Approximately 80% of human ovarian and endometrial cancers and 50% of breast cancers express GnRH and its receptor as part of an autocrine regulatory system. After binding of its ligand the tumor GnRH receptor couples to G-protein alphai and activates a variety of intracellular signaling mechanisms. (1) Through activation of a protein tyrosine phosphatase, autophosphorylation of growth factor receptors is reverted leading to an inhibition of mitogenic signaling and reduced cell proliferation. (2) Through activation of nuclear factor kappa B antiapoptotic mechanisms are induced protecting tumor cells from apoptosis induced, for example, by doxorubicin. (3) Through activation of the Jun kinase pathway AP-1 is induced, leading to cell cycle arrest in the G0/G1 phase. It seems reasonable to speculate that this system enables the tumor cell to reduce proliferation and to activate repair mechanisms while being protected simultaneously from apoptosis. Interestingly, GnRH antagonists show the same activity in this system as agonists, indicating that the dichotomy GnRH agonist-GnRH antagonist defined in the pituitary gonadotrope is not valid for the tumor GnRH system. Recently, a second type of GnRH receptor, specific for GnRH-II, has been identified in ovarian and endometrial cancers, which transmits significantly stronger antiproliferative effects than the GnRH-I receptor. GnRH antagonists have agonistic effects on this type II receptor. In animal models of human cancers, GnRH antagonists had stronger antitumor effects than GnRH agonists. Therefore, we performed a phase II clinical trial with the GnRH antagonist, cetrorelix (10 mg/day), in patients with ovarian or mullerian carcinoma refractory to platinum chemotherapy. Of 17 evaluable patients treated with cetrorelix, 3 obtained a partial remission (18%) which lasted for 2 to 6 months. Furthermore, 6 patients experienced disease stabilization (35%) for up to 1 year. In this very refractory patient population (median number of prior chemotherapies = 3) these results are quite remarkable when compared with palliative chemotherapy. In addition, cytotoxic GnRH analogs have been developed, where for example doxorubicin was covalently coupled to GnRH analogs. These compounds have superior antitumor effects in cancers expressing GnRH receptors as compared with native doxorubicin and allow for a targeted cytotoxic chemotherapy of gynecologic and breast cancers.

This article has been cited by other articles:

				R. Lopez de Maturana, A. J. Pawson, Z.-L. Lu, L. Davidson, S. Maudsley, K. Morgan, S. P. Langdon, and R. P. Millar Gonadotropin-Releasing Hormone Analog Structural Determinants of Selectivity for Inhibition of Cell Growth: Support for the Concept of Ligand-Induced Selective Signaling Mol. Endocrinol., July 1, 2008; 22(7): 1711 - 1722. [Abstract] [Full Text] [PDF]

				K. Oktay, M. Sonmezer, O. Oktem, K. Fox, G. Emons, and H. Bang Absence of Conclusive Evidence for the Safety and Efficacy of Gonadotropin-Releasing Hormone Analogue Treatment in Protecting Against Chemotherapy-Induced Gonadal Injury Oncologist, September 1, 2007; 12(9): 1055 - 1066. [Abstract] [Full Text] [PDF]

				S. Fister, A. R. Gunthert, G. Emons, and C. Grundker Gonadotropin-Releasing Hormone Type II Antagonists Induce Apoptotic Cell Death in Human Endometrial and Ovarian Cancer Cells In vitro and In vivo Cancer Res., February 15, 2007; 67(4): 1750 - 1756. [Abstract] [Full Text] [PDF]

				H. Zhang, J. S. Bailey, D. Coss, B. Lin, R. Tsutsumi, M. A. Lawson, P. L. Mellon, and N. J. G. Webster Activin Modulates the Transcriptional Response of LssT2 Cells to Gonadotropin-Releasing Hormone and Alters Cellular Proliferation Mol. Endocrinol., November 1, 2006; 20(11): 2909 - 2930. [Abstract] [Full Text] [PDF]

				S. J. Lee, L. R. Schover, A. H. Partridge, P. Patrizio, W. H. Wallace, K. Hagerty, L. N. Beck, L. V. Brennan, and K. Oktay American Society of Clinical Oncology Recommendations on Fertility Preservation in Cancer Patients J. Clin. Oncol., June 20, 2006; 24(18): 2917 - 2931. [Abstract] [Full Text] [PDF]

				M. Enomoto, M. Utsumi, and M. K. Park Gonadotropin-Releasing Hormone Induces Actin Cytoskeleton Remodeling and Affects Cell Migration in a Cell-Type-Specific Manner in TSU-Pr1 and DU145 Cells Endocrinology, January 1, 2006; 147(1): 530 - 542. [Abstract] [Full Text] [PDF]

				K. Kawamura, J. Fukuda, J. Kumagai, Y. Shimizu, H. Kodama, A. Nakamura, and T. Tanaka Gonadotropin-Releasing Hormone I Analog Acts as an Antiapoptotic Factor in Mouse Blastocysts Endocrinology, September 1, 2005; 146(9): 4105 - 4116. [Abstract] [Full Text] [PDF]

				K. Maiti, D. Y. Oh, J. S. Moon, S. Acharjee, J. H. Li, D. G. Bai, H.-S. Park, K. Lee, Y. C. Lee, N. C. Jung, et al. Differential Effects of Gonadotropin-Releasing Hormone (GnRH)-I and GnRH-II on Prostate Cancer Cell Signaling and Death J. Clin. Endocrinol. Metab., July 1, 2005; 90(7): 4287 - 4298. [Abstract] [Full Text] [PDF]

				W. Chen, S. Yoshida, N. Ohara, H. Matsuo, M. Morizane, and T. Maruo Gonadotropin-Releasing Hormone Antagonist Cetrorelix Down-Regulates Proliferating Cell Nuclear Antigen and Epidermal Growth Factor Expression and Up-Regulates Apoptosis in Association with Enhanced Poly(Adenosine 5'-Diphosphate-Ribose) Polymerase Expression in Cultured Human Leiomyoma Cells J. Clin. Endocrinol. Metab., February 1, 2005; 90(2): 884 - 892. [Abstract] [Full Text] [PDF]

				L. Ding, J. Xu, X. Luo, and N. Chegini Gonadotropin Releasing Hormone and Transforming Growth Factor {beta} Activate Mitogen-Activated Protein Kinase/Extracellularly Regulated Kinase and Differentially Regulate Fibronectin, Type I Collagen, and Plasminogen Activator Inhibitor-1 Expression in Leiomyoma and Myometrial Smooth Muscle Cells J. Clin. Endocrinol. Metab., November 1, 2004; 89(11): 5549 - 5557. [Abstract] [Full Text] [PDF]

				X. Luo, L. Ding, and N. Chegini Gonadotropin-releasing hormone and TGF-{beta} activate MAP kinase and differentially regulate fibronectin expression in endometrial epithelial and stromal cells Am J Physiol Endocrinol Metab, November 1, 2004; 287(5): E991 - E1001. [Abstract] [Full Text] [PDF]

				R J Playford, H Wassan, and S Ghosh Effects of growth factors and receptor blockade on gastrointestinal cancer Gut, August 1, 2004; 53(8): 1059 - 1063. [Abstract] [Full Text] [PDF]

				K. Oktay, M. Sonmezer, and O. Oktem 'Ovarian cryopreservation versus ovarian suppression by GnRH analogues: primum non nocere': Reply Hum. Reprod., July 1, 2004; 19(7): 1681 - 1683. [Full Text] [PDF]