This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Emons, G. Articles by Schally, A. V. Search for Related Content PubMed PubMed Citation Articles by Emons, G. Articles by Schally, A. V.

High Affinity Binding and Direct Antiproliferative Effects of LHRH Analogues in Human Ovarian Cancer Cell Lines^{1 ,2}

Department of Obstetrics and Gynecology [G. E., O. O., M. B., G. I., B. S., R. L., K-D. S.], Philipps University, D-3550 Marburg, Germany; Departments of Physiological Chemistry and Obstetrics and Gynecology [F. H.], University of Hamburg, D-2000 Hamburg, Germany, and Endocrine, Polypeptide and Cancer Institute [A. V. S.], Veterans Administration Medical Center and Tulane University School of Medicine, New Orleans, Louisiana 70146

Recently, specific binding sites for luteinizing hormone releasing hormone (LHRH) and its analogues have been demonstrated in biopsy samples of human epithelial ovarian cancer. Their biological significance remained obscure. In this study we ascertained whether such LHRH-binding sites are also present in the human epithelial ovarian cancer cell lines EFO-21 and EFO-27 and if they could mediate antiproliferative effects of LHRH analogues. Using [¹²⁵I, D-Trp⁶]LHRH, a high affinity/low capacity binding site was detected in both lines: EFO-21 (Kd₁ = 1.5 x 10^-9 M; binding capacity (Bmax₁) = 4.9 fmol/10⁶ cells) and EFO-27 (Kd₁ = 1.7 x 10^-9 M; Bmax₁ = 3 fmol/10⁶ cells). In addition, a second class of low affinity/high capacity binding sites (EFO-21: Kd₂ = 7.5 x 10^-6 M; Bmax₂ = 24 pmol/10⁶ cells; EFO-27: Kd₂ = 4.3 x 10^-6 M; Bmax₂ = 14.5 pmol/10⁶ cells) was demonstrated. Specific binding of [¹²⁵I, D-Trp⁶]LHRH was displaced with nearly equal efficiency by unlabeled [D-Trp⁶]LHRH, the LHRH-antagonists SB-75 and Hoe-013, and by native LHRH but not by unrelated peptides such as oxytocin and somatostatin. In the presence of 10^-5 M agonist [D-Trp⁶]LHRH, the proliferation of both cell lines was significantly reduced to 77% of controls after 24 h and to approx. 60% after 6 days. Lower concentrations (10^-9 M) of the agonist, significantly decreased the proliferation to 87.5% for EFO-21 and 86% for EFO-27 after 6 days. These antiproliferative effects were enhanced by increasing doses of [D-Trp⁶]LHRH and were maximal at 10^-5 M (EFO-21: 65.5% of control, EFO-27: 68% of control). Similar dose-dependent antiproliferative effects were obtained in EFO-21 line with the LHRH-antagonists SB-75 and Hoe-013, while these analogues had no effects on the proliferation of EFO-27 cells. SB-75 partly antagonized the antiproliferative effect of [D-Trp⁶]LHRH in a dose dependent way in the EFO-27 line. These data suggest that LHRH analogues can directly inhibit the in vitro proliferation of human ovarian cancer cells. This effect might be mediated through the high affinity LHRH binding sites.

¹ Dedicated to Professor Dr. H. Maass, President of the German Cancer Society, on the occasion of his 65th birthday.

² This study was supported by the foundations P. E. Kempkes and A. and U. Kulemann, Marburg, by Ferring Arzneimittel GmbH, Kiel, Germany, and in part by the Deutsche Forschungsgemeinschaft (SFB 215, B10). M. B. received a grant of the Fachbereich Humanmedizin of Philipps University, Marburg.

³ To whom requests for reprints should be addressed at the Department of Obstetrics and Gynecology, Phillipps-University, Pilgrimstein 3, D-35037 Marburg, Germany

Received 12/11/92. Accepted 9/15/93.

This article has been cited by other articles:

				S. Fister, A. R. Gunthert, B. Aicher, K. W. Paulini, G. Emons, and C. Grundker GnRH-II Antagonists Induce Apoptosis in Human Endometrial, Ovarian, and Breast Cancer Cells via Activation of Stress-Induced MAPKs p38 and JNK and Proapoptotic Protein Bax Cancer Res., August 15, 2009; 69(16): 6473 - 6481. [Abstract] [Full Text] [PDF]

				K. Morgan, A. J. Stewart, N. Miller, P. Mullen, M. Muir, M. Dodds, F. Medda, D. Harrison, S. Langdon, and R. P. Millar Gonadotropin-Releasing Hormone Receptor Levels and Cell Context Affect Tumor Cell Responses to Agonist In vitro and In vivo Cancer Res., August 1, 2008; 68(15): 6331 - 6340. [Abstract] [Full Text] [PDF]

				J.-H. Choi, A. S. T. Wong, H.-F. Huang, and P. C. K. Leung Gonadotropins and Ovarian Cancer Endocr. Rev., June 1, 2007; 28(4): 440 - 461. [Abstract] [Full Text] [PDF]

				P. C.K. Leung and J.-H. Choi Endocrine signaling in ovarian surface epithelium and cancer Hum. Reprod. Update, March 1, 2007; 13(2): 143 - 162. [Abstract] [Full Text] [PDF]

				E. L. Baldwin, I. N. Wegorzewska, M. Flora, and T. J. Wu Regulation of Type II Luteinizing Hormone-Releasing Hormone (LHRH-II) Gene Expression by the Processed Peptide of LHRH-I, LHRH-(1-5) in Endometrial Cells Experimental Biology and Medicine, January 1, 2007; 232(1): 146 - 155. [Abstract] [Full Text] [PDF]

				J.-H. Choi, K.-C. Choi, N. Auersperg, and P. C K Leung Differential regulation of two forms of gonadotropin-releasing hormone messenger ribonucleic acid by gonadotropins in human immortalized ovarian surface epithelium and ovarian cancer cells. Endocr. Relat. Cancer, June 1, 2006; 13(2): 641 - 651. [Abstract] [Full Text] [PDF]

				K. E. Ratcliffe, H. M. Fraser, R. Sellar, J. Rivier, and R. P. Millar Bifunctional Gonadotropin-Releasing Hormone Antagonist-Progesterone Analogs with Increased Efficacy and Duration of Action Endocrinology, January 1, 2006; 147(1): 571 - 579. [Abstract] [Full Text] [PDF]

				A. R Gunthert, C. Grundker, A. Olota, J. Lasche, N. Eicke, and G. Emons Analogs of GnRH-I and GnRH-II inhibit epidermal growth factor-induced signal transduction and resensitize resistant human breast cancer cells to 4OH-tamoxifen Eur. J. Endocrinol., October 1, 2005; 153(4): 613 - 625. [Abstract] [Full Text] [PDF]

				S. Maudsley, L. Davidson, A. J. Pawson, R. Chan, R. L. de Maturana, and R. P. Millar Gonadotropin-Releasing Hormone (GnRH) Antagonists Promote Proapoptotic Signaling in Peripheral Reproductive Tumor Cells by Activating a G{alpha}i-Coupling State of the Type I GnRH Receptor Cancer Res., October 15, 2004; 64(20): 7533 - 7544. [Abstract] [Full Text] [PDF]

				G. Bifulco, C. Miele, M. Pellicano, A. Trencia, M. Ferraioli, F. Paturzo, G.A. Tommaselli, F. Beguinot, and C. Nappi Molecular mechanisms involved in GnRH analogue-related apoptosis for uterine leiomyomas Mol. Hum. Reprod., January 1, 2004; 10(1): 43 - 48. [Abstract] [Full Text] [PDF]

				L. E. C. Miles, A. C. Hanyaloglu, J. R. Dromey, K. D. G. Pfleger, and K. A. Eidne Gonadotropin-Releasing Hormone Receptor-Mediated Growth Suppression of Immortalized L{beta}T2 Gonadotrope and Stable HEK293 Cell Lines Endocrinology, January 1, 2004; 145(1): 194 - 204. [Abstract] [Full Text] [PDF]

				W.-H. Yang, M. Wieczorck, M. C. Allen, and T. M. Nett Cytotoxic Activity of Gonadotropin-Releasing Hormone (GnRH)-Pokeweed Antiviral Protein Conjugates in Cell Lines Expressing GnRH Receptors Endocrinology, April 1, 2003; 144(4): 1456 - 1463. [Abstract] [Full Text] [PDF]

				G. Cobellis, R. Meccariello, S. Minucci, C. Palmiero, R. Pierantoni, and S. Fasano Cytoplasmic Versus Nuclear Localization of Fos-Related Proteins in the Frog, Rana esculenta, Testis: In Vivo and Direct In Vitro Effect of a Gonadotropin-Releasing Hormone Agonist Biol Reprod, March 1, 2003; 68(3): 954 - 960. [Abstract] [Full Text] [PDF]

				C.-S. Chou, H. Zhu, E. Shalev, C. D. MacCalman, and P. C. K. Leung The Effects of Gonadotropin-Releasing Hormone (GnRH) I and GnRH II on the Urokinase-Type Plasminogen Activator/Plasminogen Activator Inhibitor System in Human Extravillous Cytotrophoblasts in Vitro J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5594 - 5603. [Abstract] [Full Text] [PDF]

				X. Tang, T. Yano, Y. Osuga, H. Matsumi, N. Yano, J. Xu, O. Wada, K. Koga, K. Kugu, O. Tsutsumi, et al. Cellular Mechanisms of Growth Inhibition of Human Epithelial Ovarian Cancer Cell Line by LH-Releasing Hormone Antagonist Cetrorelix J. Clin. Endocrinol. Metab., August 1, 2002; 87(8): 3721 - 3727. [Abstract] [Full Text] [PDF]

				N. Auersperg, A. S. T. Wong, K.-C. Choi, S. K. Kang, and P. C. K. Leung Ovarian Surface Epithelium: Biology, Endocrinology, and Pathology Endocr. Rev., April 1, 2001; 22(2): 255 - 288. [Abstract] [Full Text]

				S. K. Kang, K.-C. Choi, C.-J. Tai, N. Auersperg, and P. C. K. Leung Estradiol Regulates Gonadotropin-Releasing Hormone (GnRH) and its Receptor Gene Expression and Antagonizes the Growth Inhibitory Effects of GnRH in Human Ovarian Surface Epithelial and Ovarian Cancer Cells Endocrinology, February 1, 2001; 142(2): 580 - 588. [Abstract] [Full Text] [PDF]

				C. Gründker, K. Schulz, A. R. Günthert, and G. Emons Luteinizing Hormone-Releasing Hormone Induces Nuclear Factor {kappa}B-Activation and Inhibits Apoptosis in Ovarian Cancer Cells J. Clin. Endocrinol. Metab., October 1, 2000; 85(10): 3815 - 3820. [Abstract] [Full Text]

				L. J. Krebs, X. Wang, H. E. Pudavar, E. J. Bergey, A. V. Schally, A. Nagy, P. N. Prasad, and C. Liebow Regulation of Targeted Chemotherapy with Cytotoxic Lutenizing Hormone-releasing Hormone Analogue by Epidermal Growth Factor Cancer Res., August 1, 2000; 60(15): 4194 - 4199. [Abstract] [Full Text]

				A. Schultze-Mosgau, A. C. Katzur, K. K. Arora, S. S. Stojilkovic, K. Diedrich, and O. Ortmann Characterization of calcium-mobilizing, purinergic P2Y2 receptors in human ovarian cancer cells Mol. Hum. Reprod., May 1, 2000; 6(5): 435 - 442. [Abstract] [Full Text] [PDF]

				S. K. Kang, K.-C. Choi, K. W. Cheng, P. S. Nathwani, N. Auersperg, and P. C. K. Leung Role of Gonadotropin-Releasing Hormone as an Autocrine Growth Factor in Human Ovarian Surface Epithelium Endocrinology, January 1, 2000; 141(1): 72 - 80. [Abstract] [Full Text] [PDF]

				A. C. Katzur, T.-A. Koshimizu, M. Tomic, A. Schultze-Mosgau, O. Ortmann, and S. S. Stojilkovic Expression and Responsiveness of P2Y2 Receptors in Human Endometrial Cancer Cell Lines J. Clin. Endocrinol. Metab., November 1, 1999; 84(11): 4085 - 4091. [Abstract] [Full Text]

				A. Kimura, M. Ohmichi, H. Kurachi, H. Ikegami, J. Hayakawa, K. Tasaka, Y. Kanda, Y. Nishio, H. Jikihara, N. Matsuura, et al. Role of Mitogen-activated Protein Kinase/Extracellular Signal-regulated Kinase Cascade in Gonadotropin-releasing Hormone-induced Growth Inhibition of a Human Ovarian Cancer Cell Line Cancer Res., October 1, 1999; 59(20): 5133 - 5142. [Abstract] [Full Text] [PDF]

				A. Amsterdam and N. Selvaraj Control of Differentiation, Transformation, and Apoptosis in Granulosa Cells by Oncogenes, Oncoviruses, and Tumor Suppressor Genes Endocr. Rev., August 1, 1997; 18(4): 435 - 461. [Abstract] [Full Text] [PDF]

				M. Kovacs, A. V. Schally, A. Nagy, M. Koppan, and K. Groot Recovery of pituitary function after treatment with a targeted cytotoxic analog of luteinizing hormone-releasing hormone PNAS, February 18, 1997; 94(4): 1420 - 1425. [Abstract] [Full Text] [PDF]