title: Novel antagonists of growth hormone-releasing hormone inhibit growth and vascularization of human experimental ovarian cancers.
abstract: BACKGROUND
  Antagonists of growth hormone-releasing hormone (GHRH) inhibit the proliferation of various human cancer cell lines and experimental tumors by mechanisms that include direct action on GHRH receptors in cancer cells.
  
  
  METHODS
  In this study, the effects of newly synthesized GHRH antagonists, MIA-313, MIA-602, MIA-604, and MIA-610, were investigated in 2 human ovarian epithelial adenocarcinoma cell lines, OVCAR-3 and SKOV-3, in vitro and in vivo. The expression of receptors for GHRH was demonstrated by Western blot analysis and ligand competition methods in the OVCAR-3 and SKOV-3 cell lines and in tumors from those cells grown in athymic nude mice. The effects of GHRH antagonists on the secretion of vascular endothelial growth factor (VEGF) by OVCAR-3 cells and on the vascularization of OVCAR-3 xenografts also were evaluated.
  
  
  RESULTS
  Both the pituitary and the splice variant type 1 (SV1) GHRH receptors were detected in the 2 cell lines and in tumor xenografts, and SV1 was expressed at higher levels. Cell viability assays revealed the antiproliferative effect of all GHRH antagonists that were. Maximal tumor growth inhibition was approximately 75% in both models. MIA-313 and MIA-602 decreased VEGF secretion of OVCAR-3 cells, as measured by enzyme-linked immunosorbent assay, and reduced tumor vascularization in a Matrigel plug assay, but caused no change in the expression of VEGF or VEGF receptor in the terminal ileum of mice with OVCAR-3 tumors.
  
  
  CONCLUSIONS
  Results from the current study indicated that a he novel approach based on GHRH antagonists may offer more effective therapeutic alternatives for patients with advanced ovarian cancer and who do not tolerate conventional anti-VEGF therapy.
authors.affiliation: Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education, Miami, Florida, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Klukovits
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Schally
authors.forename: Luca
authors.initials: L
authors.lastname: Szalontay
authors.forename: Irving
authors.initials: I
authors.lastname: Vidaurre
authors.forename: Andrea
authors.initials: A
authors.lastname: Papadia
authors.forename: Marta
authors.initials: M
authors.lastname: Zarandi
authors.forename: Jozsef L
authors.initials: JL
authors.lastname: Varga
authors.forename: Norman L
authors.initials: NL
authors.lastname: Block
authors.forename: Gabor
authors.initials: G
authors.lastname: Halmos
mesh_terms: D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D013007:Growth Hormone-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D010051:Ovarian Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology; D017337:Sermorelin / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C550121:GHRH(1-29)NH2, (PhAc-Ada)(0)-Tyr(1), Arg(2), Fpa(5,6), Ala(8), Har(9), Tyr(Me)(10), His(11), Orn(12,) Abu(15), His(20), Orn(21), Nle(27), Arg(28), Har(29)-; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D017337:Sermorelin; D013007:Growth Hormone-Releasing Hormone