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Antagonists of growth-hormone-releasing hormone: an emerging new therapy for cancer

Nature Clinical Practice Endocrinology & Metabolism volume 4, pages 33–43 (2008)Cite this article

Abstract

This article reviews the potential clinical uses of antagonists of growth-hormone-releasing hormone (GHRH) for tumor therapy. GHRH antagonists suppress the growth of various human cancer lines xenografted into nude mice; such tumors include breast, ovarian, endometrial and prostate cancers, lung cancers (small-cell lung carcinomas and non-small-cell lung carcinomas), renal, pancreatic, gastric and colorectal carcinomas, brain tumors (malignant gliomas), osteogenic sarcomas and non-Hodgkin's lymphomas. The antitumor effects of GHRH antagonists are exerted in part indirectly through the inhibition of the secretion of GH from the pituitary and the resulting reduction in the levels of hepatic insulin-like growth factor I (IGF-I). The main effects of the GHRH antagonists are, however, exerted directly on tumors. GHRH ligand is present in various human cancers and might function as an autocrine and/or paracrine growth factor. Pituitary-type GHRH receptors and their splice variants are also found in many human cancers. The inhibitory effects of GHRH antagonists seem to be due to the blockade of action of tumoral GHRH. Antagonists of GHRH can also suppress cancer growth by blocking production of IGF-I and/or IGF-II by the tumor. Further development of GHRH antagonists that are still-more potent should lead to potential therapeutic agents for various cancers.

Key Points

  • The presence of growth-hormone-releasing hormone (GHRH) ligand has been demonstrated in various cancers, suggesting that GHRH could be an autocrine growth factor

  • GHRH antagonists inhibit the growth of various human cancer lines xenografted into nude mice; such lines include breast cancers, prostate cancers, small cell lung carcinomas (SCLC) and non-SCLC, malignant gliomas, renal cell carcinomas, pancreatic cancers, colorectal carcinomas and lymphomas

  • Splice variants of GHRH receptors and pituitary-type GHRH receptors that might mediate effects of tumoral GHRH and of GHRH antagonists have been demonstrated in many human cancers

  • GHRH antagonists seem to be devoid of major adverse effects, which would offer a distinct advantage over other classes of antitumor agents

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Figure 1: Comparative structures of the bioactive amino-terminal 29-amino-acid core fragment of human growth-hormone-releasing hormone—hGHRH(1–29)NH2—and early antagonists of GHRH that were synthesized.
Figure 2: Comparative structures of the most potent antagonists of human growth-hormone-releasing hormone (hGHRH).
Figure 3: Schematic representation of the three potential mechanisms through which growth-hormone-releasing hormone (GHRH) antagonists mediate the inhibition of tumor growth.

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References

  1. Schally AV et al. (1965) Effect of hypothalamic extracts on release of growth hormone in vitro . Proc Soc Exp Biol Med 119: 208–212

    CAS  PubMed  Google Scholar 

  2. Krulich L et al. (1968) Stimulatory and inhibitory effects of purified hypothalamic extracts on growth hormone release from rat pituitary in vitro . Endocrinology 83: 783–790

    CAS  PubMed  Google Scholar 

  3. Frohman LA and Szabo M (1981) Ectopic production of growth hormone-releasing factor by carcinoid and pancreatic islet tumors associated with acromegaly. Prog Clin Biol Res 74: 259–271

    CAS  PubMed  Google Scholar 

  4. Guillemin R et al. (1982) Growth hormone-releasing factor from a human pancreatic tumor that caused acromegaly. Science 218: 585–587

    CAS  PubMed  Google Scholar 

  5. Rivier J et al. (1982) Characterization of a growth hormone-releasing factor from a human pancreatic islet tumor. Nature 300: 276–278

    CAS  PubMed  Google Scholar 

  6. Muller EE et al. (1999) Neuroendocrine control of growth hormone secretion. Physiol Rev 79: 511–607

    CAS  PubMed  Google Scholar 

  7. Gelato MC (1994) Growth hormone-releasing hormone: clinical perspectives. Endocrinologist 4: 64–68

    Google Scholar 

  8. Bagnato A et al. (1992) Expression of the growth hormone-releasing hormone gene and its peptide product in the rat ovary. Endocrinology 130: 1097–1102

    CAS  PubMed  Google Scholar 

  9. Chatzistamou I et al. (2004) Immunohistochemical detection of growth hormone-releasing hormone and its receptor splice variant 1 in primary human breast cancers. Eur J Endocrinol 151: 391–396

    CAS  PubMed  Google Scholar 

  10. Freddi S et al. (2005) Expression of growth hormone-releasing hormone receptor splicing variants in human primary adrenocortical tumours. Clin Endocrinol 62: 533–538

    CAS  Google Scholar 

  11. Halmos G et al. (2002) Expression of growth hormone-releasing hormone and its receptor splice variants in human prostate cancer. J Clin Endocrinol Metab 87: 4707–4714

    CAS  PubMed  Google Scholar 

  12. Kahan Z et al. (1999) Expression of growth hormone-releasing hormone (GHRH) messenger ribonucleic acid and the presence of biologically active GHRH in human breast, endometrial, and ovarian cancers. J Clin Endocrinol Metab 84: 582–589

    CAS  PubMed  Google Scholar 

  13. Khorram O et al. (2001) Human uterine and ovarian expression of growth hormone-releasing hormone messenger RNA in benign and malignant gynecologic conditions. Fertil Steril 75: 174–179

    CAS  PubMed  Google Scholar 

  14. Busto R et al. (2002) The expression of growth hormone-releasing hormone (GHRH) and splice variants of its receptor in human gastroenteropancreatic carcinomas. Proc Natl Acad Sci U S A 99: 11866–11871

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Busto R et al. (2002) Expression of mRNA for growth hormone-releasing hormone and splice variants of GHRH receptors in human malignant bone tumors. Regul Pept 108: 47–53

    CAS  PubMed  Google Scholar 

  16. Chopin LK and Herington AC (2001) A potential autocrine pathway for growth hormone releasing hormone (GHRH) and its receptor in human prostate cancer cell lines. Prostate 49: 116–121

    CAS  PubMed  Google Scholar 

  17. Engel JB et al. (2005) Inhibition of growth of experimental human endometrial cancer by an antagonist of growth hormone-releasing hormone. J Clin Endocrinol Metab 90: 3614–3621

    CAS  PubMed  Google Scholar 

  18. Garcia-Fernandez MO et al. (2003) The expression of growth hormone-releasing hormone (GHRH) and its receptor splice variants in human breast cancer lines; the evaluation of signaling mechanisms in the stimulation of cell proliferation. Breast Cancer Res Treat 77: 15–26

    CAS  PubMed  Google Scholar 

  19. Kanashiro CA et al. (2003) Inhibition of mutant P53 expression and growth of DMS-153 small cell lung carcinoma by antagonists of growth hormone-releasing hormone and bombesin. Proc Natl Acad Sci U S A 100: 15836–15841

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Havt A et al. (2005) The expression of the pituitary GHRH receptor and its splice variants in normal and neoplastic human tissues. Proc Natl Acad Sci U S A 102: 17424–17429

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Keller G et al. (2005) Effective treatment of experimental human non Hodgkin's lymphomas with antagonists of growth hormone-releasing hormone. Proc Natl Acad Sci U S A 102: 10628–10633

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Khorram O et al. (2001) The influence of aging and sex hormones on expression of growth hormone-releasing hormone in the human immune system. J Clin Endocrinol Metab 86: 3157–3161

    CAS  PubMed  Google Scholar 

  23. Kiaris H et al. (1999) Growth hormone-releasing hormone: an autocrine growth factor for small cell lung carcinoma. Proc Natl Acad Sci U S A 96: 14894–14898

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Plonowski A et al. (2002) Expression of growth hormone-releasing hormone (GHRH) and splice variants of GHRH receptors in human experimental prostate cancers. Peptides 23: 1127–1133

    CAS  PubMed  Google Scholar 

  25. Szereday Z et al. (2003) Antagonists of growth hormone-releasing hormone inhibit the proliferation of experimental non-small cell lung carcinoma. Cancer Res 63: 7913–7919

    CAS  PubMed  Google Scholar 

  26. Losa M et al. (1990) Presence of growth hormone-releasing hormone-like immunoreactivity in human tumors: characterization of immunological and biological properties. J Clin Endocrinol Metab 70: 62–68

    CAS  PubMed  Google Scholar 

  27. Kiaris H et al. (2003) Ligand-dependent and -independent effects of splice variant 1 of growth hormone-releasing hormone receptor. Proc Nat Acad Sci U S A 100: 9512–9517

    CAS  Google Scholar 

  28. Schally AV and Varga JL (1999) Antagonistic analogs of growth hormone-releasing hormone: new potential antitumor agents. Trends Endocrinol Metab 10: 383–391

    CAS  PubMed  Google Scholar 

  29. Rekasi Z et al. (2000) Isolation and sequencing of cDNAs for splice variants of growth hormone-releasing hormone receptors from human cancers. Proc Natl Acad Sci U S A 97: 10561–10566

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Kiaris H et al. (2005) Extrapituitary effects of the growth hormone-releasing hormone. In Vitamins and Hormones, 1–24 (Ed. Litwack G) Amsterdam: Elsevier

    Google Scholar 

  31. Toller GL et al. (2004) Development of a polyclonal antiserum for the detection of the isoforms of the receptors for human growth hormone-releasing hormone on tumors. Proc Natl Acad Sci U S A 101: 15160–15165

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Halmos G et al. (2000) Human renal cell carcinoma expresses distinct binding sites for growth hormone-releasing hormone. Proc Natl Acad Sci U S A 97: 10555–10560

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Kanashiro CA et al. (2007) Alterations of EGFR/HER, angiogenesis and apoptosis pathways after therapy with antagonists of growth hormone releasing hormone and bombesin in non-small cell lung cancer. Int J Oncol 30: 1019–1028

    CAS  PubMed  Google Scholar 

  34. Chatzistamou I et al. (2001) Inhibition of growth and metastases of MDA-MB-435 human estrogen-independent breast cancers by an antagonist of growth hormone-releasing hormone. Anticancer Drugs 12: 761–768

    CAS  PubMed  Google Scholar 

  35. Kiaris H et al. (2000) Antagonists of growth hormone-releasing hormone inhibit the growth of U-87MG human glioblastoma in nude mice. Neoplasia 2: 242–250

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Schulz S et al. (2006) Immunocytochemical localisation of plasma membrane GHRH receptors in human tumours using a novel anti-peptide antibody. Eur J Cancer 42: 2390–2396

    CAS  PubMed  Google Scholar 

  37. Barabutis N et al. (2007) Ligand dependent and independent stimulation of proliferation of MCF-7 breast cancer cells by a splice variant of growth hormone releasing hormone receptor. Proc Natl Acad Sci U S A 104: 5575–5579

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Westley BR and May FEB (1995) Insulin-like growth factors: the unrecognized oncogenes. Br J Cancer 72: 1065–1066

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Toretsky JA and Helman LJ (1996) Involvement of IGF-II in human cancer. J Endocrinol 149: 367–372

    CAS  PubMed  Google Scholar 

  40. Pollak MN et al. (1990) Insulin-like growth factor I: a potent mitogen for human osteogenic sarcoma. J Natl Cancer Inst 82: 301–305

    CAS  PubMed  Google Scholar 

  41. Pollak M et al. (1992) Inhibition of metastatic behavior of murine osteosarcoma by hypophysectomy. J Natl Cancer Inst 84: 966–971

    CAS  PubMed  Google Scholar 

  42. Robberecht P et al. (1985) Structural requirements for the activation of rat anterior pituitary adenylate cyclase by growth hormone-releasing factor (GRF): discovery of (N-Ac-Tyr1, D-Arg2)-GRF(1-29)-NH2 as a GRF antagonist on membranes. Endocrinology 117: 1759–1764

    CAS  PubMed  Google Scholar 

  43. Zarandi M et al. (1994) Synthesis and biological activities of highly potent antagonists of growth hormone-releasing hormone. Proc Natl Acad Sci U S A 91: 12298–12302

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Zarandi M et al. (1997) Synthesis and in vitro evaluation of new potent antagonists of growth hormone-releasing hormone (GH-RH). Peptides 18: 423–430

    CAS  PubMed  Google Scholar 

  45. Schally AV and Varga JL (2006) Antagonists of growth hormone-releasing hormone in oncology. Comb Chem High Throughput Screen 9: 163–170

    CAS  PubMed  Google Scholar 

  46. Varga JL and Schally AV (2006) Analogues of growth hormone-releasing hormone (GH-RH) in cancer. In Handbook of Peptides, 483–489 (Ed. Kastin A) London: Elsevier

    Google Scholar 

  47. Kovács M et al. (1997) Inhibition of GH release in rats by new potent antagonists of growth hormone-releasing hormone (GH-RH). Peptides 18: 431–438

    PubMed  Google Scholar 

  48. Varga JL et al. (1999) Synthesis and biological evaluation of antagonists of growth hormone-releasing hormone with high and protracted in vivo activities. Proc Natl Acad Sci U S A 96: 692–697

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Varga JL et al. (2004) Increased activity of antagonists of growth hormone-releasing hormone substituted at positions 8, 9 and 10. Proc Natl Acad Sci U S A 101: 1708–1713

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Zarandi M et al. (2006) Lipopeptide antagonists of growth hormone-releasing hormone with improved antitumor activities. Proc Natl Acad Sci U S A 103: 4610–4615

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Buchholz S et al. (2007) Potentiation of mammary cancer inhibition by combination of antagonists of growth hormone-releasing hormone with docetaxel. Proc Natl Acad Sci U S A 104:1943–1946

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Stangelberger A et al. (2007) The combination of antagonists of LHRH with antagonists of GHRH improves inhibition of androgen sensitive MDA-PCa-2b and LuCaP-35 prostate cancers. Prostate 67: 1339–1353

    CAS  PubMed  Google Scholar 

  53. Stangelberger A et al. (2005) Antagonists of growth hormone releasing hormone (GHRH) and of bombesin/gastrin releasing peptide (BN/GRP) suppress the expression of VEGF, bFGF, and EGF/HER receptors in PC-3 and DU-145 human androgen-independent prostate cancers. Prostate 64: 303–315

    CAS  PubMed  Google Scholar 

  54. Stangelberger A (2005) Inhibitory effect of antagonists of bombesin and growth hormone-releasing hormone on orthotopic and intraosseous growth and invasiveness of PC-3 human prostate cancer in nude mice. Clin Cancer Res 11: 49–57

    CAS  PubMed  Google Scholar 

  55. Csernus VJ et al. (1999) Inhibition of growth, production of insulin-like growth factor-II (IGF-II), and expression of IGF-II mRNA of human cancer cell lines by antagonistic analogs of growth hormone-releasing hormone in vitro . Proc Natl Acad Sci U S A 96: 3098–3103

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Braczkowski R et al. (2002) Inhibition of proliferation in human MNNG/HOS osteosarcoma and SK-ES-1 Ewing's sarcoma cell lines in vitro and in vivo by antagonists of growth hormone-releasing hormone: effects on IGF-II. Cancer 95: 1735–1745

    CAS  PubMed  Google Scholar 

  57. Letsch M et al. (2004) Antagonists of growth hormone-releasing hormone (GH-RH) enhance tumor growth inhibition induced by androgen deprivation in human MDA-PCa-2b prostate cancers. Eur J Cancer 40: 436–444

    CAS  PubMed  Google Scholar 

  58. Szepeshazi K et al. (2001) Antagonists of GHRH decrease production of GH and IGF-I in MXT mouse mammary cancers and inhibit tumor growth. Endocrinology 142: 4371–4378

    CAS  PubMed  Google Scholar 

  59. Letsch M et al. (2003) Growth hormone-releasing hormone (GH-RH) antagonists inhibit the proliferation of androgen- dependent and -independent prostate cancers. Proc Nat Acad Sci U S A 100: 1250–1255

    CAS  Google Scholar 

  60. Hohla F et al. (2006) Synergistic inhibition of growth of lung carcinomas by antagonists of growth hormone-releasing hormone in combination with docetaxel. Proc Natl Acad Sci U S A 103: 14513–14518

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Chatzistamou I et al. (2001) Antagonists of growth hormone-releasing hormone and somatostatin analog RC-160 inhibit the growth of the OV-1063 human epithelial ovarian cancer cell line xenografted into nude mice. J Clin Endocrinol Metab 86: 2144–2152

    CAS  PubMed  Google Scholar 

  62. Pinski J et al. (1996) Inhibition of growth of human small-cell and non-small-cell lung carcinomas by antagonists of growth hormone-releasing hormone (GH-RH). Int J Oncol 9: 1099–1105

    CAS  PubMed  Google Scholar 

  63. Szepeshazi K et al. (2000) Antagonists of growth hormone-releasing hormone (GH-RH) inhibit in vivo proliferation of experimental pancreatic cancers and decrease IGF-II levels in tumors. Eur J Cancer 36: 128–136

    CAS  PubMed  Google Scholar 

  64. Szepeshazi K et al. (2000) Antagonists of growth hormone-releasing hormone (GH-RH) inhibit IGF-II production and growth of HT-29 human colon cancers. Brit J Cancer 82: 1724–1731

    CAS  PubMed  Google Scholar 

  65. Jaffe CA et al. (1993) Suppression of growth hormone (GH) secretion by a selective GH-releasing hormone (GHRH) antagonist. Direct evidence for involvement of endogenous GHRH in the generation of GH pulses. J Clin Invest 92: 695–701

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Hanew K et al. (1996) Plasma GH responses to human GHRH-antagonist in normal subjects. Eur J Endocrinol 134: 67–72

    CAS  PubMed  Google Scholar 

  67. Ocampo-Lim B et al. (1996) Nocturnal growth hormone (GH) secretion is eliminated by infusion of GH-releasing hormone antagonist. J Clin Endocrinol Metab 81: 4396–4399

    CAS  PubMed  Google Scholar 

  68. Hanew K et al. (1996) The inhibitory effects of growth hormone-releasing hormone (GHRH)-antagonist on GHRH, L-DOPA, and clonidine-induced GH secretion in normal subjects. J Clin Endocrinol Metab 81: 1952–1955

    CAS  PubMed  Google Scholar 

  69. Russell-Aulet M et al. (1999) In vivo semiquantification of hypothalamic growth hormone-releasing hormone (GHRH) output in humans: evidence for relative GHRH deficiency in aging. J Clin Endocrinol Metab 84: 3490–3497

    CAS  PubMed  Google Scholar 

  70. Orrego JJ et al. (2001) Semiquantification of hypothalamic GH-releasing hormone output in women: evidence for sexual dimorphism in the mechanism of the somatopause. J Clin Endocrinol Metab 86: 5485–5490

    CAS  PubMed  Google Scholar 

  71. Jessup SK et al. (2003) Sexual dimorphism of growth hormone (GH) regulation in humans: endogenous GH-releasing hormone maintains basal GH in women but not in men. J Clin Endocrinol Metab 88: 4776–4780

    CAS  PubMed  Google Scholar 

  72. Jessup SK et al. (2004) Blockade of endogenous growth hormone-releasing hormone receptors dissociates nocturnal growth hormone secretion and slow-wave sleep. Eur J Endocrinol 151: 561–566

    CAS  PubMed  Google Scholar 

  73. Jaffe CA et al. (1996) Endogenous growth hormone (GH)-releasing hormone is required for GH responses to pharmacological stimuli. J Clin Invest 97: 934–940

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Jaffe CA et al. (1997) Suppression of growth hormone (GH) hypersecretion due to ectopic GH-releasing hormone (GHRH) by a selective GHRH antagonist. J Clin Endocrinol Metab 82: 634–637

    CAS  PubMed  Google Scholar 

  75. Dimaraki EV et al. (2006) The role of endogenous growth hormone-releasing hormone in acromegaly. J Clin Endocrinol Metab 91: 2185–2190

    CAS  PubMed  Google Scholar 

  76. Gelato M (2005) Growth hormone releasing hormone: clinical perspectives revisited. Endocrinologist 15: 159–164

    CAS  Google Scholar 

  77. Smith LE et al. (1997) Essential role of growth hormone in ischemia-induced retinal neovascularization. Science 276: 1706–1709

    CAS  Google Scholar 

  78. Reddy GR et al. (2007) Identification of the glomerular podocyte as a target for growth hormone action. Endocrinology 148: 2045–2055

    CAS  PubMed  Google Scholar 

  79. Stephanou A et al. (1991) Production of a growth hormone-releasing hormone-like peptide and its mRNA by human lymphocytes. Neuroendocrinology 53: 628–633

    CAS  PubMed  Google Scholar 

  80. Guarcello V et al. (1991) Growth hormone releasing hormone receptors on thymocytes and splenocytes from rats. Cell Immunol 136: 291–302

    CAS  PubMed  Google Scholar 

  81. Khorram O et al. (1997) Effects of [norleucine27] growth hormone-releasing hormone (GHRH) (1-29)-NH2 administration on the immune system of aging men and women. J Clin Endocrinol Metab 82: 3590–3596

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. USA and Distinguished Professor at the Department of Pathology and Department of Medicine, Division of Hematology-Oncology, AV Schally is Chief of the Endocrine, Polypeptide and Cancer Institute at the Veterans Affairs Medical Center, Miami, FL, University of Miami Miller School of Medicine.,

    Andrew V Schally

  2. JL Varga is Research Associate Professor at the Department of Medicine, Division of Hematology-Oncology, University of Miami Miller School of Medicine, Wurzburg, Germany.,

    Jozsef L Varga

  3. JB Engel is associated with the Medical University of Wurzburg, Wurzburg, Germany.,

    Jörg B Engel

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  1. Andrew V Schally
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Correspondence to Andrew V Schally.

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Schally, A., Varga, J. & Engel, J. Antagonists of growth-hormone-releasing hormone: an emerging new therapy for cancer. Nat Rev Endocrinol 4, 33–43 (2008). https://doi.org/10.1038/ncpendmet0677

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