Molecular Mechanisms of Anti-Tumor Effect of Peptide Analogs and Their Direct Effect on the Ovary

1) GnRH I拮抗剂Cetrorelix通过GnRH I受体介导的机制，直接抑制HEC-1A人子宫内膜癌细胞系的增殖，涉及细胞周期进程中的多个事件，包括G2期细胞周期阻滞，加上p53的激活和cdc2的失活，可能是由于wel的上调。2)鉴于GnRH II对子宫内膜异位症基质细胞（ESC）的抗增殖和抗炎作用，子宫内膜异位症患者的异位和异位子宫内膜中GnRH II的低表达提示内源性GnRH II介导的细胞抑制调节可能在子宫内膜异位症的发生中受损。3) Cetrorelix直接抑制大鼠成熟颗粒细胞的增殖，其机制涉及细胞周期进程中的多个事件，包括G2期细胞周期阻滞与细胞周期蛋白B1-cdc2复合物水平下调，可能与p53水平上调和细胞凋亡有关。4) Fas/Fas配体系统通过激活caspase介导的级联反应参与大鼠颗粒细胞凋亡的诱导，并伴有iNOS表达的降低。NO通过抑制caspase的激活抑制Fas/Fas配体系统诱导的细胞凋亡，提示在卵巢卵泡闭锁中Fas/Fas配体系统诱导的细胞凋亡通路与NO介导的抗凋亡通路之间存在交叉对话。

1) GnRH I antagonist, Cetrorelix, directly inhibits the proliferation of HEC-1A human endometrial cancer cell line through mechanisms mediated by GnRH I receptor and involving multiple events in cell-cycle progression, including G2 phase cell cycle arrest coupled with the activation of p53 and the inactivation of cdc2, presumably attributable to an up-regulation of Weel.2) In light of the anti-proliferative and anti-inflammatory effects of GnRH II on endometriotic stromal cells (ESC), the lower expression of GnRH II in eutopic and ectopic endometrium of women with endometriosis suggests that endogenous GnRH II-mediated cytostatic regulation may be impaired in the development of endometriosis.3) Cetrorelix directly inhibits the proliferation of rat mature granulosa cells through mechanisms involving multiple events in cell cycle progression, including G2 phase cell cycle arrest coupled with down-regulation of cyclin B1-cdc2 complex levels, presumably attributable to an up-regulation of p53 levels and apoptosis.4) Fas/Fas ligand system is involved in inducing apoptosis through activation of a caspase-mediated cascade in rat granulosa cells, which is coupled with a decrease in iNOS expression. NO inhibits Fas/Fas ligand system-induced apoptosis by suppressing activation of the caspases, pointing to a cross-talk between Fas/Fas ligand system-induced apoptosis pathway and NO-mediated anti-apoptotic pathway in ovarian follicle atresia.