GnRH antagonists in the treatment of gynecological and breast cancers.

Abstract

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 αi 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 G 0 /G 1 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.

Gonadotropin-releasing hormone receptor expression in endometrial stromal sarcomas: an immunohistochemical study

“…6,7,17,18 GnRH agonists are widely used in the systemic treatment of premenopausal women with estrogen-dependent breast cancer, both in the setting of adjuvant treatment of the primary carcinoma and for metastatic disease. 19 GnRH agonists have also been used in patients with ovarian cancer and endometrial cancer.…”

“…19 GnRH agonists have also been used in patients with ovarian cancer and endometrial cancer. 6,20,21 GnRH analogs with a cytotoxic agent covalently linked to a GnRH analog have been developed. 22 Furthermore, GnRH antagonists are used in cancer therapy.…”

“…22 Furthermore, GnRH antagonists are used in cancer therapy. 6,15 The demonstration of GnRH-R I and II expression in endometrial stromal sarcomas may be a rationale for a clinical study of GnRH analogs in the treatment of women with endometrial stromal sarcomas. Anecdotal reports of successful adjuvant hormonal therapy have been published.…”

“…4 Gonadotropin-releasing hormone receptors (GnRH-R) have been demonstrated in approximately 80% of ovarian and endometrial cancers and 50% of breast cancers. 5,6 Furthermore, GnRH agonists have been shown to decrease aromatase expression in adenomyosis, endometriosis and leiomyomas. 7 The use of GnRH agonists and antagonists is presently under investigation as treatment modality for several human malignancies including breast, endometrial and ovarian cancer.…”

Diversity of actions of GnRHs mediated by ligand-induced selective signaling

“…15). A number of antagonists of gonadotrope GnRH receptors act as GnRH agonists in the inhibition of tumor cell lines [32,34,44,81,128].…”