title: 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.
abstract: 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.
authors.affiliation: Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center and Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112-2699, USA.
authors.forename: G
authors.initials: G
authors.lastname: Halmos
authors.forename: A V
authors.initials: AV
authors.lastname: Schally
authors.forename: Z
authors.initials: Z
authors.lastname: Kahan
mesh_terms: D000231:Adenocarcinoma, Papillary / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D015536:Down-Regulation; D004354:Drug Screening Assays, Antitumor; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006727:Hormone Antagonists / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011966:Receptors, LHRH / Q000187:drug effects* / Q000378:metabolism; D017329:Triptorelin Pamoate / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
chemical_list: D018931:Antineoplastic Agents, Hormonal; D006727:Hormone Antagonists; D011966:Receptors, LHRH; D017329:Triptorelin Pamoate; D007987:Gonadotropin-Releasing Hormone; C062876:cetrorelix