title: High affinity binding and direct antiproliferative effects of luteinizing hormone-releasing hormone analogs in human endometrial cancer cell lines.
abstract: Although specific binding sites for LH-releasing hormone (LHRH) and its analogs have been demonstrated in biopsy samples of human endometrial cancer, their biological significance remains obscure. In this study we evaluated whether binding sites for LHRH are also present in the human endometrial cancer cell lines HEC-1A and Ishikawa and if such sites could mediate antiproliferative effects of LHRH analogs. Using [125I,D-Trp6]LHRH as a ligand, a high affinity/low capacity binding site was detected in both lines: HEC-1A line, dissociation constant (Kd)1 = 5.7 x 10(-9) mol/L, binding capacity (Bmax)1 = 78 fmol/10(6) cells; Ishikawa line, Kd1 = 4.2 x 10(-9) mol/L, Bmax1 = 29 fmol/10(6) cells. In addition, a second class of low affinity/high capacity binding sites for LHRH was demonstrated (HEC-1A line, Kd2 = 1.4 x 10(-6) mol/L, Bmax2 = 21 pmol/10(6) cells; Ishikawa, Kd2 = 4 x 10(-6) mol/L, Bmax2 = 32 pmol/10(6) cells). In the presence of 10(-5) mol/L agonist [D-Trp6]LHRH (triptorelin), the proliferation of HEC-1A and Ishikawa cell lines was significantly reduced to 76 +/- 2% and 88 +/- 4% of controls, respectively, after 24 h and to 64 +/- 2% and 62 +/- 2%, respectively, after 6 days. Dose-response experiments showed that lower concentrations (10(-9) mol/L) of the agonist decreased the proliferation to 80 +/- 1% for the HEC-1A line and 71 +/- 2% of controls for the Ishikawa line after 6 days. Antiproliferative effects are enhanced by increasing the doses of triptorelin and were maximal in this series of experiments at 10(-5) mol/L, the proliferation in the HEC-1A line being 62 +/- 1% and in the Ishikawa line 52 +/- 2% of controls, respectively. Similar time- and dose-dependent antiproliferative effects were obtained in both cell lines with the LHRH antagonist SB-75 (cetrorelix). These data suggest that LHRH analogs can directly inhibit the proliferation of human endometrial cancer cells in vitro. This direct action could be mediated through the high affinity LHRH binding sites.
authors.affiliation: Department of Obstetrics and Gynecology, Philipps University, Marburg, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Emons
authors.forename: B
authors.initials: B
authors.lastname: Schröder
authors.forename: O
authors.initials: O
authors.lastname: Ortmann
authors.forename: S
authors.initials: S
authors.lastname: Westphalen
authors.forename: K D
authors.initials: KD
authors.lastname: Schulz
authors.forename: A V
authors.initials: AV
authors.lastname: Schally
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008969:Molecular Sequence Data; D017329:Triptorelin Pamoate / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
chemical_list: D017329:Triptorelin Pamoate; D007987:Gonadotropin-Releasing Hormone; C062876:cetrorelix