lhrh--his(5)-trp(7)-tyr(8)- and cetrorelix

GnRH-I and its receptor (GnRHR-I) have previously been demonstrated and shown to be biologically active in the immune system, notably within peripheral lymphocytes. Recently however, a second form of GnRH (GnRH-II) has been described in the human. The functions of both these neuropeptides in PMBCs have not been understood yet. The present study was therefore designed to investigate the effects of GnRH-I and/or GnRH-II on human PMBC proliferation in males. Secondly, the effects of GnRH-I and GnRH-II on IL-2 dependent lymphocyte proliferation were examined. Finally, we analysed the role of GnRH-I and GnRH-II in IL-2R gamma-chain expression. Peripheral venous blood samples were obtained from six male healthy volunteers (Mean age 27.75 +/- 1.5). Non-radioactive cell proliferation assay was used for proliferation studies and we used quantitative real-time RT-PCR to examine the role of GnRH-I and GnRH-II on IL-2R gamma-chain expression in PMBCs. Treatment of PMBCs with GnRH-I (10(-9) M and 10(-5) M) and with interleukin-2 (IL-2) (50 U/ml) resulted in a significant increase in cell proliferation compared with the untreated control. PMBCs cotreated with IL-2 and GnRH-I demonstrated higher proliferative responses than IL-2 treatment alone, the enhancement of GnRH-I on IL-2 response being significant only at GnRH-I concentration of 10(-5) M. Co-incubation of IL-2+ GnRH 10(-5) M with a GnRH antagonist (Cetrorelix; 10(-6) M) significantly decreased the proliferation. GnRH-II did not affect the proliferation of PMBCs alone, and did not alter the proliferative response to IL-2. The proliferative responses to GnRH-I (alone and with IL-2) were significantly attenuated by GnRH-II coincubation (each in equal molar concentrations; 10(-9) M to 10(-5) M). It was found that GnRH-I increased the expression of IL-2Rgamma mRNA in a dose dependent manner, with a significant increase of percentage 162.3 +/- 14 of control at 10(-5) M. In contrast, IL-2Rgamma expression was significantly decreased in all concentrations of GnRH-II (10(-9) M to10(-5) M), and the maximum decrease was detected at 10(-5) M, with percentage 37.7 +/- 6.6 of control. All these findings strongly suggest that regulation of IL-2R expression may therefore be an important target for GnRH-I and GnRH-II in PMBCs in males. In summary, present study clearly demonstrates the differential effects of GnRH-I and GnRH-II on PMBC proliferation, IL-2 proliferative response, and IL-2Rgamma expression in PMBCs in males. To ou

Topics: Adult; Cell Division; Cells, Cultured; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Interleukin Receptor Common gamma Subunit; Interleukin-2; Leukocytes, Mononuclear; Male; Receptors, Interleukin-2; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

The majority of human endometrial and ovarian cancer cell lines express receptors for GnRH. Their proliferation is time- and dose-dependently reduced by GnRH-I and its superagonistic analogues. Recently, we have demonstrated that, in human endometrial and ovarian cancer cell lines except for the ovarian cancer cell line EFO-27, the GnRH-I antagonist cetrorelix has antiproliferative effects comparable to those of GnRH-I agonists, indicating that the dichotomy between GnRH-I agonists and antagonists might not apply to the GnRH system in cancer cells. We were also able to show that the proliferation of human endometrial and ovarian cancer cells was dose- and time-dependently reduced by GnRH-II to a greater extent than by GnRH-I agonists.. In this study we have assessed whether or not the antiproliferative effects of the GnRH-I antagonist cetrorelix in endometrial and ovarian cancer cells are mediated through the GnRH-I receptor.. We analysed the antiproliferative effects of the GnRH-I agonist triptorelin, the GnRH-I antagonist cetrorelix and GnRH-II in a panel of endometrial and ovarian cancer cell lines expressing GnRH-I receptors, in the SK-OV-3 ovarian cancer cell line that does not express GnRH-I receptors, and in four GnRH-I receptor positive GnRH-I receptor knockout cell lines.. We found that, after knockout of the GnRH-I receptor, the antiproliferative effects of the GnRH-I agonist triptorelin were abrogated, whereas those of the GnRH-I antagonist cetrorelix and of GnRH-II persisted.. These data suggest that, in endometrial and ovarian cancer cells, the antiproliferative effects of cetrorelix and of GnRH-II are not mediated through the GnRH-I receptor.

Topics: Antineoplastic Agents, Hormonal; Cell Division; Cell Line, Tumor; Endometrial Neoplasms; Female; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Mutagenesis; Ovarian Neoplasms; Receptors, LHRH; Triptorelin Pamoate