340408)

    • Search Google Scholar
    • Export Citation
  • 13

    CreutzfeldtWLembckeBFolschURSchleserSKoopI. Effect of somatostatin analogue (SMS 201–995, Sandostatin) on pancreatic secretion in humans. American Journal of Medicine 1987 4954. (https://doi.org/10.1016/0002-9343(87)90426-8)

    • Search Google Scholar
    • Export Citation
  • 14

    LondongWAngererMKutzKLandgrafRLondongV. Diminishing efficacy of octreotide (SMS 201–995) on gastric functions of healthy subjects during one-week administration. Gastroenterology 1989 713722.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    MoschettaAStolkMFRehfeldJFPortincasaPSleePHKoppeschaarHPVan ErpecumKJVanberge-HenegouwenGP. Severe impairment of postprandial cholecystokinin release and gall-bladder emptying and high risk of gallstone formation in acromegalic patients during Sandostatin LAR. Alimentary Pharmacology and Therapeutics 2001 181185. (https://doi.org/10.1046/j.1365-2036.2001.00924.x)

    • Search Google Scholar
    • Export Citation
  • 16

    HarrisAGO’DorisioTMWolteringEAAnthonyLBBurtonFRGellerRBGrendellJHLevinBRedfernJS. Consensus statement: octreotide dose titration in secretory diarrhea. Diarrhea Management Consensus Development Panel. Digestive Diseases and Sciences 1995 14641473. (https://doi.org/10.1007/bf02285194)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    BurroughsAKMcCormickPAHughesMDSprengersDD’HeygereFMcIntyreN. Randomized, double-blind, placebo-controlled trial of somatostatin for variceal bleeding. Emergency control and prevention of early variceal rebleeding. Gastroenterology 1990 13881395. (https://doi.org/10.1016/0016-5085(90)91166-4)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    VanceMLHarrisAG. Long-term treatment of 189 acromegalic patients with the somatostatin analog octreotide. Results of the International Multicenter Acromegaly Study Group. Archives of Internal Medicine 1991 15731578. (https://doi.org/10.1001/archinte.151.8.1573)

    • Search Google Scholar
    • Export Citation
  • 19

    EzzatSSnyderPJYoungWFBoyajyLDNewmanCKlibanskiAMolitchMEBoydAESheelerLCookDM. Octreotide treatment of acromegaly. A randomized, multicenter study. Annals of Internal Medicine 1992 711718. (https://doi.org/10.7326/0003-4819-117-9-711)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    SwearingenBBarkerFG2ndKatznelsonLBillerBMGrinspoonSKlibanskiAMoayeriNBlackPMZervasNT. Long-term mortality after transsphenoidal surgery and adjunctive therapy for acromegaly. Journal of Clinical Endocrinology and Metabolism 1998 34193426. (https://doi.org/10.1210/jcem.83.10.5222)

    • Search Google Scholar
    • Export Citation
  • 21

    HoldawayIMBollandMJGambleGD. A meta-analysis of the effect of lowering serum levels of GH and IGF-I on mortality in acromegaly. European Journal of Endocrinology 2008 8995. (https://doi.org/10.1530/EJE-08-0267)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    LambertsSWUitterlindenPVerschoorLvan DongenKJdel PozoE. Long-term treatment of acromegaly with the somatostatin analogue SMS 201–995. New England Journal of Medicine 1985 15761580. (https://doi.org/10.1056/NEJM198512193132504)

    • Search Google Scholar
    • Export Citation
  • 23

    FredaPUKatznelsonLvan der LelyAJReyesCMZhaoSRabinowitzD. Long-acting somatostatin analog therapy of acromegaly: a meta-analysis. Journal of Clinical Endocrinology and Metabolism 2005 44654473. (https://doi.org/10.1210/jc.2005-0260)

    • Search Google Scholar
    • Export Citation
  • 24

    MurrayRDMelmedS. A critical analysis of clinically available somatostatin analog formulations for therapy of acromegaly. Journal of Clinical Endocrinology and Metabolism 2008 29572968. (https://doi.org/10.1210/jc.2008-0027)

    • Search Google Scholar
    • Export Citation
  • 25

    CarmichaelJDBonertVSNunoMLyDMelmedS. Acromegaly clinical trial methodology impact on reported biochemical efficacy rates of somatostatin receptor ligand treatments: a meta-analysis. Journal of Clinical Endocrinology and Metabolism 2014 18251833. (https://doi.org/10.1210/jc.2013-3757)

    • Search Google Scholar
    • Export Citation
  • 26

    ColaoAAuriemmaRSPivonelloRKasukiLGadelhaMR. Interpreting biochemical control response rates with first-generation somatostatin analogues in acromegaly. Pituitary 2016 235247. (https://doi.org/10.1007/s11102-015-0684-z)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    MelmedSBronsteinMDChansonPKlibanskiACasanuevaFFWassJAHStrasburgerCJLugerAClemmonsDRGiustinaA. A Consensus Statement on acromegaly therapeutic outcomes. Nature Reviews: Endocrinology 2018 552561. (https://doi.org/10.1038/s41574-018-0058-5)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    LambertsSW. The role of somatostatin in the regulation of anterior pituitary hormone secretion and the use of its analogs in the treatment of human pituitary tumors. Endocrine Reviews 1988 417436. (https://doi.org/10.1210/edrv-9-4-417)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    GattoFFeeldersRAvan der PasRKrosJMWaaijersMSprij-MooijDNeggersSJvan der LelijAJMinutoFLambertsSW et al. Immunoreactivity score using an anti-sst2A receptor monoclonal antibody strongly predicts the biochemical response to adjuvant treatment with somatostatin analogs in acromegaly. Journal of Clinical Endocrinology and Metabolism 2013 E66E71. (https://doi.org/10.1210/jc.2012-2609)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30

    TaboadaGFLuqueRMNetoLVMachado EdeEde OSbaffiBCDominguesRCMarcondesJBChimelliLMFontesRNiemeyerP et al. Quantitative analysis of somatostatin receptor subtypes (1–5) gene expression levels in somatotropinomas and correlation to in vivo hormonal and tumor volume responses to treatment with octreotide LAR. European Journal of Endocrinology 2008 295303. (https://doi.org/10.1530/EJE-07-0562)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    FougnerSLLekvaTBorotaOCHaldJKBollerslevJBergJP. The expression of E-cadherin in somatotroph pituitary adenomas is related to tumor size, invasiveness, and somatostatin analog response. Journal of Clinical Endocrinology and Metabolism 2010 23342342. (https://doi.org/10.1210/jc.2009-2197)

    • Search Google Scholar
    • Export Citation
  • 32

    GattoFBiermaszNRFeeldersRAKrosJMDoganFvan der LelyAJNeggersSJLambertsSWPereiraAMFeroneD et al. Low beta-arrestin expression correlates with the responsiveness to long-term somatostatin analog treatment in acromegaly. European Journal of Endocrinology 2016 651662. (https://doi.org/10.1530/EJE-15-0391)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    PeverelliEGiardinoETreppiediDVitaliECambiaghiVLocatelliMLasioGBSpadaALaniaAGMantovaniG. Filamin A (FLNA) plays an essential role in somatostatin receptor 2 (SST2) signaling and stabilization after agonist stimulation in human and rat somatotroph tumor cells. Endocrinology 2014 29322941. (https://doi.org/10.1210/en.2014-1063)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    DavisJRWilsonEMVidalMEJohnsonAPLynchSSSheppardMC. Regulation of growth hormone secretion and messenger ribonucleic acid accumulation in human somatotropinoma cells in vitro. Journal of Clinical Endocrinology and Metabolism 1989 704708. (https://doi.org/10.1210/jcem-69-4-704)

    • Search Google Scholar
    • Export Citation
  • 35

    TsukamotoNNagayaTKuwayamaATakanoKShizumeKSugitaKSeoH. Octreotide treatment results in the inhibition of GH gene expression in the adenoma of the patients with acromegaly. Endocrine Journal 1994 437444. (https://doi.org/10.1507/endocrj.41.437)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36

    AsaSLFelixIKovacsKRamyarL. Effects of somatostatin on somatotroph adenomas of the human pituitary: an in vitro functional and morphological study. Endocrine Pathology 1990 228235. (https://doi.org/10.1007/BF02915416)

    • Search Google Scholar
    • Export Citation
  • 37

    ChansonPWeintraubBDHarrisAG. Octreotide therapy for thyroid-stimulating hormone-secreting pituitary adenomas. A follow-up of 52 patients. Annals of Internal Medicine 1993 236240. (https://doi.org/10.7326/0003-4819-119-3-199308010-00010)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38

    TjornstrandANystromHF. DIAGNOSIS of ENDOCRINE DISEASE: Diagnostic approach to TSH-producing pituitary adenoma. European Journal of Endocrinology 2017 R183R197. (https://doi.org/10.1530/EJE-16-1029)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 39

    ReubiJCKrenningELambertsSWKvolsL. Somatostatin receptors in malignant tissues. Journal of Steroid Biochemistry and Molecular Biology 1990 10731077. (https://doi.org/10.1016/0960-0760(90)90468-Z)

    • Search Google Scholar
    • Export Citation
  • 40

    ReubiJCKvolsLKrenningELambertsSW. Distribution of somatostatin receptors in normal and tumor tissue. Metabolism: Clinical and Experimental 1990 7881. (https://doi.org/10.1016/0026-0495(90)90217-z)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41

    KvolsLKMoertelCGO’ConnellMJSchuttAJRubinJHahnRG. Treatment of the malignant carcinoid syndrome. Evaluation of a long-acting somatostatin analogue. New England Journal of Medicine 1986 663666. (https://doi.org/10.1056/NEJM198609113151102)

    • Search Google Scholar
    • Export Citation
  • 42

    KvolsLKBuckMMoertelCGSchuttAJRubinJO’ConnellMJHahnRG. Treatment of metastatic islet cell carcinoma with a somatostatin analogue (SMS 201–995). Annals of Internal Medicine 1987 162168. (https://doi.org/10.7326/0003-4819-107-2-162)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43

    SchallyAV. Oncological applications of somatostatin analogues. Cancer Research 1988 69776985.

  • 44

    LiebowCLeeMTSchallyA. Antitumor effects of somatostatin mediated by the stimulation of tyrosine phosphatase. Metabolism: Clinical and Experimental 1990 163166. (https://doi.org/10.1016/0026-0495(90)90237-7)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45

    RinkeAMullerHHSchade-BrittingerCKloseKJBarthPWiedMMayerCAminossadatiBPapeUFBlakerM et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. Journal of Clinical Oncology 2009 46564663. (https://doi.org/10.1200/JCO.2009.22.8510)

    • Search Google Scholar
    • Export Citation
  • 46

    CaplinMEPavelMCwiklaJBPhanATRadererMSedlackovaECadiotGWolinEMCapdevilaJWallL et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. New England Journal of Medicine 2014 224233. (https://doi.org/10.1056/NEJMoa1316158)

    • Search Google Scholar
    • Export Citation
  • 47

    PagesPBenaliNSaint-LaurentNEsteveJPSchallyAVTkaczukJVaysseNSusiniCBuscailL. sst2 somatostatin receptor mediates cell cycle arrest and induction of p27(Kip1). Evidence for the role of SHP-1. Journal of Biological Chemistry 1999 1518615193. (https://doi.org/10.1074/jbc.274.21.15186)

    • Search Google Scholar
    • Export Citation
  • 48

    FerranteEPellegriniCBondioniSPeverelliELocatelliMGelminiPLucianiPPeriAMantovaniGBosariS et al. Octreotide promotes apoptosis in human somatotroph tumor cells by activating somatostatin receptor type 2. Endocrine-Related Cancer 2006 955962. (https://doi.org/10.1677/erc.1.01191)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 49

    Garcia de la TorreNWassJATurnerHE. Antiangiogenic effects of somatostatin analogues. Clinical Endocrinology 2002 425441. (https://doi.org/10.1046/j.1365-2265.2002.01619.x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 50

    LambertsSWPietersGFMetselaarHJOngGLTanHSReubiJC. Development of resistance to a long-acting somatostatin analogue during treatment of two patients with metastatic endocrine pancreatic tumours. Acta Endocrinologica 1988 561566. (https://doi.org/10.1530/acta.0.1190561)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 51

    WynickDAndersonJVWilliamsSJBloomSR. Resistance of metastatic pancreatic endocrine tumours after long-term treatment with the somatostatin analogue octreotide (SMS 201–995). Clinical Endocrinology 1989 385388. (https://doi.org/10.1111/j.1365-2265.1989.tb00436.x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 52

    LambertsSWKrenningEPReubiJC. The role of somatostatin and its analogs in the diagnosis and treatment of tumors. Endocrine Reviews 1991 450482. (https://doi.org/10.1210/edrv-12-4-450)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 53

    KrenningEPBakkerWHBreemanWAKoperJWKooijPPAusemaLLamerisJSReubiJCLambertsSW. Localisation of endocrine-related tumours with radioiodinated analogue of somatostatin. Lancet 1989 242244. (https://doi.org/10.1016/s0140-6736(89)91258-0)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 54

    LambertsSWBakkerWHReubiJCKrenningEP. Somatostatin-receptor imaging in the localization of endocrine tumors. New England Journal of Medicine 1990 12461249. (https://doi.org/10.1056/NEJM199011013231805)

    • Search Google Scholar
    • Export Citation
  • 55

    LambertsSWHoflandLJvan KoetsveldPMReubiJCBruiningHABakkerWHKrenningEP. Parallel in vivo and in vitro detection of functional somatostatin receptors in human endocrine pancreatic tumors: consequences with regard to diagnosis, localization, and therapy. Journal of Clinical Endocrinology and Metabolism 1990 566574. (https://doi.org/10.1210/jcem-71-3-566)

    • Search Google Scholar
    • Export Citation
  • 56

    BakkerWHKrenningEPReubiJCBreemanWASetyono-HanBde JongMKooijPPBrunsCvan HagenPMMarbachP. In vivo application of [111In-DTPA-D-Phe1]-octreotide for detection of somatostatin receptor-positive tumors in rats. Life Sciences 1991 15931601. (https://doi.org/10.1016/0024-3205(91)90053-e)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 57

    KrenningEPKwekkeboomDJBakkerWHBreemanWAKooijPPOeiHYvan HagenMPostemaPTde JongMReubiJC. Somatostatin receptor scintigraphy with [111In-DTPA-D-Phe1]- and [123I-Tyr3]-octreotide: the Rotterdam experience with more than 1000 patients. European Journal of Nuclear Medicine 1993 716731. (https://doi.org/10.1007/BF00181765)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 58

    ItoTLeeLJensenRT. Treatment of symptomatic neuroendocrine tumor syndromes: recent advances and controversies. Expert Opinion on Pharmacotherapy 2016 21912205. (https://doi.org/10.1080/14656566.2016.1236916)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 59

    DeppenSABlumeJBobbeyAJShahCGrahamMMLeePDelbekeDWalkerRC. 68Ga-DOTATATE compared with 111In-DTPA-Octreotide and conventional imaging for pulmonary and gastroenteropancreatic neuroendocrine tumors: a systematic review and meta-analysis. Journal of Nuclear Medicine 2016 872878. (https://doi.org/10.2967/jnumed.115.165803)

    • Search Google Scholar
    • Export Citation
  • 60

    LambertsSWJde HerderWWvan KoetsveldPMKoperJWvan der LelyAJVisser-WisselaarHAHoflandLJ. Somatostatin receptors: clinical implications for endocrinology and oncology. In Somatostatin and Its Receptors. Eds ChadwickD & CardewG. Chichester, West Suusex, UK: John Wiley & Sons1995.

    • Search Google Scholar
    • Export Citation
  • 61

    HoflandLJvan KoetsveldPMWaaijersMZuyderwijkJBreemanWALambertsSW. Internalization of the radioiodinated somatostatin analog [125I-Tyr3]octreotide by mouse and human pituitary tumor cells: increase by unlabeled octreotide. Endocrinology 1995 36983706. (https://doi.org/10.1210/endo.136.9.7649075)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 62

    KwekkeboomDJKrenningEP. Peptide receptor radionuclide therapy in the treatment of neuroendocrine tumors. Hematology/Oncology Clinics of North America 2016 179191. (https://doi.org/10.1016/j.hoc.2015.09.009)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 63

    StrosbergJEl-HaddadGWolinEHendifarAYaoJChasenBMittraEKunzPLKulkeMHJaceneH et al. Phase 3 trial of (177)Lu-Dotatate for midgut neuroendocrine tumors. New England Journal of Medicine 2017 125135. (https://doi.org/10.1056/NEJMoa1607427)

    • Search Google Scholar
    • Export Citation
  • 64

    MelmedS. Medical progress: acromegaly. New England Journal of Medicine 2006 25582573. (https://doi.org/10.1056/NEJMra062453)

  • 65

    de HerderWWHoflandLJvan der LelyAJLambertsSW. Somatostatin receptors in gastroentero-pancreatic neuroendocrine tumours. Endocrine-Related Cancer 2003 451458. (https://doi.org/10.1677/erc.0.0100451)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 66

    SchmidHASchoeffterP. Functional activity of the multiligand analog SOM230 at human recombinant somatostatin receptor subtypes supports its usefulness in neuroendocrine tumors. Neuroendocrinology 2004 (Supplement 1) 4750. (https://doi.org/10.1159/000080741)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 67

    de BruinCPereiraAMFeeldersRARomijnJARoelfsemaFSprij-MooijDMvan AkenMOvan der LelijAJde HerderWWLambertsSW et al. Coexpression of dopamine and somatostatin receptor subtypes in corticotroph adenomas. Journal of Clinical Endocrinology and Metabolism 2009 11181124. (https://doi.org/10.1210/jc.2008-2101)

    • Search Google Scholar
    • Export Citation
  • 68

    KornerMWaserBChristEBeckJReubiJC. A critical evaluation of sst3 and sst5 immunohistochemistry in human pituitary adenomas. Neuroendocrinology 2018 116127. (https://doi.org/10.1159/000472563)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 69

    HoflandLJvan der HoekJFeeldersRvan AkenMOvan KoetsveldPMWaaijersMSprij-MooijDBrunsCWeckbeckerGde HerderWW et al. The multi-ligand somatostatin analogue SOM230 inhibits ACTH secretion by cultured human corticotroph adenomas via somatostatin receptor type 5. European Journal of Endocrinology 2005 645654. (https://doi.org/10.1530/eje.1.01876)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 70

    ColaoAPetersennSNewell-PriceJFindlingJWGuFMaldonadoMSchoenherrUMillsDSalgadoLRBillerBM et al. A 12-month phase 3 study of pasireotide in Cushing’s disease. New England Journal of Medicine 2012 914924. (https://doi.org/10.1056/NEJMoa1105743)

    • Search Google Scholar
    • Export Citation
  • 71

    ShimonIYanXTaylorJEWeissMHCullerMDMelmedS. Somatostatin receptor (sstr) subtype-selective analogues differentially suppress in vitro growth hormone and prolactin in human pituitary adenomas. Novel potential therapy for functional pituitary tumors. Journal of Clinical Investigation 1997 23862392. (https://doi.org/10.1172/JCI119779)

    • Search Google Scholar
    • Export Citation
  • 72

    van der HoekJde HerderWWFeeldersRAvan der LelyAJUitterlindenPBoerlinVBrunsCPoonKWLewisIWeckbeckerG et al. A single-dose comparison of the acute effects between the new somatostatin analog SOM230 and octreotide in acromegalic patients. Journal of Clinical Endocrinology and Metabolism 2004 638645. (https://doi.org/10.1210/jc.2003-031052)

    • Search Google Scholar
    • Export Citation
  • 73

    ColaoABronsteinMDFredaPGuFShenCCGadelhaMFleseriuMvan der LelyAJFarrallAJHermosillo ResendizK et al. Pasireotide versus octreotide in acromegaly: a head-to-head superiority study. Journal of Clinical Endocrinology and Metabolism 2014 791799. (https://doi.org/10.1210/jc.2013-2480)

    • Search Google Scholar
    • Export Citation
  • 74

    WeckbeckerGBrinerULewisIBrunsC. SOM230: a new somatostatin peptidomimetic with potent inhibitory effects on the growth hormone/insulin-like growth factor-I axis in rats, primates, and dogs. Endocrinology 2002 41234130. (https://doi.org/10.1210/en.2002-220219)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 75

    FeeldersRAde BruinCPereiraAMRomijnJANetea-MaierRTHermusARZelissenPMvan HeerebeekRde JongFHvan der LelyAJ et al. Pasireotide alone or with cabergoline and ketoconazole in Cushing’s disease. New England Journal of Medicine 2010 18461848. (https://doi.org/10.1056/NEJMc1000094)

    • Search Google Scholar
    • Export Citation
  • 76

    MelmedSPopovicVBidlingmaierMMercadoMvan der LelyAJBiermaszNBolanowskiMCoculescuMSchopohlJRaczK et al. Safety and efficacy of oral octreotide in acromegaly: results of a multicenter phase III trial. Journal of Clinical Endocrinology and Metabolism 2015 16991708. (https://doi.org/10.1210/jc.2014-4113)

    • Search Google Scholar
    • Export Citation
  • 77

    NeggersSJFranckSEde RooijFWDallengaAHPoublonRMFeeldersRAJanssenJABuchfelderMHoflandLJJorgensenJO et al. Long-term efficacy and safety of pegvisomant in combination with long-acting somatostatin analogs in acromegaly. Journal of Clinical Endocrinology and Metabolism 2014 36443652. (https://doi.org/10.1210/jc.2014-2032)

    • Search Google Scholar
    • Export Citation
  • 78

    SundinAArnoldRBaudinECwiklaJBErikssonBFantiSFazioNGiammarileFHicksRJKjaerA et al. Enets consensus guidelines for the standards of care in neuroendocrine tumors: radiological, nuclear medicine and hybrid imaging. Neuroendocrinology 2017 212244. (https://doi.org/10.1159/000471879)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 79

    VeenstraMJvan KoetsveldPMDoganFFarrellWEFeeldersRALambertsSWJde HerderWWVitaleGHoflandLJ. Epidrug-induced upregulation of functional somatostatin type 2 receptors in human pancreatic neuroendocrine tumor cells. Oncotarget 2018 1479114802. (https://doi.org/10.18632/oncotarget.9462)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 80

    FaniMPeitlPKVelikyanI. Current status of radiopharmaceuticals for the theranostics of neuroendocrine neoplasms. Pharmaceuticals 2017 E30. (https://doi.org/10.3390/ph10010030)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 81

    RahbarKAhmadzadehfarHKratochwilCHaberkornUSchafersMEsslerMBaumRPKulkarniHRSchmidtMDrzezgaA et al. German multicenter study investigating 177Lu-PSMA-617 radioligand therapy in advanced prostate cancer patients. Journal of Nuclear Medicine 2017 8590. (https://doi.org/10.2967/jnumed.116.183194)

    • Search Google Scholar
    • Export Citation

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