Photoaffinity labelling of gonadotropin releasing hormone binding sites in human epithelial ovarian carcinomata

Pahwa, G. S.; Vollmer, Günter; Knüppen, R.; Emons, Günter

doi:10.1016/0006-291x(89)91354-5

Cited by 33 publications

(15 citation statements)

References 17 publications

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“…Acad Receptor-mediated internalization of LH-RH has been previously observed in rat pituitary cells (20). As shown by our internalization assay, the temperature-dependent uptake of (21). The presence of LH-RH receptors in ovarian cancer suggests that LH-RH analogs could exert direct inhibitory effects on the growth of ovarian cancers (11).…”

supporting

confidence: 67%

Inhibition of human epithelial ovarian cancer cellgrowth in vitro by agonistic and antagonistic analogues of luteinizinghormone-releasing hormone.

Yano¹,

Pinski²,

Radulović³

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

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In this study, we investigated the effects of luteinnimig hormone-releasing hormone (LH-RH) agonist ]LH-RH, LH-RH antagonist [Ac-D-Nal(2)1,DPhe(pCI)2,n-Pal(3)3,D-Cit',D-Ala"'JLU-RH (SB-75), and estradiol on the growth of human epithellal ovarian cancer cell line OV-1063. Cells were cultured under estrogen-deprived conditions. Estradiol inhibited cell proliferation, as measured by cell number at 10-9-10-7 M and Epithelial ovarian cancer is the most common cause of death from gynecologic malignancies in the United States. It is estimated that 21,000 cases ofovarian cancer were diagnosed and 13,000 deaths from this disease occurred in 1992 (1). Treatment of ovarian cancer is based on surgery and chemotherapy but is far from satisfactory and new approaches must be explored to improve the therapy.The normal ovary is a hormone-dependent organ and receptors for estrogen, progesterone, androgen, luteinizing hormone (LH), and luteinizing hormone-releasing hormone (LH-RH) are found in ovarian cancers (2, 3). It (12, 13). The use of LH-RH antagonists in cancer therapy would prevent the temporary clinical "flare-up" of disease that occurs initially in response to LH-RH agonists in some malignancies such as prostate cancer (11-13).OV-1063 human epithelial ovarian cancer cell lines originated from a metastatic papillary cystadenocarcinoma of the ovary in a 57-year-old woman (14). OV-1063 cells are positive for carcinoembryonic antigen (14).The purpose of the present study was to investigate the presence of LH-RH binding sites on OV-1063 Cell Culture. OV-1063 cells were originally kindly provided by S. Biran (Hadassah University, Jerusalem) and were maintained in phenol red-free RPMI 1640 medium supplemented with 10% heat-inactivated and dextran-coated charcoal-treated FBS (DCC/FBS), which was prepared as described (15). RPMI 1640 medium also contained 25 mM Hepes buffer, 2 mM glutamine, penicillin (100 units/ml), streptomycin (100 pg/ml), and amphotericin B (0.25 pu/ml). 1701The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

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supporting

confidence: 67%

Inhibition of human epithelial ovarian cancer cellgrowth in vitro by agonistic and antagonistic analogues of luteinizinghormone-releasing hormone.

Yano¹,

Pinski²,

Radulović³

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

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“…Recently, GnRH-a was reported to suppress the growth of ovarian cancers that express the GnRH-a receptor [10]. Thus GnRH-a might be tried in the near future as a treatment for ovarian cancer that is refractory to standard chemotherapy [11].…”

Section: Discussionmentioning

confidence: 99%

Increased Natural Killer Cell Activities in Patients Treated with Gonadotropin Releasing Hormone Agonist

Umesaki

Tanaka²,

Miyama³

et al. 1999

Gynecol Obstet Invest

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Natural killer (NK) cell activity in patients treated with gonadotropin-releasing hormone agonists (GnRH-a) was studied. The subjects were 8 patients with endometriosis (6 with ovarian endometrial cyst, 2 with adenomyosis) and 3 patients with uterine leiomyoma. Changes in serum estradiol (E₂) concentration and NK cell activity in peripheral blood were analyzed before and after GnRH-a treatment (buserelin 900 μg/day for 4–5 months). NK cell activity was determined by ⁵¹Cr release assay and E₂ by radioimmunoassay. NK cell activity before GnRH-a treatment was 37.7 ± 19.0%, and after therapy activity increased significantly to 50.8 ± 18.2%. However, no significant correlation between the increase in NK cell activity and the decrease in E₂ concentration was found. Results indicate that the standard GnRH-a treatment for endometriosis and uterine leiomyoma might increase NK cell activity. The etiology of the increase of NK activity with GnRH-a treatment is likely related to factors other than E₂ concentration.

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“…Since 1985 the expression of GnRH and its receptor as well as direct antiproliferative effects of GnRH and its analogs have been demonstrated in a number of malignant human tumors, including cancers of the breast (Blankenstein et al 1985, Miller et al 1985, Eidne et al 1987, Fekete et al 1989, Baumann et al 1993, ovary (Emons et al 1989, Pahwa et al 1989, Emons et al 1993a, Ohno et al 1993, Thompson et al 1991, Yano et al 1994a,b, Kakar et al 1994, Irmer et al 1995, and endometrium (Srkalovic et al 1990, Pahwa et al 1991, Emons et al 1993b, Imai et al 1994a,b, Irmer et al 1994, Chatzaki et al 1996. About 50% of breast, 70% of ovarian and 80% of endometrial cancers express GnRH and its receptor (Emons et al 1997, Gründker et al 2002a, Völker et al 2002 (Table 1).…”

Section: Gnrh Systems In Human Cancersmentioning

confidence: 99%

GnRH antagonists in the treatment of gynecological and breast cancers.

Emons

Gründker²,

Günthert³

et al. 2003

Endocrine-Related Cancer

133

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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.

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Photoaffinity labelling of gonadotropin releasing hormone binding sites in human epithelial ovarian carcinomata

Cited by 33 publications

References 17 publications

Inhibition of human epithelial ovarian cancer cellgrowth in vitro by agonistic and antagonistic analogues of luteinizinghormone-releasing hormone.

Inhibition of human epithelial ovarian cancer cellgrowth in vitro by agonistic and antagonistic analogues of luteinizinghormone-releasing hormone.

Increased Natural Killer Cell Activities in Patients Treated with Gonadotropin Releasing Hormone Agonist

GnRH antagonists in the treatment of gynecological and breast cancers.

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