Endocrine and antineoplastic actions of growth hormone-releasing hormone antagonists

Magdolna Kovács, Andrew V. Schally, József L. Varga, Márta Zarándi

Research output: Contribution to journalReview articlepeer-review

17 Scopus citations

Abstract

Potent antagonists of growth hormone-releasing hormone (GHRH) have been developed for the treatment of disorders caused by excessive GHRH or growth hormone (GH) production and or therapy of cancers. GHRH antagonists suppressed the release of GH and insulin-like growth factor (IGF)-I in transgenic mice overexpressing human (h) GHRH gene, an animal model of human acromegaly. It was also shown in GH3 rat pituitary tumor cells overexpressing the human pituitary GHRH receptor (pGHRH-R) that GHRH antagonists can inhibit c-AMP production and GH secretion through the human receptor. These observations indicate that GHRH antagonists could be used clinically in disorders characterized by excessive GHRH/GH secretion. Many recent studies demonstrate that GHRH antagonists can inhibit tumor growth by several mechanisms. By indirect action through pGHRH-Rs these antagonists suppress circulating GH/IGF-I level, which results in the inhibition of cancers that depend on GH and/or IGF-I as growth factors. However, GHRH antagonists are also effective inhibitors of tumor IGF-II production, which is a potent mitogen but independent of GH. GHRH antagonists can inhibit tumor cell proliferation by direct action on tumor cell receptors, suppressing the IGF-II and other growth factor production of tumor cells. In addition, various human tumors and tumor cell lines secrete GHRH peptide and respond to GHRH with proliferation. This finding suggests that GHRH functions as an autocrine growth factor and that GHRH antagonists can block its effects on tumor growth. Recently, we demonstrated the expression of hGHRH-R and its splice variants in various human cancers. Antiprofiferative action of GHRH antagonists on these cancers indicates that the direct inhibitory effects of GHRH antagonists are mediated by tumoral GHRH receptors.

Original languageEnglish (US)
Pages (from-to)314-321
Number of pages8
JournalCurrent medicinal chemistry
Volume15
Issue number4
DOIs
StatePublished - Feb 1 2008

Keywords

  • Antagonistic analogs
  • Anti-cancer
  • Cell proliferation
  • Growth hormone (GH)
  • Inhibition
  • Insulin like growth factor (IGF)
  • Oncogene
  • Tumor growth

ASJC Scopus subject areas

  • Organic Chemistry
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Pharmacology

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