Pharmacological identity between somatostatin SS-2 binding sites and SSTR-1 receptors
Daniël HoyerJ. PérezPhilippe SchoeffterDaniel LangeneggerE. SchüpbachKlemens KaupmannHermann LübbertChristian BrunsJean Claude Reubi
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Somatostatin receptors expressed on tumor cells form the rationale for somatostatin analog treatment of patients with somatostatin receptor-positive neuroendocrine tumors. Nevertheless, although somatostatin analogs effectively control hormonal hypersecretion by GH-secreting pituitary adenomas, islet cell tumors, and carcinoid tumors, significant differences are observed among patients with respect to the efficacy of treatment. This may be related to a differential expression of somatostatin receptor subtypes among tumors. In addition, the property of somatostatin receptor subtypes to undergo agonist-induced internalization has important consequences for visualizing, as well as for therapy, of receptor-postive tumors using radioisotope- or chemotherapeutic-compound-coupled somatostatin analogs. This review covers the pathophysiological role of somatostatin receptor subtypes in determining the efficacy of treatment of patients with somatostatin receptor-positive tumors using somatostatin analogs, as well as the preclinical and clinical consequences of agonist-induced receptor internalization for somatostatin receptor-targeted radio- and chemotherapy. Herein, the development and potential role of novel somatostatin analogs is discussed.
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Subclasses of receptors exist for most neurotransmitters. Frequently, two subtypes of receptors coexist in the same tissue and, in some cases, they mediate the same physiological response. In tissues with two classes of binding sites for a given hormone, an estimate of the proportion of each class of binding sites is obtained by inhibiting the binding of a single concentration of a radioligand with a selective unlabeled ligand. Accurate estimates of the density of each class of receptors will only be obtained, however, if the radioligand is entirely nonselective. Selectivity of just 2- to 3-fold can markedly influence the results of subtype analysis. The conclusion that a radioligand is nonselective is usually based on the results of a saturation binding curve. If Scatchard analysis of such data results in a linear plot, then it is concluded that the radioligand is nonselective. However, Scatchard analysis cannot distinguish between a radioligand that is nonselective and one that is slightly selective. The use of a slightly selective radioligand can lead to errors of 50% or more, depending on the concentration of the radioligand relative to the Kd values of the two classes of sites. A new analytical method has been developed that can be used to quantitate 2- to 3-fold differences in the affinity of two distinct classes of binding sites for a radioligand. This new approach requires that a series of inhibition experiments with a selective unlabeled ligand be performed in the presence of increasing concentrations of the radioligand. Analysis of the resulting inhibition curves, utilizing the mathematical modeling program MLAB on the PROPHET system, yields accurate estimates of the density of each class of receptor as well as the affinity of each receptor for the labeled and unlabeled ligands. This approach was used to determine whether 125I-iodopindolol shows selectivity for beta 1- or beta 2-adrenergic receptors. A series of inhibition curves was generated with the unlabeled ligands ICI 89,406 (beta 1-selective) and ICI 118,551 (beta 2-selective), using membranes prepared from C6 glioma cells. These cells contain both beta 1- and beta 2-adrenergic receptors. 125I-Iodopindolol was determined to be 3-fold selective for beta 2-adrenergic receptors. Since the sensitivity of this approach is superior to that of Scatchard analysis, it is likely that other radioligands, previously thought to be nonselective, will be shown to be selective when analyzed by this method.
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Somatostatin blocks the release of numerous growth factors and is therefore a potent inhibitor of cell division and/or secretion. It exerts its effects through binding to somatostatin receptors. Five different subtypes of such receptors are identified (SSTR1 to SSTR5), having various tissue expression. The detection of their presence in tumours can be performed on histological sections and has potential therapeutic implications.
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Neuroendocrine neoplasms (NENs) are heterogeneous neoplasms which arise from neuroendocrine cells that are distributed widely throughout the body. Although heterogenous, many of them share their ability to overexpress somatostatin receptors (SSTR) on their cell surface. Due to this, SSTR and somatostatin have been a large subject of interest in the discovery of potential biomarkers and treatment options for the disease. The aim of this review is to describe the molecular characteristics of somatostatin and somatostatin receptors and its application in diagnosis and therapy on patients with NENs as well as the use in the near future of somatostatin antagonists.
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Most neuroendocrine tumors express receptors for somatostatin which was originally isolated as a hormone with growth hormone releasing inhibiting potential. The molecular cloning of five receptor subtypes for somatostatin has expanded our knowledge on the actions of this peptide. We studied the expression of all five somatostatin receptor subtypes in various normal human tissues and a variety of endocrine tumors. Different quantitative expression rates in normal tissues were identified by realtime RT-PCR. Expression in these tissues was confirmed by immunohistochemical analysis. We then compared the physiological expression to the somatostatin receptor expression in tumors arising from the same tissue. Our investigation of pituitary adenomas revealed that somatostatin receptor subtypes are not only expressed in GH-producing adenomas but also in ACTH-producing adenomas and prolactinomas as well as in non-functioning pituitary adenomas. Further analysis of other endocrine tumors demonstrated expression in pheochromocytomas as well as in tumors of the adrenal cortex with tumor-specific distribution pattern. This may offer new diagnostic and therapeutic possibilities with multiligand or subtype specific somatostatin analogs. Somatostatin analogues are very effective in the treatment of symptoms related to endocrine tumors. New analogues like the multi-ligand SOM230 are currently studied in phase 2 studies. The high expression of somatostatin receptors is used to localize endocrine tumors by receptor szintigraphy with radiolabeled somatostatin analogues. Tumor-targeted radioactive treatment based on somatostatin analogues is currently evaluated as a treatment option.
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Somatostatin is a tetradecapeptide, which mediates its action via five receptor subtypes (sst1–5). Because of the inhibitory and antiproliferative effects, long-acting somatostatin analogues were developed. While octreotide binds with high affinity to sst2a only, the new analogue SOM230 demonstrates high affinity to sst1, 3 and 5 in addition.
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In the past year, there have been major advances in our understanding of the mechanisms of action of somatostatin. The cloning and characterizing of genes encoding five structurally similar somatostatin receptors and their transfection into cells have allowed identification of analogues that are receptor-subtype specific. There is now a significant opportunity for the development of somatostatin analogues that are targeted more specifically to the individual tissue or hormone that is in excess. Work continues to demonstrate the antiproliferative action of somatostatin on tumor cells; however, there have been examples of tumor cell-line proliferation in response to somatostatin. This highlights the need for caution in the use of somatostatin analogues as adjuncts to other chemotherapeutic agents, even in somatostatin receptor-positive tumors. The role of; somatostatin in the diagnosis of neuroendocrine tumors is to define the position and extent, and studies continue to support its role in this area. It is the functional characterization of the receptor genes, however, that represents the most significant advance. This characterization may change somatostatin-analogue therapy from its current use as a general endocrine “off switch” to a more targeted treatment that is used only when the receptor-subtype status of the tumor has been established. In this setting, somatostatin analogues may rank among the most specific therapeutic agents at our disposal.
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