Down-regulation and change in subcellular distribution of receptors for luteinizing hormone-releasing hormone in OV-1063 human epithelial ovarian cancers during therapy with LH-RH antagonist Cetrorelix

Int J Oncol. 2000 Aug;17(2):367-73. doi: 10.3892/ijo.17.2.367.


The inhibition of growth of various hormone-dependent cancers by analogs of luteinizing hormone-releasing hormone (LH-RH) may be exerted in part through receptors for LH-RH present on tumor cells, but the direct mode of action of LH-RH agonists and antagonists is still not completely understood. The aim of this study was to investigate the effects of agonist [D-Trp6]LH-RH and antagonist Cetrorelix, administered s.c. at a dose of 100 microg/day for 3 weeks on the binding characteristics and subcellular localization of receptors for LH-RH in OV-1063 human epithelial ovarian cancers xenografted into nude mice. Using radioligand binding studies, following in vitro desaturation, we demonstrated the presence of specific, high affinity binding sites for LH-RH in both cell membrane and nuclear fraction of OV-1063 tumors. Treatment with Cetrorelix, but not [D-Trp6]LH-RH, caused about 60% reduction (p<0. 01) in tumor volume and weight. [D-Trp6]LH-RH decreased the number of LH-RH receptors on OV-1063 tumor membranes by 44% after 14 days (p<0.01), and the concentration of receptors remained at that level on day 21. The maximal binding capacity of receptors for LH-RH in the nuclei was significantly higher (p<0.05) after 3 weeks of treatment with [D-Trp6]LH-RH. Cetrorelix decreased the concentration of membrane receptors for LH-RH by 53% (p<0.01) after 14 days and the levels on day 21 were even lower, showing a 70% reduction (p<0. 01). In contrast, the number of LH-RH binding sites in the nuclear pellet was significantly increased (p<0.01) by Cetrorelix at that time. Our results demonstrate for the first time that the down-regulation of LH-RH receptors on the cell membranes of OV-1063 human ovarian cancers after therapy with antagonist Cetrorelix or agonist [D-Trp6]LH-RH is associated with an increase in receptor concentration in the nuclei. These phenomena could be related to the internalization and subcellular translocation of receptors in these tumor cells.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenocarcinoma, Papillary / drug therapy*
  • Adenocarcinoma, Papillary / metabolism
  • Animals
  • Antineoplastic Agents, Hormonal / therapeutic use*
  • Down-Regulation
  • Drug Screening Assays, Antitumor
  • Female
  • Gonadotropin-Releasing Hormone / analogs & derivatives*
  • Gonadotropin-Releasing Hormone / pharmacokinetics
  • Gonadotropin-Releasing Hormone / therapeutic use
  • Hormone Antagonists / pharmacokinetics
  • Hormone Antagonists / therapeutic use*
  • Humans
  • Mice
  • Mice, Nude
  • Middle Aged
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / metabolism
  • Receptors, LHRH / drug effects*
  • Receptors, LHRH / metabolism
  • Triptorelin Pamoate / therapeutic use*
  • Tumor Cells, Cultured


  • Antineoplastic Agents, Hormonal
  • Hormone Antagonists
  • Receptors, LHRH
  • Triptorelin Pamoate
  • Gonadotropin-Releasing Hormone
  • cetrorelix