Basic Research on Peptide Analogs

在本研究中，我们研究了(1)各种肽类似物，特别是黄体生成素释放激素（LHRH）和生长抑素类似物对人卵巢癌或子宫内膜癌生长的影响，(2)LHRH类似物对大鼠卵巢卵泡发育的影响。在HTOA人上皮性卵巢癌细胞系中检测到高亲和力LHRH结合位点和LHRH受体mRNA。LHRH激动剂（buserelin）和拮抗剂（SB-75）对胸腺裸鼠异种移植HTOA肿瘤的生长具有剂量依赖性。LHRH类似物通过凋亡和干扰EGF受体磷酸化直接抑制HTOA细胞的增殖。在HEC-1人子宫内膜癌细胞系中检测到生长抑素高亲和力结合位点和生长抑素受体mRNA。生长抑素类似物（RC-160）在体内和体外也能抑制HEC-1细胞的生长。RC-160抑制EGF受体磷酸化，但不诱导HEC-1细胞凋亡。LHRH类似物通过凋亡直接抑制大鼠颗粒细胞增殖，而不干扰EGF受体磷酸化。采用非放射性原位杂交方法，在雌激素诱导的去垂体未成熟雌性大鼠卵巢颗粒细胞中检测LHRH和LHRH受体的mRNA。LHRH激动剂降低卵泡生长，增加闭锁卵泡。相比之下，当LHRH拮抗剂阻断局部LHRH时，在直径小于200mum的第二和第三卵泡中，卵泡生长得到促进，闭锁发生率显著降低。这些结果支持内源性LHRH参与未成熟卵泡闭锁的可能性。

In this study, we investigated (1) the effect of various peptide analogs, especialy analogs of luteinizing hormone releasing hormone (LHRH) and somatostatin, on the growth of human ovarian cancer or endometrial cancer and (2) the effect of LHRH analogs on rat ovarian follicle development.High-affinity LHRH binding sites and mRNA for LHRH receptor were detected in HTOA human epithelial ovarian cancer cell line. LHRH agonist (buserelin) and antagonist (SB-75) inhibited the growth of HTOA tumors xenografted in athymic nude mice dose-dependently. LHRH analogs directly inhibited the proliferation of HTOA cells through apoptosis and interference with EGF receptor phosphorylation. High-affinity somatostatin binding sites and mRNA for somatostatin receptor were detected in HEC-1 human endometrial cancer cell line. Somatostatin analog (RC-160) also inhibited the growth of HEC-1 cells in vivo and in vitro. RC-160 suppressed EGF receptor phosphorylation, but did not induce apoptosis in HEC-1 cells.LHRH analogs directly inhibited the proliferation of rat granulosa cells through apoptosis without interference with EGF receptor phosphorylation. In estrogen-primed hypophysectomized immature female rats, mRNA for LHRH and LHRH receptor was detected in ovarian granulosa cells by non-radioactive in situ hybridization. LHRH agonist decreased follicular growth and increased atretic follicles. In contrast, when local LHRH was blocked by administration of LHRH antagonist, follicular growth was promoted and incidence of atresia was significantly decreased in secondary and tertiary follicles less than 200mum in diameter. These results support that the possibility that endogenous LHRH is involved in atresia of immature follicles.