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  • Review Article
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Opportunities in somatostatin research: biological, chemical and therapeutic aspects

Nature Reviews Drug Discovery volume 2, pages 999–1017 (2003)Cite this article

A Correction to this article was published on 01 December 2005

A Correction to this article was published on 01 December 2005

Key Points

  • Somatostatins, or somatotropin-release inhibiting factors (SRIFs), are a family of cyclopeptides that are produced in hypothalamus, brain, pancreas and gut, among other tiusses.

  • SRIFs usually exert broad inhibitory effects on the secretion of hormones, such as growth hormone, as well as on the proliferation and survival of cells.

  • Accordingly, SRIF analogues with increased metabolic stability over SRIF — namely octreotide and lanreotide — are used clinically in the treatment of acromegaly and endocrine tumours.

  • The discovery of five SRIF receptor subtypes has opened new therapeutic opportunities. Ground-breaking chemical strategies have been successful in the synthesis of peptide and non-peptide SRIF analogues with agonistic or antagonistic properties, and a binding profile that is selective for one or a combination of SRIF receptors.

  • From this work, a set of SRIF analogues has recently become available that enables the elucidation of the complex somatostatin pharmacology and the probing of new indications.

  • Significant progress has made with labelled SRIF analogues that are used for radiodiagnosis and/or radiotherapy of SRIF receptor-expressing tumours. In fact, the detection of otherwise undetectable tumours, as well as the regression of otherwise unresponsive tumours, has been reported for labelled SRIF analogues.

  • On the basis of SRIF receptor action and distribution, a number of new indications are presently being explored. They include diabetic retinopathy and nephropathy; certain solid tumours; disorders of the central nervous system, such as epilepsy, impaired behaviour and pain; diseases associated with vascular remodeling, such as restenosis; and chronic transplant rejection, as well as inflammatory and gastrointestinal disorders.

  • Although preclinical knowledge of the potential use of new analogues in available, and the list of indications for which they might be used is growing steadily, progress at the clinical level is still limited because only a few of the vast array of new analogues have entered clinical testing.

  • Here, we review recent advances in SRIF biology, the chemistry of SRIF agonists and antagonists, and the potential of such compounds in a wide range of established and novel indications.

Abstract

Somatostatins — also known as somatotropin-release inhibiting factors (SRIFs) — are a family of cyclopeptides that have broad inhibitory effects on the secretion of hormones such as growth hormone, insulin and glucagon. These effects have formed the basis for the clinical use of SRIF analogues in the treatment of acromegaly and endocrine tumours. The discovery of the five SRIF receptor subtypes in the 1990s further enhanced our understanding of the biological roles of SRIFs, and paved the way for new therapeutic opportunities. Here we review recent advances in SRIF biology, the chemistry of SRIF agonists and antagonists, and the therapeutic potential of such compounds in a wide range of established and novel indications.

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Figure 1: Structure of SRIF receptors exemplified by subtype sst2A receptor.
Figure 2: Sequence homology between the respective receptor subtypes SRIF1 (sst2,3,5) and SRIF2 (sst1,4).
Figure 3: SRIF-receptor-mediated modulation of signalling cascades leading to changes in hormone secretion, apoptosis and cell growth.
Figure 4: Autoradiographic distribution of [125I]LTT SRIF-28 binding sites in a coronal section of adult rat brain.
Figure 5: Structures of the natural somatostatin peptide agonists SRIF-14 and SRIF-28.
Figure 6
Figure 7
Figure 8
Figure 9
Figure 10
Figure 11: SRIF receptor-based tumour diagnosis and therapy.

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References

  1. Brazeau, P. et al. Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone. Science 179, 77–79 (1973). Describes the isolation and characterization of somatostatin as antisecretory peptide hormone.

    Article  CAS  PubMed  Google Scholar 

  2. Reichlin, S. Somatostatin. N. Engl. J. Med. 309, 1495–1501 (1983).

    Article  CAS  PubMed  Google Scholar 

  3. Reichlin, S. Somatostatin (second of two parts). N. Engl. J. Med. 309, 1556–1563 (1983). References 2 and 3 comprise a major, early two-part clinical review on SRIF.

    Article  CAS  PubMed  Google Scholar 

  4. Delesque, N. et al. Sst2 somatostatin receptor expression reverses tumorigenicity of human pancreatic cancer cells. Cancer Res. 57, 956–962 (1997).

    CAS  PubMed  Google Scholar 

  5. Froidevaux, S. & Eberle, A. N. Somatostatin analogs and radiopeptides in cancer therapy. Biopolymers 66, 161–183 (2002).

    Article  CAS  PubMed  Google Scholar 

  6. Reubi, J. C., Perrin, M. H., Rivier, J. E. & Vale, W. High-affinity binding sites for a somatostatin-28 analog in rat brain. Life Sci. 28, 2191–2198 (1981).

    Article  CAS  PubMed  Google Scholar 

  7. Ensinck, J. W. et al. Thrittene, homologous with somatostatin-28(1–13), is a novel peptide in mammalian gut and circulation. Endocrinology 143, 2599–2609 (2002).

    Article  CAS  PubMed  Google Scholar 

  8. De Lecea, L. et al. A cortical neuropeptide with neuronal depressant and sleep-modulating properties. Nature 381, 242–245 (1996). Reports the discovery of cortistatin.

    Article  CAS  PubMed  Google Scholar 

  9. Spier, A. D. & De Lecea, L. Cortistatin: a member of the somatostatin neuropeptide family with distinct physiological functions. Brain Res. Rev. 33, 228–241 (2000).

    Article  CAS  PubMed  Google Scholar 

  10. Dalm, V. A. et al. Cortistatin rather than somatostatin as a potential endogenous ligand for somatostatin receptors in the human immune system. J. Clin. Endocrinol. Metab. 88, 270–276 (2003). This paper discusses the role of cortistatin in the immune system.

    Article  CAS  PubMed  Google Scholar 

  11. Yamada, Y. et al. Cloning and functional characterization of a family of human and mouse somatostatin receptors expressed in brain, gastrointestinal tract and kidney. Proc. Natl Acad. Sci. USA 89, 251–255 (1992). Groundbreaking work on SRIF receptor subtype discovery.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Weckbecker, G., Raulf, F., Stolz, B. & Bruns, C. Somatostatin analogs for diagnosis and treatment of cancer. Pharmac. Ther. 60, 245–264 (1993).

    Article  CAS  Google Scholar 

  13. Gillies, G. Somatostatin: the neuroendocrine story. Trends Pharmacol. Sci. 18, 87–95 (1997).

    Article  CAS  PubMed  Google Scholar 

  14. Patel, Y. C. & Wheatley, T. In vivo and in vitro plasma disappearance and metabolism of somatostatin-28 and somatostatin-14 in the rat. Endocrinology 112, 220–225 (1983).

    Article  CAS  PubMed  Google Scholar 

  15. Siler, T. M. et al. Inhibition of growth hormone release in humans by somatostatin. J. Clin. Endocrinol. Metab. 37, 632–634 (1973).

    Article  CAS  PubMed  Google Scholar 

  16. Coy, D. H., Coy, E. J., Arimura, A. & Schally, A. V. Solid phase synthesis of growth hormone-release inhibiting factor. Biochem. Biophys. Res. Commun. 54, 1267–1273 (1973).

    Article  CAS  PubMed  Google Scholar 

  17. Rivier, J., Brown, M., Rivier, C., Ling, N. & Vale, W. in Peptides 1976 (ed. Loffet, A.) 427–521 (Editions de l'Universites, Bruxelles, 1976).

    Google Scholar 

  18. Gottesman, I. S., Mandarino, L. J. & Gerich, J. E. in Special Topics in Endocrinology and Metabolism Vol. 4 (eds Cohen, M. & Foa, P.) 177–243 (Alan R. Liss, New York, 1982). An early review on SRIF analogues.

    Google Scholar 

  19. Bauer, W. et al. SMS 201-995: a very potent and selective analogue of somatostatin with prolonged action. Life Sci. 31, 1134–1140 (1982). Describes the first SRIF analogue approved for clinical use.

    Article  Google Scholar 

  20. Lamberts, S. W. J., van der Lely, A. -J., de Herder, W. W. & Hofland, L. J. Octreotide. Drug therapy. New Engl. J. Med. 334, 246–254 (1996). A comprehensive review on the clinical use of octreotide.

    Article  CAS  PubMed  Google Scholar 

  21. Pallai, P., Struthers, S., Goodman, M., Rivier, J. & Vale, W. Extended retro-inverso analogs of somatostatin. Biopolymers 22, 2523–2538 (1983).

    Article  CAS  PubMed  Google Scholar 

  22. Rohrer, S. P. et al. Rapid identification of subtype-selective agonists of the somatostatin receptor through combinatorial chemistry. Science 282, 737–740 (1998). Reports a breakthrough in non-peptide agonists.

    Article  CAS  PubMed  Google Scholar 

  23. Crider, M. Recent advances in the development of non-peptide somatostatin receptor ligands. Mini Rev. Med. Chem. 2, 507–517 (2002).

    Article  CAS  PubMed  Google Scholar 

  24. Bruns, C., Lewis, I., Shi, V., Briner, U. & Weckbecker, G. Broad SRIF receptor binding and potent hormone lowering effects of the novel somatostatin (SRIF) SOM230. Endocrine Soc. 83rd Ann. Mtg Denver, Colorado, USA (June, 2001).

  25. Weckbecker, G., Lewis, I., Briner, U. & Bruns, C. SOM230, A new somatostatin peptidomimetic with unique binding and endocrine profile. Proc. 5th Eur. Congr. Endocrinol. Turin, Italy (June, 2001).

  26. Lewis, I. et al. Rational approach to stable, universal somatostatin analogues with superior therapeutic potential. Peptides: The Wave of the Future. Proc. 17th Am./2nd Int. Peptide Symp. (eds Houghten, R. & Lebl, M.) 718–720 (2001).

    Google Scholar 

  27. Weckbecker, G., Briner, U., Lewis, I. & Bruns, C. 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 143, 4123–4130 (2002).

    Article  CAS  PubMed  Google Scholar 

  28. Bruns, C., Lewis, I., Briner, U., Meno-Tetang, G. & Weckbecker, G. SOM230: a novel somatostatin peptidomimetic with a broad somatotropin release inhibiting factor (SRIF) receptor binding and a unique antisecretory profile. Eur. J. Endocrinol. 146, 707–716 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Lewis, I. et al. A novel somatostatin mimic with broad somatotropin release inhibitory factor receptor binding and superior therapeutic potential. J. Med. Chem. 46, 2334–2344 (2003). References 24–29 describe the in vivo studies, binding and functional studies, and the synthesis and medicinal chemistry of SOM230.

    Article  CAS  PubMed  Google Scholar 

  30. Patel, Y. C. Somatostatin and its receptor family. Front. Neuroendocrinol. 20, 157–198 (1999). A comprehensive review on somatostatin receptors.

    Article  CAS  PubMed  Google Scholar 

  31. Meyerhof, W. The elucidation of somatostatin receptor functions: a current view. Rev. Physiol. Biochem. Pharmacol. 133, 55–108 (1998).

    Article  CAS  PubMed  Google Scholar 

  32. Sellers, L. A., Alderton, F., Carruthers, A. M., Schindler, M. & Humphrey, P. P. A. Receptor isoforms mediate opposing proliferative effects through Gβγ-activated p38 or Akt pathways. Mol. Cell. Biol. 20, 5974–5985 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Rosskopf, D. et al. Signal transduction of somatostatin in human B lymphoblasts. Am. J. Physiol. Cell Physiol. 284, C179–C190 (2003). Comprehensive work on somatostatin signalling.

    Article  CAS  PubMed  Google Scholar 

  34. Hoyer, D. et al. in The IUPHAR Compendium of Receptor Characterisation and Classification (IUPHAR Committee on Receptor Nomenclature and Drug Classification) 354–356 (IUPHAR Media, London, 2000). This section of the compendium presents the IUPHAR-based SRIF receptor nomenclature.

    Google Scholar 

  35. Hannon, J. P. et al. Drug design at peptide receptors: somatostatin receptor ligands. J. Mol. Neurosci. 18, 15–27 (2002).

    Article  CAS  PubMed  Google Scholar 

  36. Bruns, C. et al. Molecular pharmacology of somatostatin-receptor subtypes. Ann. NY Acad. Sci. 733, 138–146 (1994).

    Article  CAS  PubMed  Google Scholar 

  37. Fukusumi, S. et al. Identification and characterization of a novel human cortistatin-like peptide. Biochem. Biophys. Res. Commun. 232, 157–163 (1997).

    Article  CAS  PubMed  Google Scholar 

  38. Siehler, S., Seuwen, K. & Hoyer, D. [125I]Tyr10-cortistatin14 labels all five somatostatin receptors. Naunyn Schmiedebergs Arch. Pharmacol. 357, 483–489 (1998).

    Article  CAS  PubMed  Google Scholar 

  39. Broglio, F. et al. Endocrine activities of cortistatin-14 and its interaction with GHRH and ghrelin in humans. J. Clin. Endocrinol. Metab. 87, 3783–3790 (2002).

    Article  CAS  PubMed  Google Scholar 

  40. Siehler, S., Seuwen, K. & Hoyer, D. Characterization of human recombinant somatostatin receptors. 1. Radioligand binding studies. Naunyn Schmiedebergs Arch. Pharmacol. 360, 488–499 (1999).

    Article  CAS  PubMed  Google Scholar 

  41. Bruns, C. et al. Binding properties of somatostatin receptor subtypes. Metab. Clin. Exp. 44, 17–20 (1996).

    Article  CAS  Google Scholar 

  42. Florio, T. et al. Somatostatin inhibits PC C13 thyroid cell proliferation through the modulation of phosphotyrosine phosphatase activity—impairment of the somatostatinergic effects by stable expression of EIA viral oncogene. J. Biol. Chem. 271, 6129–6136 (1996).

    Article  CAS  PubMed  Google Scholar 

  43. Akbar, M. et al. Phospholipase C activation and Ca2+ mobilization by cloned human somatostatin receptor subtypes 1–5 in transfected COS–7 cells. FEBS Lett. 348, 192–196 (1994).

    Article  CAS  PubMed  Google Scholar 

  44. Murthy, K. S., Coy, D. H. & Makhlouf, G. Somatostatin receptor-mediated signalling in smooth muscle. J. Biol. Chem. 271, 23458–23463 (1996).

    Article  CAS  PubMed  Google Scholar 

  45. Cheng, H., Yibchok-anun, S., Coy, D. H. & Hsu, W. H. SSTR2 mediates the somatostatin-induced increase in intracellular Ca2+ concentration and insulin secretion in the presence of arginine vasopressin in clonal β-cell HIT-T15. Life Sci. 71, 927–936 (2002).

    Article  CAS  PubMed  Google Scholar 

  46. Gromada, J., Hoy, M., Buschard, K., Salehi, A. & Rorsman P. Somatostatin inhibits exocytosis in rat pancreatic a-cells by Gi2-dependent activation of calcineurin and depriming of secretory granules. J. Physiol. 535, 519–532 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Chisholm, C. & Greenberg, G. R. Somatostatin-28 regulates GLP-1 secretion via somatostatin receptor subtype 5 in rat intestinal cultures. Am. J. Physiol. Endocrinol. Metab. 283, E311–E317 (2002).

    Article  CAS  PubMed  Google Scholar 

  48. Zatelli, M. C. et al. Somatostatin receptor subtype 1-selective activation reduces cell growth and calcitonin secretion in a human medullary thyroid carcinoma cell line. Biochem. Biophys. Res. Commun. 297, 828–834 (2002).

    Article  CAS  PubMed  Google Scholar 

  49. Cervia, D., Petrucci, C., Bluet-Pajot, M. T., Epelbaum, J. & Bagnoli, P. Inhibitory control of growth hormone secretion by somatostatin in rat pituitary GC cells: sst2 but not sst1 receptors are coupled to inhibition of single-cell intracellular free calcium concentrations. Neuroendocrinology 76, 99–110 (2002).

    Article  CAS  PubMed  Google Scholar 

  50. Strowski, M. Z. et al. Somatostatin receptor subtypes 2 and 5 inhibit corticotropin-releasing hormone-stimulated adrenocorticotropin secretion from AtT-20 cells. Neuroendocrinology 75, 339–346 (2002).

    Article  CAS  PubMed  Google Scholar 

  51. Strowski, M. Z. et al. Somatostatin receptor subtype 5 regulates insulin secretion and glucose homeostasis. Mol. Endocrinol. 17, 93–106 (2003).

    Article  CAS  PubMed  Google Scholar 

  52. Cejvan, K., Coy, D. H. & Efendic, S. Intra-islet somatostatin regulates glucagon release via type 2 somatostatin receptors in rats. Diabetes 52, 1176–1181 (2003).

    Article  CAS  PubMed  Google Scholar 

  53. Barkan, A. L. et al. Ghrelin secretion in humans is sexually dimorphic, suppressed by somatostatin, and not affected by the ambient growth hormone levels. J. Clin. Endocrinol. Metab. 88, 2180–2184 (2003).

    Article  CAS  PubMed  Google Scholar 

  54. Tannenbaum, G. S., Epelbaum, J. & Bowers C. Y. Interrelationship between the novel peptide ghrelin and somatostatin/growth hormone-releasing hormone in regulation of pulsatile growth hormone secretion. Endocrinology 144, 967–974 (2003).

    Article  CAS  PubMed  Google Scholar 

  55. Dimaraki, E. V., Jaffe, C. A., Bowers, C. Y., Marbach, P. & Barkan, A. L. Pulsatile and nocturnal growth hormone secretions in men do not require periodic declines of somatostatin. Am. J. Physiol. Endocrinol. Metabol. 285, C1205–C1204 (2003).

    Article  Google Scholar 

  56. Gong, A. Y. et al. Somatostatin stimulates ductal bile absorption and inhibits ductal bile secretion in mice via SSTR2 on cholangiocytes. Am. J. Physiol. Cell Physiol. 284, 1205–1214 (2003).

    Article  Google Scholar 

  57. Renstrom, E., Ding, W. G., Bokvist, K. & Rorsman, P. Neurotransmitter-induced inhibition of exocytosis in insulin-secreting β-cells by activation of calcineurin. Neuron 17, 513–522 (1996).

    Article  CAS  PubMed  Google Scholar 

  58. Mascardo, R. N., Barton, R. W. & Sherline, P. Somatostatin has an antiproliferative effect on concanavalin-activated rat thymocytes. Clin. Immunol. Immunopathol. 33, 131–138 (1984). The first demonstration of antiproliferative effects of somatostatin.

    Article  CAS  PubMed  Google Scholar 

  59. Weckbecker, G., Raulf, F., Tolcsvai, L. & Bruns, C. Potentiation of the antiproliferative effects of anticancer drugs by octreotide in vitro and in vivo. Digestion 57, 22–28 (1996).

    Article  CAS  PubMed  Google Scholar 

  60. Srikant, C. B. Cell cycle dependent induction of apoptosis by somatostatin analog SMS201-995 in AtT-20 mouse pituitary tumor cells. Biochem. Biophys. Res. Commun. 209, 400–407 (1995) A report of SRIF analogue-induced apoptosis.

    Article  CAS  PubMed  Google Scholar 

  61. Liu, D. et al. Caspase-8-mediated intracellular acidification precedes mitochondrial dysfunction in somatostatin-induced apoptosis. J. Biol. Chem. 275, 9244–9250 (2000).

    Article  CAS  PubMed  Google Scholar 

  62. Teijeiro, R. et al. Activation of human somatostatin receptor 2 promotes apoptosis through a mechanism that is independent from induction of p53. Cell. Physiol. Biochem. 12, 31–38 (2002).

    Article  CAS  PubMed  Google Scholar 

  63. Danila, D. C. et al. Somatostatin receptor-specific analogs: effects on cell proliferation and growth hormone secretion in human somatotroph tumors. J. Clin. Endocrinol. Metab. 86, 2976–2981 (2001).

    CAS  PubMed  Google Scholar 

  64. Lamberts, S. W. J., van der Lely, A. J. & Hofland, L. J. New somatostatin analogs: will they fulfil old promises? Eur. J. Endocrinol. 146, 701–705 (2002).

    Article  CAS  PubMed  Google Scholar 

  65. Tahiri-Jouti, N. et al. Characterization of a membrane tyrosine phosphatase in AR42J cells: regulation by somatostatin. Am. J. Physiol. 262, G1007–G1014 (1992).

    CAS  PubMed  Google Scholar 

  66. Weckbecker, G., Stolz, B., Susini, C. & Bruns, C. in Octreotide: the Next Decade (ed. Lamberts, S. W. J.) 339–352 (BioScientifica, Bristol, 1999).

    Google Scholar 

  67. Oomen, S. P. M. A., Hofland, L. J., Lamberts, S. W. J., Lowenberg, B. & Touw, I. P. Internalization-defective mutants of somatostatin receptor subtype 2 exert normal signaling functions in hematopoietic cells. FEBS Lett. 503, 163–167 (2001).

    Article  CAS  PubMed  Google Scholar 

  68. Sharma, K. & Srikant, C. B. Induction of wild-type p53, Bax, and acidic endonuclease during somatostatin-signaled apoptosis in MCF-7 human breast cancer cells. Int. J. Cancer 76, 259–266 (1998).

    Article  CAS  PubMed  Google Scholar 

  69. Ferone, D. et al. Quantitative and functional expression of somatostatin receptor subtypes in human thymocytes. Am. J. Physiol. Endocrinol. Metab. 283, E1056–E1066 (2002).

    Article  CAS  PubMed  Google Scholar 

  70. Lattuada, D., Casnici, C., Venuto, A. & Marelli, O. The apoptotic effect of somatostatin analogue SMS 201-995 on human lymphocytes. J. Neuroimmunol. 133, 211–216 (2002).

    Article  CAS  PubMed  Google Scholar 

  71. Florio, T. et al. Somatostatin inhibits tumor angiogenesis and growth via somatostatin receptor-3-mediated regulation of endothelial nitric oxide synthase and mitogen-activated protein kinase activities. Endocrinology 144, 1574–1584 (2003).

    Article  CAS  PubMed  Google Scholar 

  72. Reyl, F. J. & Lewin, M. J. M. Intracellular receptor for somatostatin in gastric mucosal cells: decomposition and reconstitution of somatostatin-stimulated phosphoprotein phosphatases. Proc. Natl Acad. Sci. USA 79, 978–982 (1982). Early demonstration of SRIF-modulated protein phosphatase.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Srikant, C. B. & Shen, S. H. Octapeptide somatostatin analog SMS 201-995 induces translocation of intracellular PTP1C to membranes in MCF-7 human breast cancer adenocarcinoma cells. Endocrinology 137, 3461–3468 (1996).

    Article  CAS  PubMed  Google Scholar 

  74. Florio, T. et al. The activation of the phosphotyrosine phosphatase-η (r-PTPη) is responsible for the somatostatin inhibition of PC CI3 thyroid cell proliferation. Mol. Endocrinol. 15, 1838–1852 (2001).

    CAS  PubMed  Google Scholar 

  75. Hortala, M. et al. Inhibitory role of the somatostatin receptor SST2 on the intracrine-regulated cell proliferation induced by the 210-amino acid fibroblast growth factor-2 isoform: implication of JAK2. J. Biol. Chem. 278, 20574–20581 (2003).

    Article  CAS  PubMed  Google Scholar 

  76. Cordelier, P. et al. Characterization of the antiproliferative signal mediated by the somatostatin receptor subtype sst5. Proc. Natl Acad. Sci. USA 94, 9343–9348 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Weckbecker, G., Raulf, F., Bodmer, D. & Bruns, C. Indirect antiproliferative effect of the somatostatin analog octreotide on MIA PaCa-2 human pancreatic carcinoma in nude mice. Yale J. Biol. Med. 70, 549–554 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Weckbecker, G., Tolcsvai, L., Stolz, B., Pollak, M. & Bruns, C. Somatostatin analog octreotide enhances the antineoplastic effects of tamoxifen and ovariectomy on 7,12-dimethylbenz(a)anthracene-induced rat mammary carcinomas. Cancer Res. 54, 6334–6337 (1994).

    CAS  PubMed  Google Scholar 

  79. Sun, Q. -Q., Huguenard, J. R. & Prince D. A. Somatostatin inhibits thalamic network oscillations in vitro: actions on the GABAergic neurons of the reticular nucleus. J. Neurosci. 22, 5374–5386 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Reubi, J. C. & Waser, B. Concomitant expression of several peptide receptors in neuroendocrine tumours: molecular basis for in vivo multireceptor tumour targeting. Eur. J. Nucl. Med. Mol. Imaging 30, 781–793 (2003).

    Article  CAS  PubMed  Google Scholar 

  81. Hofland, L. J. & Lamberts, S. W. J. The pathophysiological consequences of somatostatin receptor internalization and resistance. Endocrine Rev. 24, 28–47 (2003). Comprehensive review on SRIF receptor internalization.

    Article  CAS  Google Scholar 

  82. Reubi, J. C., Waser, B., Schaer, J. -C. & Laissue, J. A. Somatostatin receptor sst1–sst5 expression in normal and neoplastic human tissues using receptor autoradiography with subtype-selective ligands. Eur. J. Nucl. Med. Mol. Imaging 28, 836–846 (2001).

    Article  CAS  Google Scholar 

  83. Kulaksiz, H. et al. Identification of somatostatin receptor subtypes 1,2A, 3, and 5 in neuroendocrine tumors with subtype specific antibodies. Gut 50, 52–60 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Öberg, K. Carcinoid tumors: molecular genetics, tumor biology. Curr. Opin. Oncol. 14, 38–45 (2002).

    Article  PubMed  Google Scholar 

  85. Csaba, Z., Bernard, V., Helboe, L., Bluet-Pajot, M. T. & Bloch, B. In vivo internalization of the somatostatin sst2A receptor in rat brain: evidence for translocation of cell-surface receptors into the endosomal recycling pathway. Mol. Cell. Neuroscience 17, 646–661 (2001).

    Article  CAS  Google Scholar 

  86. Krenning, E. P. et al. Somatostatin receptor scintigraphy with [111In-DTPA-D-Phe1]- and [123I-Tyr3]-octreotide: the Rotterdam experience with more than 1000 patients. Eur. J. Nucl. Med. 20, 716–731 (1993). The first major clinical experience with SRIF receptor scintigraphy.

    Article  CAS  PubMed  Google Scholar 

  87. De Jong, M. et al. Internalization of radiolabelled [DTPA0]octreotide and [DOTA0,Tyr3]octreotide: peptides for somatostatin receptor–targeted scintigraphy and radionuclide therapy. Nucl. Med. Commun. 19, 283–288 (1998).

    Article  CAS  PubMed  Google Scholar 

  88. Schally, A. V. & Nagy A. Cancer chemotherapy based on targeting of cytotoxic peptide conjugates to their receptors on tumors. Eur. J. Endocrinol. 141, 1–14 (1999).

    Article  CAS  PubMed  Google Scholar 

  89. Froidevaux, S. et al. Differential regulation of somatostatin receptor type 2 (sst 2) expression in AR4-2J tumor cells implanted into mice during octreotide treatment. Cancer Res. 59, 3652–3657 (1999).

    CAS  PubMed  Google Scholar 

  90. Arnold, R., Simon, B. & Wied, M. Treatment of neuroendocrine GEP tumours with somatostatin analogues: a review. Digestion 62, 84–91 (2000).

    Article  CAS  PubMed  Google Scholar 

  91. George, S. R., O'Dowd, B. F. & Lee, S. P. G-protein-coupled receptor oligomerization and its potential for drug discovery. Nature Rev. Drug Discov. 2, 808–820 (2002).

    Article  CAS  Google Scholar 

  92. Rocheville, M. et al. Receptors for dopamine and somatostatin: formation of hetero-oligomers with enhanced functional activity. Science 288, 154–157 (2000). Describes the hetero-oligomerization of SRIF receptors.

    Article  CAS  PubMed  Google Scholar 

  93. Rocheville, M. et al. Subtypes of the somatostatin receptor assemble as functional homo- and heterodimers J. Biol. Chem. 275, 7862–7869 (2000).

    Article  CAS  PubMed  Google Scholar 

  94. Pfeiffer, M. et al. Homo- and heterodimerization of somatostatin receptor subtypes. Inactivation of sst(3) receptor function by heterodimerization with sst(2A). J. Biol. Chem. 276, 14027–14036 (2001).

    Article  CAS  PubMed  Google Scholar 

  95. Pfeiffer, M. et al. Heterodimerization of somatostatin and opioid receptors cross-modulates phosphorylation, internalization, and desensitization. J. Biol. Chem. 277, 19762–19772 (2002).

    Article  CAS  PubMed  Google Scholar 

  96. Selmer, I. -S., Schindler, M., Allen, J. P., Humphrey, P. P. A. & Emson, P. C. Advances in understanding neuronal somatostatin receptors. Regul. Pept. 90, 1–18 (2000).

    Article  CAS  PubMed  Google Scholar 

  97. Murphy, W. A., Lance, V. A., Moreau, S., Moreau, J. & Coy, D. H. Inhibition of rat prostate tumor growth by an octapeptide analog of somatostatin. Life Sci. 40, 2515–2522 (1987).

    Article  CAS  PubMed  Google Scholar 

  98. Caron, P., Morange-Ramos, I., Cogne, M. & Jaquet, P. Three year follow-up of acromegalic patients treated with intramuscular slow-release lanreotide. J. Clin. Endocrinol. Metab. 82, 18–22 (1997).

    CAS  PubMed  Google Scholar 

  99. Veber, D. F. et al. A potent cyclic hexapeptide analogue of somatostatin. Nature 292, 55–58 (1981). Reports a SRIF analogue structure with further reduced size.

    Article  CAS  PubMed  Google Scholar 

  100. Van der Hoek, J. et al. A single dose comparison of the acute effects between the new somatostatin analog SOM230 and octreotide in acromegalic patients. J. Clin. Endocrinol. Metab. 88 (in the press). Demonstration of efficacy of SOM230 in acromegalic patients.

  101. Raynor, K. et al. Cloned somatostatin receptors: identification of subtype-selective peptides and demonstration of high affinity binding of linear peptides. Mol. Pharmacol. 43, 838–844 (1993).

    CAS  PubMed  Google Scholar 

  102. Shimon, I. et al. Somatostatin receptor subtype specificity in human fetal pituitary cultures, differential role of SSTR2 and SSTR5 for growth hormone, thyroid-stimulating hormone, and prolactin regulation. J. Clin. Invest. 99, 789–798 (1997). Describes the role of sst 5 in controlling growth hormone release.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Reubi, J. C., Eisenwiener, K. -P., Rink, H., Waser, B. & Mäcke, H. R. A new peptidic somatostatin agonist with high affinity to all five somatostatin receptors. Eur. J. Pharmacol. 456, 45–49 (2002). Report on a novel universal SRIF receptor ligand.

    Article  CAS  PubMed  Google Scholar 

  104. Rivier, J. E. et al. Potent somatostatin undecapeptide agonists selective for somatostatin receptor 1 (sst1). J. Med. Chem. 44, 2238–2246 (2001).

    Article  CAS  PubMed  Google Scholar 

  105. Rajeswaran, W. G., Hocart, S. J., Murphy, W. A., Taylor, J. E. & Coy, D. H. N-methyl scan of somatostatin octapeptide agonists produces interesting effects on receptor subtype specificity. J. Med. Chem. 44, 1416–1421 (2001).

    Article  CAS  PubMed  Google Scholar 

  106. Afargan, M. et al. Novel long-acting somatostatin analog with endocrine selectivity: potent suppression of growth hormone but not of insulin. Endocrinology 142, 477–486 (2001). Reports the discovery of PTR3173.

    Article  CAS  PubMed  Google Scholar 

  107. Gazal, S. et al. Human somatostatin receptor specificity of backbone-cyclic analogues containing novel sulfur building units. J. Med. Chem. 45, 1665–1671 (2002).

    Article  CAS  PubMed  Google Scholar 

  108. Gademann, K., Kimmerlin, T., Hoyer, D. & Seebach, D. Peptide folding induces high and selective affinity of a linear and small β-peptide to the human somatostatin receptor 4. J. Med. Chem. 44, 2460–2468 (2001). Describes the discovery of a β-peptide SRIF analogue.

    Article  CAS  PubMed  Google Scholar 

  109. Nunn, C. et al. β2/β3- and α/β3-tetrapeptide derivatives as potent agonists at somatostatin sst4 receptors. Naunyn Schmiedeberg's Arch. Pharmacol. 367, 95–103 (2003).

    Article  CAS  Google Scholar 

  110. Seebach, D., Schaeffer, L., Brenner, M. & Hoyer, D. Design and synthesis of γ-dipeptide derivatives with submicromolar affinities for human somatostatin receptors. Angew. Chem. Int. Ed. Engl. 42, 776–778 (2003). Reports the discovery of γ-dipeptide SRIF mimics.

    Article  CAS  PubMed  Google Scholar 

  111. Bass, R. T. et al. Identification and characterization of novel somatostatin antagonists. Mol. Pharmacol. 50, 709–715 (1996). First SRIF peptide antagonist published.

    CAS  PubMed  Google Scholar 

  112. Feniuk, W., Jarvie, E., Luo, J. & Humphrey, P. P. A. Selective somatostatin sst2 receptor blockade with the novel cyclic octapeptide, CYN-154806. Neuropharmacology 39, 1443–1450 (2000).

    Article  CAS  PubMed  Google Scholar 

  113. Hocart, S. J., Jain, R., Murphy, W. A., Taylor, J. E. & Coy, D. H. Highly potent cyclic disulfide antagonists of somatostatin. J. Med. Chem. 42, 1863–1871 (1999).

    Article  CAS  PubMed  Google Scholar 

  114. Reubi, J. C. et al. SST3-selective potent peptidic somatostatin receptor antagonists. Proc. Natl Acad. Sci. USA 97, 13973–13978 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Keri, G. et al. Novel somatostatin analogs with tyrosine kinase inhibitory and antitumor activity. Biochem. Biophys. Res. Commun. 191, 681–687 (1993).

    Article  CAS  PubMed  Google Scholar 

  116. Pinter, E. et al. Pharmacological characterization of the somatostatin analogue TT-232: effects on neurogenic and non-neurogenic inflammation and neuropathic hyperalgesia. Naunyn Schmiedebergs Arch. Pharmacol. 366, 142–150 (2002).

    Article  CAS  PubMed  Google Scholar 

  117. Li, H., Jiang, X., Howell, S. B. & Goodman, M. Synthesis, conformational analysis and bioactivity of Lan-7, a lanthionine analog of TT-232. J. Pept. Sci. 6, 26–35 (2000).

    Article  CAS  PubMed  Google Scholar 

  118. Yang, L. Non-peptide somatostatin receptor ligands. Ann. Rep. Med. Chem. 34, 209–218 (1999).

    CAS  Google Scholar 

  119. Rohrer, S. P. & Schaeffer, J. M. Identification and characterization of subtype selective somatostatin receptor agonists. J. Physiol. 94, 211–215 (2000).

    CAS  Google Scholar 

  120. Pasternak, A. et al. Potent, orally bioavailable somatostatin agonists: good absorption achieved by urea backbone cyclization. Bioorg. Med. Chem. Lett. 9, 491–496 (1999). This paper describes orally available SRIF mimetics.

    Article  CAS  PubMed  Google Scholar 

  121. Hirschmann, R. et al. Nonpeptidal peptidomimetics with β-D-glucose scaffolding. A partial somatostatin agonist bearing a close structural relationship to a potent, selective substance P antagonist. J. Am. Chem. Soc. 114, 9217–9218 (1992). Early work on non-peptide SRIF analogues.

    Article  CAS  Google Scholar 

  122. Hirschmann, R. et al. Modulation of receptor and receptor subtype affinities using diastereomeric and enantiomeric monosaccharide scaffolds as a means to structural and biological diversity. A new route to ether synthesis. J. Med. Chem. 41, 1382–1391 (1998).

    Article  CAS  PubMed  Google Scholar 

  123. Prasad, V. et al. Effects of heterocyclic aromatic substituents on binding affinities at two distinct sites of somatostatin receptors. Correlation with the electrostatic potential of the substituents. J. Med. Chem. 46, 1858–1869 (2003).

    Article  CAS  PubMed  Google Scholar 

  124. Ankersen, M. et al. Discovery of a novel non-peptide somatostatin agonist with SST4 selectivity. J. Am. Chem. Soc. 120, 1368–1373 (1998). Discovery of a selective non-peptide SRIF agonist.

    Article  CAS  Google Scholar 

  125. Souers, A. J. et al. Optimization of a somatostatin mimetic via constrained amino acid and backbone incorporation. Bioorg. Med. Chem. Lett. 10, 2731–2733 (2000). Discovery of a thioether SRIF mimic.

    Article  CAS  PubMed  Google Scholar 

  126. Hoyer, D. et al. NVP-SRA880, a somatostatin sst1 receptor antagonist promotes social interactions, reduces aggressive behaviour and stimulates learning. The Pharmacologist 44 (Suppl. 1), A254 (2002). First SRIF antagonist tested in clinical trials.

    Google Scholar 

  127. Poitout, L. et al. Identification of potent non-peptide somatostatin antagonists with sst3 selectivity. J. Med. Chem. 44, 2990–3000 (2001).

    Article  CAS  PubMed  Google Scholar 

  128. Bakker, W. H. et al. [111In-DTPA-D-Phe1]-octreotide, a potential radiopharmaceutical for imaging of somatostatin receptor-positive tumors: synthesis, radiolabeling and in vitro validation. Life Sci. 49, 1583–1591 (1991). Discovery of radiolabelled octreotide.

    Article  CAS  PubMed  Google Scholar 

  129. Stolz, B. et al. The somatostatin receptor-targeted radiotherapeutic [90Y-DOTA-D-Phe1, Tyr3](octreotide (90Y-SMT 487) eradicates experimental rat pancreatic CA 20948 tumours. Eur. J. Nucl. Med. 25, 668–674 (1998). Discovery of the first SRIF analogue radiotherapeutic, SMT487, which is presently being tested clinically.

    Article  CAS  PubMed  Google Scholar 

  130. Virgolini, I. et al. Experience with indium-111 and yttrium-90-labeled somatostatin analogs. Curr. Pharm. Des. 8, 1781–1807 (2002). A comprehensive review of radiolabelled SRIF analogues.

    Article  CAS  PubMed  Google Scholar 

  131. De Jong, M. et al. Somatostatin receptor-targeted radiotherapy of tumors: preclinical and clinical findings. Sem. Nucl. Med. 32, 133–140 (2002).

    Article  Google Scholar 

  132. Reubi, J. C. et al. Affinity profiles for human somatostatin receptor subtypes SST1-SST5 of somatostatin radiotracers selected for scintigraphic and radiotherapeutic use. Eur. J. Nuc. Med. 27, 273–282 (2000).

    Article  CAS  Google Scholar 

  133. Jamar, F. et al. 86Y-DOTA0-D-Phe1-Tyr3-octreotide (SMT487) a phase 1 clinical study: pharmacokinetics, biodistribution and renal protective effect of different regimens of amino acid co-infusion. Eur. J. Nucl. Med. Mol. Imaging 30, 510–518 (2003).

    Article  CAS  PubMed  Google Scholar 

  134. Bolli, G. B., Gottesman, I. S. & Gerich, J. E. Preliminary experience on treatment of insulin-dependent diabetes mellitus with a long-acting somatostatin analogue (L363,586). Hormone Res. 29, 95–98 (1988).

    Article  CAS  PubMed  Google Scholar 

  135. Gerich, J. E. Lorenzi, M., Schneider, V. & Forsham, P. H. Effect of somatostatin on plasma glucose and insulin responses to glucagon and tolbutamide in man. J. Clin. Endocrinol. Metab. 39, 1057–1060 (1974).

    Article  CAS  PubMed  Google Scholar 

  136. Rizza, R. et al. Somatostatin does not cause sustained fasting hyperglycemia in man. Horm. Metab. Res. 11, 643–644 (1979).

    Article  CAS  PubMed  Google Scholar 

  137. Campbell, P. J., Bolli, G. B. & Gerich, J. E. Prevention of the Dawn phenomenon (early morning hyperglycemia) in insulin-dependent diabetes mellitus by bedtime intranasal administration of a long-acting somatostatin analog. Metab. 37, 34–37 (1988).

    Article  CAS  Google Scholar 

  138. Boehm, B. O. The therapeutic potential of somatostatin receptor ligands in the treatment of obesity and diabetes. Exp. Opin. Investig. Drugs 12, 1501–1509 (2003).

    Article  CAS  Google Scholar 

  139. Kayasseh, L., Gyr, K., Keller, U. & Stalder, G. A. Somatostatin in peptic ulcer bleeding. Lancet 2, 861 (1980).

    Article  CAS  PubMed  Google Scholar 

  140. Usadel, K. H., Leuschner, U. & Uberla, K. K. Treatment of acute pancreatitis with somatostatin: a multicenter double blind study. N. Engl. J. Med. 303, 999–1000 (1980).

    Article  CAS  PubMed  Google Scholar 

  141. Szabo, S. & Usadel, K. H. Cytoprotection — organoprotection by somatostatin: gastric and hepatic lesions. Experientia 38, 254–256 (1982).

    Article  CAS  PubMed  Google Scholar 

  142. Avgerinos, A., Nevens, F., Raptis, S. & Fevery, J. Early administration of somatostatin and efficacy of sclerotherapy in acute oesophageal variceal bleeds: the European Acute Bleeding Oesophageal Variceal Episodes (ABOVE) randomised trial. Lancet 350, 1495–1499 (1997).

    Article  CAS  PubMed  Google Scholar 

  143. Lancranjan, I. & Atkinson, A. B. Results of a European multicentre study with Sandostatin LAR in acromegalic patients. Sandostatin LAR Group. Pituitary 1, 105–114 (1999).

    Article  CAS  PubMed  Google Scholar 

  144. Papotti, M. et al. Expression of somatostatin receptor types 1–5 in 81 cases of gastrointestinal and pancreatic endocrine tumors. A correlative immunohistochemical and reverse-transcriptase polymerase chain reaction analysis. Virchows Arch. 440, 461–475 (2002).

    Article  CAS  PubMed  Google Scholar 

  145. Karashima, T., Cai, R. Z. & Schally, A. V. Effects of highly potent octapeptide analogs of somatostatin on growth hormone, insulin and glucagon release. Life Sci. 41, 1011–1019 (1987).

    Article  CAS  PubMed  Google Scholar 

  146. Newman, C. B. et al. Safety and efficacy of longterm octreotide therapy of acromegaly: results of a multicenter trial in 103 patients. A clinical research center study. J. Clin. Endocrinol. Metabol. 80, 2768–2775 (1995).

    CAS  Google Scholar 

  147. Lamberts, S. W. J., Krenning, E. P. & Reubi, J. C. The role of somatostatin and its analogs in the diagnosis and treatment of tumors. Endocrine Rev. 12, 450–482 (1991). A comprehensive review of somatostatin in cancer.

    Article  CAS  Google Scholar 

  148. Jensen, R. T. Carcinoid and pancreatic endocrine tumors: recent advances in molecular pathogenesis, localization, and treatment. Curr. Opin. Oncol. 12, 368–377 (2000).

    Article  CAS  PubMed  Google Scholar 

  149. 'Vance, M. L. Medical treatment of functional pituitary tumors. Neurosurgery Clin. N. Am. 14, 81–87 (2003).

    Article  Google Scholar 

  150. De Herder, W. & Lamberts, S. Somatostatin analog therapy in treatment of gastrointestinal disorders and tumors. Endocrine 20, 285–290 (2003).

    Article  CAS  PubMed  Google Scholar 

  151. Freda, P. U. Somatostatin analogs in acromegaly. J. Clin. Endocrinol. Metab. 87, 3013–3018 (2002).

    Article  CAS  PubMed  Google Scholar 

  152. Bevan, J. S. et al. Primary medical therapy for acromegaly: an open, prospective, multicenter study of the effects of subcutaneous and intramuscular slow-release octreotide on growth hormone, insulin-like growth factor-1, and tumor size. J. Clin. Endocrinol. Metab. 87, 4554–4563 (2002). Demonstration of the utility of octreotide as primary therapy of acromegaly.

    Article  CAS  PubMed  Google Scholar 

  153. Nieman, L. K. Medical therapy of Cushing's disease. Pituitary 5, 77–82 (2002).

    Article  CAS  PubMed  Google Scholar 

  154. Hofland, L. J. et al. The novel somatostatin analog SOM230 inhibits ACTH release by cultured human corticotroph tumors. Endocrine Soc. Mtg AP2-499 (June, 2003).

  155. Schally, A. Oncological applications of somatostatin analogues. Cancer Res. 48, 6977–6985 (1988).

    CAS  PubMed  Google Scholar 

  156. Woltering, E. A. et al. Somatostatin analogues inhibit angiogenesis in the chick chorioallantoic membrane. J. Surg. Res. 50, 245–251 (1991).

    Article  CAS  PubMed  Google Scholar 

  157. Barrie, R. et al. Inhibition of angiogenesis by somatostatin and somatostatin-like compounds is structurally dependent. J. Surgical Res. 55, 446–450 (1993).

    Article  CAS  Google Scholar 

  158. Hejna, M., Schmidinger, M. & Raderer, M. The clinical role of somatostatin analogues as antineoplastic agents: much ado about nothing? Ann. Oncol. 13, 653–668 (2002). A comprehensive clinical review.

    Article  CAS  PubMed  Google Scholar 

  159. Kouroumalis, E. et al. Treatment of hepatocellular carcinoma with octreotide: a randomised controlled study. Gut 42, 442–447 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Yuen, M. F. et al. A randomized placebo-controlled study of long-acting octreotide for the treatment of advanced hepatocellular carcinoma. Hepatology 36, 687–691 (2002).

    Article  CAS  PubMed  Google Scholar 

  161. Adams, R. L., Adams, I. P., Zhong, W. & Atkin, S. L. Inhibition of endothelial proliferation by the new somatostatin analog, SOM230, and expression of somatostatin receptors in proliferating and quiescent endothelium. Endocrine Soc. Mtg AP3-371 (June, 2003).

  162. Szende, B., Horvath, A., Bokonyi, G. & Keri, G. Effect of a novel somatostatin analogue combined with cytotoxic drugs on human tumour xenografts and metastasis of B16 melanoma. Brit. J. Cancer 88, 132–136 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Guillermet, J. et al. Somatostatin receptor subtype 2 sensitizes human pancreatic cancer cells to death ligand-induced apoptosis. Proc. Natl Acad. Sci. USA 100, 155–160 (2003).

    Article  CAS  PubMed  Google Scholar 

  164. Stolz, B. et al. Somatostatin analogues for somatostatin-receptor-mediated radiotherapy of cancer. Digestion 57 (Suppl. 1), 17–21 (1996).

    Article  CAS  PubMed  Google Scholar 

  165. Van Hagen, P. M. et al. Somatostatin analogue scintigraphy of malignant lymphomas. Br. J. Haematol. 83, 75–79 (1993).

    Article  CAS  Google Scholar 

  166. Reubi, J. C., Laissue, J., Krenning, E. & Lamberts, S. W. Somatostatin receptors in human cancer: incidence, characteristics, functional correlates and clinical implications. J. Steroid Biochem. Mol. Biol. 43, 27–35 (1992). Early work on SRIF receptor distribution.

    Article  CAS  PubMed  Google Scholar 

  167. Van Eijck, C. H. et al. Somatostatin-receptor scintigraphy in primary breast cancer. Lancet 343, 640–643 (1994).

    Article  CAS  PubMed  Google Scholar 

  168. Jensen, R. T., Gibril, F. & Termanini, B. Definition of the role of somatostatin receptor scintigraphy in gastrointestinal neuroendocrine tumor localization. Yale J. Biol. Med. 70, 481–500 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Kwekkeboom, D., Krenning, E. P. & deJong, M. Peptide receptor imaging and therapy. J. Nucl. Med. 41, 1704–1713 (2000).

    CAS  PubMed  Google Scholar 

  170. Virgolini, I. et al. New trends in peptide receptor radioligands. J. Nucl. Med. 45, 153–159 (2001).

    CAS  Google Scholar 

  171. Virgolini, I., Britton, K., Buscombe, J., Moncayo, R., Paganelli, G. & Riva, P. In- and Y-DOTA-lanreotide: results and implications of the MAURITIUS trial. Seminars Nucl. Med. 32, 148–155 (2002).

    Article  Google Scholar 

  172. Paganelli, G. et al. Receptor-mediated radiotherapy with 90Y-DOTA-D-Phe1-Tyr3-octreotide. Eur. J. Nucl. Med. 28, 426–434 (2001).

    Article  CAS  PubMed  Google Scholar 

  173. Weiner, R. E. & Thakur, M. L. Radiolabeled peptides in the diagnosis and therapy of oncological diseases. Appl. Radiat. Isot. 57, 749–763 (2002).

    Article  CAS  PubMed  Google Scholar 

  174. Krassas, G. E., Doumas, A., Kaltsas, T., Halkias, A. & Pontikides, N. Somatostatin receptor scintigraphy before and after treatment with somatostatin analogues in patients with thyroid eye disease. Thyroid 9, 47–52 (1999).

    Article  CAS  PubMed  Google Scholar 

  175. Colao, A. et al. Orbital scintigraphy with [111]In-diethylenetriamine pentaacetic acid-D-Phe1]-octreotide predicts the clinical response to corticosteroid therapy in patients with Graves' ophthalmopathy. J. Clin. Endocrinol. Metab. 83, 3790–3794 (1998).

    CAS  PubMed  Google Scholar 

  176. Krassas, G. E., Pontikides, N., Doukidis, D., Heufelder, G. & Heufelder, A. E. Serum levels of tumor necrosis factor-α, soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, and soluble interleukin-1 receptor antagonist in patients with thyroid eye disease undergoing treatment with somatostatin analogues. Thyroid 11, 1115–1122 (2001).

    Article  CAS  PubMed  Google Scholar 

  177. Gabriel, M., Decristoforo, C. & Moncayo, R. Somatostatin receptor scintigraphy using Tc-99m-EDDA/HYNIC–TOC in Graves' disease. Eur. J. Nucl. Med. Mol. Imaging. 29, 1267 (2002).

    Article  PubMed  Google Scholar 

  178. Pasquali, D. et al. Somatostatin receptor genes are expressed in lymphocytes from retroorbital tissues in Graves' disease. J. Clin. Endocrinol. Metab. 87, 5125–5129 (2002).

    Article  CAS  PubMed  Google Scholar 

  179. Grant, M. B., Caballero, S. & Millard, W. J. Inhibition of IGF-I and β-FGF stimulated growth of human retinal endothelial cells by the somatostatin analog, octreotide, a potential treatment for ocular neovascularization. Regul. Pept. 48, 267–278 (1993).

    Article  CAS  PubMed  Google Scholar 

  180. Grant, M. B. & Caballero, S. Somatostatin analogues as drug therapies for retinopathies. Drugs Today 38, 783–791 (2002).

    Article  CAS  Google Scholar 

  181. Sönksen, P. H., Russell-Jones, D. & Jones, R. H. Growth hormone and diabetes mellitus. A review of sixty-three years of medical research and a glimpse into the future? Hormone Res. 40, 68–79 (1993).

    Article  PubMed  Google Scholar 

  182. Koller, E. A., Green, L., Gertner, J. M., Bost, M. & Malozowski, S. N. Retinal changes mimicking diabetic retinopathy in two nondiabetic, growth hormone-treated patients. J. Clin. Endocrinol. Metab. 83, 2380–2383 (1998).

    CAS  PubMed  Google Scholar 

  183. Burgos, R. et al. Vitreous levels of IGF-1, IGF binding protein1, and IGF binding protein 3 in proliferative diabetic retinopathy: a case-control study. Diabetes Care 23, 80–83 (2000).

    Article  CAS  PubMed  Google Scholar 

  184. Klisovic, D. D. et al. Somatostatin receptor gene expression in human ocular tissues: RT-PCR and immunohistochemical study. Invest. Ophthalmol. Vis. Sci. 42, 2193–2201 (2001).

    CAS  PubMed  Google Scholar 

  185. Spraul, C. W., Baldysiak-Figiel, A., Lang, G. K. & Lang, G. E. Octreotide inhibits growth factor-induced bovine choriocapillary endothelial cells in vitro. Graefes Arch. Clin. Exp. Ophthalmol. 240, 227–231 (2002).

    Article  CAS  PubMed  Google Scholar 

  186. Boehm, B. O., Lang, G. K., Jehle, P. M., Feldman, B. & Lang, G. E. Octreotide reduces vitreous hemorrhage and loss of visual acuity risk in patients with high-risk proliferative diabetic retinopathy. Horm. Metab. Res. 33, 300–306 (2001). Report on the efficacy of a somatostatin analogue in diabetic retinopathy.

    Article  CAS  PubMed  Google Scholar 

  187. Flyvbjerg, A. Putative pathophysiological role of growth factors and cytokines in experimental diabetic kidney disease. Diabetologia 43, 1205–1223 (2000).

    Article  CAS  PubMed  Google Scholar 

  188. Orskov, H. et al. G. Octreotide and diabetes: theoretical and experimental aspects. Metabolism 41 (Suppl. 2), 66–71 (1992). Describes the role of SRIF analogues in diabetes.

    Article  CAS  PubMed  Google Scholar 

  189. Groenbaek, H., Nielsen, B., Frystyk, J., Orskov, H. & Flyvbjerg, A. Effect of octreotide on experimental diabetic renal and glomerular growth: importance of early intervention. J. Endocrinol. 147, 95–102 (1995).

    Article  CAS  Google Scholar 

  190. Groenbaek, H. et al. Inhibitory effects of octreotide on renal and glomerular growth in early experimental diabetes in mice. J. Endocrinol. 172, 637–643 (2002).

    Article  Google Scholar 

  191. Bak, M., Thomsen, K. & Flyvbjerg, A. Effects of the somatostatin analogue octreotide on renal function in conscious diabetic rats. Nephrol. Dialysis Transplant. 16, 2002–2007 (2001).

    Article  CAS  Google Scholar 

  192. Epelbaum, J., Dournaud, P., Fodor, M. & Viollet, C. The neurobiology of somatostatin. Crit. Rev. Neurobiol. 8, 25–44 (1994).

    CAS  PubMed  Google Scholar 

  193. Nemeroff, C. B., Youngblood, W. W., Manberg, P. J., Prange, A. J. & Kizer, J. S. Regional brain concentration of neuropeptides in Huntington's chorea and schizophrenia. Science 221, 972–975 (1983). This paper discusses the role of SRIF in CNS diseases.

    Article  CAS  PubMed  Google Scholar 

  194. Riekkinen, P. J. & Pitkanen, A. Somatostatin and epilepsy. Metabolism 39, 112–115 (1990).

    Article  CAS  PubMed  Google Scholar 

  195. Vezzani, A. & Hoyer, D. Brain somatostatin: a candidate inhibitory role in seizures and epileptogenesis. Eur. J. Neurosci. 11, 3767–3776 (1999).

    Article  CAS  PubMed  Google Scholar 

  196. Viollet, C., Videau, C. & Epelbaum, J. Somatostatin and behaviour: the need for genetically engineered models. J. Physiol. 94, 179–183 (2000).

    CAS  Google Scholar 

  197. Chrubasik, J., Meynadier, J., Scherpereel, P. & Wünsch, W. The effect of epidural somatostatin on postoperative pain. Anesth. Analg. 64, 1085–1088 (1985). Early work on the role of SRIF analogues in pain treatment.

    Article  CAS  PubMed  Google Scholar 

  198. Su, X., Burton, M. B. & Gebhart, G. F. Effects of octreotide on responses to colorectal distension in the rat. Gut 48, 676–682 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Schindler, M. et al. C. Identification of somatostatin sst2a receptor expressing neurones in central regions involved in nociception. Brain Res. 798, 25–35 (1998).

    Article  CAS  PubMed  Google Scholar 

  200. Foegh, M. L., Khirabadi, B. S., Chambers, E., Amamoo, S. & Ramwell, P. W. Inhibition of coronary artery transplant atherosclerosis in rabbits with angiopeptin, an octapeptide. Atherosclerosis 78, 229–236 (1989). Early study on the effect of a somatostatin analogue on vascular remodelling.

    Article  CAS  PubMed  Google Scholar 

  201. Weckbecker, G. et al. The somatostatin analog octreotide as potential treatment for re-stenosis and chronic rejection. Transplant. Proc. 29, 2599–2600 (1997).

    Article  CAS  PubMed  Google Scholar 

  202. Bruns, C., Shi, V., Hoyer, D., Schuurman, H. & Weckbecker, G. Somatostatin receptors and the potential use of Sandostatin to interfere with vascular remodelling. Eur. J. Endocrinol. 143, S3–S7 (2000).

    Article  CAS  PubMed  Google Scholar 

  203. Häyry, P., Räisänen, A., Ustinov, J., Mennander, A. & Paavonen, T. Somatostatin analogue lanreotide inhibits myocyte replication and several growth factors in allograft arteriosclerosis. FASEB J. 7, 1055–1060 (1993).

    Article  PubMed  Google Scholar 

  204. Curtis, S. B. et al. Effect of endothelial and adventitial injury on somatostatin receptor expression. Surgery 127, 577–583 (2000).

    Article  CAS  PubMed  Google Scholar 

  205. Watson, J. C. et al. Growing vascular endothelial cells express somatostatin subtype 2 receptors. Brit. J. Cancer 85, 266–272 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Wahlers, T., Oppelt, P., Pethig, K. & Heublein, B. Current experience with somatostatin analogues, especially angiopeptine, for the prevention of transplant vasculopathy in heart transplantation. Transplant. Proc. 30, 866–867 (1998).

    Article  CAS  PubMed  Google Scholar 

  207. Eriksen, U. H. et al. Randomized double-blind Scandinavian trial of angiopeptin versus placebo for the prevention of clinical events and restenosis after coronary balloon angioplasty. Am. Heart J. 130, 1–8 (1995).

    Article  CAS  PubMed  Google Scholar 

  208. Van Bergeijk, J. D. & Wilson, J. H. P. Somatostatin in inflammatory bowel disease. Mediators Inflamm. 6, 303–309 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Van Hagen, P. M. et al. Neuropeptides and their receptors in the immune system. Ann. Med. 31 (Suppl. 2), 15–22 (1999).

    PubMed  Google Scholar 

  210. Krantic, S. Peptides as regulators of the immune system: emphasis on somatostatin. Peptides 21, 1941–1964 (2000).

    Article  CAS  PubMed  Google Scholar 

  211. Heemskerk, V. H., Daemen, M. & Buurman, W. A. Insulin-like growth factor-1 (IGF-1) and growth hormone (GH) in immunity and inflammation. Cytokine Growth Factor Rev. 10, 5–14 (1999).

    Article  CAS  PubMed  Google Scholar 

  212. Bhatena, S. J. & Recant, L. Somatostatin receptors on circulating human blood cells. Horm. Metab. Res. 12, 277–278 (1980). First demonstration of SRIF receptors on lymphocytes.

    Article  Google Scholar 

  213. Reubi, J. C., Waser, B. & Horisberger, U. In vivo autoradiographic and in vivo scintigraphic localization of somatostatin receptors in human lymphatic tissue. Blood 82, 2143–2148 (1993).

    Article  CAS  PubMed  Google Scholar 

  214. Albini, A. et al. Somatostatin controls Kaposi's sarcoma tumor growth through inhibition of angiogenesis. FASEB J. 13, 647–655 (1999).

    Article  CAS  PubMed  Google Scholar 

  215. Elliott, D. E., Li, J., Blum, A. M., Metwali, A., Patel, Y. C. & Weinstock, J. V. SSTR2A is the dominant somatostatin receptor subtype expressed by inflammatory cells, is widely expressed and directly regulates T cell IFN-γ release. Eur. J. Immunol. 29, 2454–2463 (1999).

    Article  CAS  PubMed  Google Scholar 

  216. Peluso, G. et al. Modulation of cytokine production in activated human monocytes by somatostatin. Neuropeptides 30, 443–451 (1996).

    Article  CAS  PubMed  Google Scholar 

  217. Karalis, K., Mastorakos, G., Chrousos, G. P. & Tolis, G. Somatostatin analogues suppress the inflammatory reaction in vivo. J. Clin. Invest. 93, 2000–2006 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Eliakim, R., Karmeli, F., Okon, E. & Rachmilewitz, D. Octreotide effectively decreases mucosal damage in experimental colitis. Gut 34, 264–269 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Fioravanti, A. et al. Somatostatin-14 and joint inflammation: evidence for intraarticular efficacy of prolonged administration in rheumatoid arthritis. Drugs Exp. Clin. Res. 21, 97–103 (1995).

    CAS  PubMed  Google Scholar 

  220. Cascinu, S., Fedeli, A., Fedeli, S. L. & Catalano, G. Control of chemotherapy-induced diarrhea with octreotide. A randomized trial with placebo in patients receiving cisplatin. Oncology 51, 70–73 (1994).

    Article  CAS  PubMed  Google Scholar 

  221. Nunn, C., Schoeffter, P., Langenegger, D. & Hoyer, D. Functional characterisation of the putative somatostatin sst2 receptor antagonist CYN 154806. Naunyn Schmiedeberg's Arch Pharmacol. 367, 1–9 (2003).

    Article  CAS  Google Scholar 

  222. Yang, L. et al. Synthesis and biological activities of potent peptidomimetics selective for somatostatin receptor subtype 2. Proc. Natl Acad. Sci USA 95, 10836–10841 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Yang, L. et al. Spiro[1H-indene-1,4'-piperidine] derivatives as potent and selective non–peptide human somatostatin receptor subtype 2 (sst2) agonists. J. Med. Chem. 41, 2175–2179 (1998).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to acknowledge the contributions by Drs B. Stolz, C. Nunn, G. Schettini and L. Roth.

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Authors and Affiliations

  1. Transplantation and Immunology, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, CH-4002, Switzerland

    Gisbert Weckbecker, Ian Lewis, Rainer Albert, Herbert A. Schmid, Daniel Hoyer & Christian Bruns

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  1. Gisbert Weckbecker
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  2. Ian Lewis
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  3. Rainer Albert
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  4. Herbert A. Schmid
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Correspondence to Gisbert Weckbecker.

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Competing interests

The authors work for Novartis, which produces and/or markets a number of the products mentioned in this review, including octreotide and SOM230.

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DATABASES

LocusLink

Cholecystokinin

cortistatin

gastrin

glucagon

growth hormone

growth hormone secretagogue receptor

insulin

secretin

sst1

sst2

sst3

sst4

sst5

VIP

Online Mendelian Inheritance in Man

Acromegaly

inflammatory bowel disease

multiple sclerosis

rheumatoid arthritis

psoriasis

FURTHER INFORMATION

Acromegaly

Gastroenteropancreatic (neuroendocrine) tumours

Glossary

PHARMACOPHORE

The ensemble of steric and electronic features that are necessary to ensure optimal interactions with a specific biological target structure and to trigger (or to block) its biological response.

ACROMEGALY

Chronic over-production of growth hormone, leading to metabolic changes and enlargement of, for example, hands, feet and inner organs.

M CURRENT

Voltage-dependent potassium conductance which regulates neuronal excitibility and is inhibited by muscarine.

PERIAQUEDUCTAL GREY MATTER

Brainstem region essential in the regulation of pain.

CUSHING'S DISEASE

Endocrine disorder caused by elevated cortisol levels due to excessive adrenocorticotropin hormone production.

GRAVES' DISEASE

Excessive functional activity of the thyroid gland due to auto-immune disease involving antibody formation against thyroid-stimulating hormone receptors.

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Weckbecker, G., Lewis, I., Albert, R. et al. Opportunities in somatostatin research: biological, chemical and therapeutic aspects. Nat Rev Drug Discov 2, 999–1017 (2003). https://doi.org/10.1038/nrd1255

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