Abstract

Somatostatin is a natural small cyclic peptide hormone synthesized as part of a large prohormone molecule that is enzymatically cleaved into its active form.1 (see also Chapter 1 of this book). SST is found in classic open type endocrine cells from which it is directly excreted into the blood, paracrine cells with long cytoplasmic extensions which terminate on putative effector cells and in neurones where it may function as a neurotransmitter or is released from the nerve endings into the...

Clinical Indications for Scintigraphy with Radiolabeled Peptides

The fundamental indications for a sst scintigraphy are 1. Localization of metastases to define staging of cancer process 2. Indication for the treatment at the present stage of cancer process 3. Monitoring of the progress of the therapy 4. Evaluation of the treatment with cold somatostatin analogs 5. Before the treatment with radioisotope 6. Before surgery when chemotherapy will follow it 7. Before the liver transplantation 8. Intraoperational examination for the best surgical outcome 9. In...

Protein Coupling and Signal Transduction of sst Receptors

The different biological actions of SST are initiated by interaction with specific plasma membrane receptors (ssti ). All 5 sst subtypes bind not only their natural ligands (SST-14 and SST-28) but also cortistatin with high affinity41,69 and display more selective binding profile for the synthetic SST analogs. 1 Ligand binding induces G protein (guanine triphosphate-binding protein) activation what leads to the activation of several intracellular signaling pathways. Using various methods such...

Matching SSTR Subtypes with Function Not an Easy Task

One of the simplest means to gather information about the potential function of a receptor is to determine its anatomical distribution. Analysis of the expression of the SSTR subtypes in various tissues has been ongoing since the identification of the receptors.16-27 Results from these studies, however, reveal several problems with the concept that a given biological function is regulated by a single, specific SSTR subtype. First, most potential target tissues express not just one, but multiple...

Molecular Genetic Approaches to Studying sst Receptor Subtype Function

In 1997 Zheng et al105 described the generation of the first sst receptor gene knock-out, sst2 deficient mouse (sst2 KO). These animals are reported to be normal and healthy but they are refractory to GH-induced feedback suppression of GH due to a loss of sst2 in arcuate GHRH neurons. Nowadays, the majority of the relevant data concerning the selective involvement of different sst subtypes in specific physiological responses to SST came from the studies on KO mice, in which gene encoding for a...

Other Aspects of sst Receptor Subtype Physiology

Although our understanding of sst subtype pathophysiology increases every year, we should emphasize that most of the above-mentioned findings concern the sst receptor subtypes expressed by transfection into various cell lines but not endogenous receptors. Studies of endogenous SST receptors ensure that the properties of the receptor under study are being characterized in their native environment in the presence of all the cellular machinery required for normal function. However such studies are...

Scintigraphy with Radiolabeled Peptides

Radionuclides provide a diagnostic modality in which radiopharmaceuticals are utilized for the localization of them in organs and tissues. In control clinical conditions, the application of radiolabeled somatostatin analogs visualizes thyroid gland, spleen, liver, kidneys, gut, urine bladder, and in some cases the pituitary gland (Fig. 2). The accumulation of radiolabeled soma-tostatin analogs in the pituitary gland, spleen and thyroid gland is a result of natural existence of somatostatin...

Somatostatin Analogs in Diagnostics and Therapy

Department of Neuroendocrinology Medical University of Lodz Lodz, Poland Landes Bioscience Austin, Texas U.S.A. Somatostatin Analogs in Diagnostics and Therapy Copyright 2007 Landes Bioscience All rights reserved. No part of this book may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher. Printed in the U.S.A. Please address all...

Somatostatin and Somatostatin Receptors

Although the expression of particular receptors in the tumor cells is related to various peptides, but only few of them were implemented for the clinical use. Somatostatin analogs were the first peptides widely used in the clinical practice. Somatostatin inhibits a wide spectrum of physiological processes, including peptide hormone secretion. Moreover, somatostatin inhibits several growth factors, angiogenesis. On the other side, it stimulates apoptosis and activates the reticulo-endothelial...

Somatostatin Receptor Subtypes in the Suppression of GH Secretion First Level of Complexity

As indicated previously, suppression of GH secretion was the physiological action upon SST was first identified and isolated, and it remains the most clearly recognized function of SST. Despite this, the analogs of SST that are currently available for clinical use, Lanreotide and Octreotide, are not fully efficacious in normalizing GH in all patients with excess GH secretion. These analogs normalize GH in only approximately 50 of acromegalic patients.30 It is recognized that 5-10 of...

Somatostatin Receptor Subtypes in the Suppression of Thyroid Medullary Carcinoma Proliferation Further Complexity

Adding further complexity to the interplay between the SSTR subtypes is the observation that certain combinations of SSTR subtypes are antagonistic. This concept further expands the opportunities for a target cell to exert control over its response to SST and, by extension, provides new opportunities for target-specific SST analogs. Continuing our efforts to determine Figure 3. Enhanced suppression of GH secretion from pituitary adenoma cells collected from acromegalic patients classified as...

Somatostatin Receptors

Distribution in Normal Tissues and Transduction Mechanisms Gabriela Melen-Mucha* and Slawomir Mucha Abstract Somatostatin (SST) exerts diverse biological effects acting through specific membrane receptors belonging to the family of G protein coupled receptors. So far five SST receptor subtypes (sst ) have been cloned and characterized. The genes for these receptor subtypes are localized on different chromosomes and are intronless, with one exception concerning sst2, which exists in two forms...

Somatostatin Receptors in Human Tumors

Neoplastic cells express and often even over-express the somatostatin receptors. It is important because the presence of sst receptors predicts to some extent the possibility of treatment with SST analogs. The presence of sst receptors may be examined in vivo by means of the receptor scintigraphy using the radiolabeled SST analogs. The receptors can be also detected in vitro (ex vivo) on surgical or biopsy specimens. Among the in vitro (ex vivo) methods, the immunohistochemical investigation...

SST Analogs in Diabetic Retinopathy and Senile Macular

Therefore, SST analogs which are known as the inhibitors of the secretion and action of IGF-I and VEGF could provide novel therapeutic opportunities to attenuate the improper angiogenic growth in the ocular tissues. Moreover, almost all sst receptor subtypes are expressed in the human eye with sstl and sst2 being the most widely expressed in human retina.51,52 The first clinical trial assessing the therapeutic potential of SST analogs in the treatment of diabetic retinopathy were...

Introduction

Acromegaly is a rare disease usually caused by a benign pituitary somatotroph adenoma. The disorder usually develops over many years due to a long term exposure to elevated levels of GH. The annual incidence of acromegaly is approximately 3-4 cases million and its prevalence was estimated at 40-60 cases million population,1 and more recently as much as its insidious nature, the diagnosis may be considerably delayed, by 4 to 10 or more years.1 Thranssphenoidal adenomectomy remains first-line...

Tumors Identification and Surveillance

Pet Scan Hot Spots

Octreotide scintigraphy of the pituitary visualizes tumors which produce GH, TSH and also tumors without hormonal activities. Pituitary tumors producing ACTH are not visible. On the contrary, ACTH producing tumors located besides the pituitary are characterized by the existence of sst receptors and therefore octreotide scintigraphy is the method of choice for their diagnosis.30 Following pathological processes located in the region of sella turcica should be taken for differentiation diagnosis...

SSTDA Interactions How Does It Work and What Does It Mean

The findings described in the previous section collectively illustrate the enhanced efficacy that can be achieved through concurrent activation of SST and DA receptors with a single molecule possessing both SST and DA activities. While the mechanism(s) by which this effect is achieved remains to be elucidated, several possibilities have been proposed. The first, as already mentioned, is the formation of heterodimers between the SST and DA receptors resulting in altered binding and enhanced...

Expanding beyond SSTR Subtypes Interactions between SST and Dopamine Receptors

Another recent finding that further expands the complexity of the SST system is the demonstration that not only are there functional and, perhaps, physical interactions between the subtypes of a particular receptor family, such as the opiates or SST, there are also interactions between the members of different receptor families. Directly related to the present discussion of GH regulation is the interaction between the SSTR subtypes and members of the dopamine (DA) receptor family. Suggestions...

Physiology of Somatostatin

Somatostatin (SST) was originally discovered as a hypothalamic peptide which inhibits growth hormone (GH) secretion from the pituitary gland. It appears in two molecular forms, composed of 14 or 28 amino-acid residues. Moreover, another family of peptides, called cortistatins (CST), was described. CST are encoded by a different gene, but they share partly the structure of SST and bind to SST receptors. Further studies revealed that SST is expressed not only in the hypothalamus but is widely...

Control of Symptoms and Biochemical Responses in Functionally Active Gep Net

Octreotide controlled symptoms caused by hormone overproduction in about 70-90 of carcinoid patients. In a direct comparison, diarrhea and flushing were successfully controlled with octreotide in 50 and 68 of carcinoid patients, respectively. Similar potencies on diarrhea and flushing (45 and 54 , respectively) have been reported with lanreotide in patients with functional GEP NET. Although symptoms improve initially in most patients, a loss of response occurs in about 50 with continuous...

The Analogs of Somatostatin as Radiopharmaceutics

Because the time of disappearance of somatostatin is short (1-2 minutes), it was necessary to find the somatostatin analogs with much prolonged half-life time in plasma and tissues. The use of analogs has several advantages they have the fast clearance, the fast penetration into the tumors, they do not cause allergic reactions and they are quite simply synthesized and modified. However, in contrary to the native somatostatin, they have the different binding affinities for the particular...

Conclusion

SMS analogs have been successfully used to treat patients with GH secreting pituitary adenomas they are safe, effective and usually well tolerated. The results of studies evaluating biochemical, clinical, and tumor size outcome as well as safety and tolerability of the SMS receptor ligands, octreotide and lanreotide, support the use of these agents for both primary and secondary medical therapy in acromegaly. 1. Alexander S, Appelton D, Hall R et al. Epidemiology of acromegaly in the Newcastle...

Incidence of Somatostatin Receptors in Human Tumors

The normal human anterior pituitary gland is found to express all subtypes of sst receptors, except sst2B and sst4. However, the latter subtype is detectable in fetal pituitary tissue.1 In pituitary adenomas the all subtypes are detectable at least in some cases, depending on the hormone phenotype of the tumors. GH-secreting adenomas expressed mostly sst2 (the distinction between sst2A and sst2B was not done in majority of studies) and sst51-4 (Fig. 1A). The data on sst1 and sst3 are variable...

Antiproliferative Effect of SST Analogs on Gep Net

Somatostatin Analogues

Evidence for antiproliferative properties of somatostatin and its analogs derives from in vitro and in vivo studies. Somatostatin can exert both cytotoxic and cytostatic actions. It has been demonstrated that it mediated arrest at the Glphase of the cell cycle and that this effect is mediated through activation of sstr-2 and sstr-5.3, 3,24 The antiproliferative effects of SST analogs on GEP NET may be the result of direct and indirect actions (Fig. l).33 Faiss et al15 showed that...

Opportunity from Complexity

The foregoing observations regarding the interaction between SSTR subtypes, and between members of different receptor families, demonstrate the complexity of the interplay between ligand and receptor, and the potential for regulation of the cellular response. If G-protein-coupled receptors from different families can combine, either physically, functionally or both, to enhance or suppress cellular responses, or to create a novel response, then the types and ratio of different receptors present...

Conclusions

Human tumors often express or even over-express the somatostatin receptors. These receptors can be detected in vivo, by means of the receptor scintigraphy, and in vitro (ex vivo) in tumor samples obtained by surgery or by biopsy. Although the receptor scintigraphy presents the clear advantages, the ex vivo detection allows the precise determination of the particular receptor subtypes and their precise cellular localization. Among the different in vitro (ex vivo) techniques, the...

Treatment Algorithm of Acromegaly

Effective treatment is aimed at improving survival and ameliorating many of the deleterious signs and symptoms of acromegalic patients. Survival has been strongly correlated with reduced post-treatment GH levels.6 Thus, the primary goal of treatment for acromegaly is to normalize GH lt 1 g L within 2 hours after 75 oral g glucose load and serum IGF-I age and gender matched .7 Surgery remains the first-line treatment in most cases. GH-producing adenoma should be removed completely, with...