ANTIPROLIFERAT EFFECT OF ZK 230 211 ON ENDOMETRIUM IN OVARIECTOM RHESUS MONKEYS

ZK 230 211对去势恒河猴子宫内膜的抗增殖作用

• 批准号: 6592356
• 负责人: ROBERT M BRENNER
• 金额: $ 11.11万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6592356
• 关键词: Mammalia; clinical research; hormones; model design /development; reproductive system; women's health

In primates, treatment with antiprogestins including RU 486 and ZK 137 316 will both block progesterone (P) action, and also inhibit estrogen stimulated proliferation in the endometrium. This action of antiprogestins would be of benefit to women treated with estrogen replacement therapy as a method of blocking untoward effects of estrogen on the endometrium. ZK 230 211 (ZK211) is a potent new generation antiprogestin produced by Schering AG, that can be administered both orally and systemically. The goal of this research was to determine if ZK211 will inhibit the proliferative actions of estrogen delivered continuously for 5 months. Six groups of rhesus macaques (n = 5 each) were treated with estradiol (E2)-filled implants for 5 months. Three of the groups were also injected daily with 3 different doses of ZK211 (0. 01, 0.05 and 0.25 mg/kg). P is known to oppose the proliferative action of E2 in the endometrium. Therefore, for comparison, 1 group received E2 plus a low dose of P (2 cm P implants) and one group received E2 plus a high dose of P (6 cm P implants). Control animals (group 6) received estrogen alone. Treatment with ZK211 resulted in a severe reduction of endometrial mass, which was associated with a dose dependent inhibition of epithelial cell proliferation. At higher doses of ZK211, this effect resulted in the upper portions of the glands degenerating and trapping secretory material. These higher doses led to formation of moderate size endometrial cysts, which appeared to contain trapped secretory material. There was no evidence of endometrial hyperplasia or metaplasia. As anticipated, long-term E2 + P treatment resulted in a dose-dependent decidualization response that was marked by extensive spiral artery hypertrophy. This effect on the spiral arteries was opposite to the reaction to that seen with ZK 211 which inhibited vascular development. We conclude that inhibition of vascular development by ZK 211 may be the key factor underlying the degenerative inhibition and blockade of estrogen-dependent endometrial proliferation induced by this antiprogestin. FUNDING Contract with Schering AG, Berlin, Germany PUBLICATIONS None

在灵长类动物中，使用抗孕激素（包括 RU 486 和 ZK）治疗 137 316 既会阻断黄体酮 (P) 的作用，也会抑制 雌激素刺激子宫内膜增殖。 这个动作的 抗孕激素对接受雌激素治疗的女性有益 替代疗法作为阻止不良影响的一种方法 雌激素对子宫内膜的作用。 ZK 230 211 (ZK211) 是一款强大的新型 先灵公司生产的第一代抗孕激素，可以 口服和全身给药。 本研究的目标 是为了确定ZK211是否会抑制增殖作用 连续5个月给予雌激素。 六组恒河猴 用雌二醇 (E2) 填充的植入物治疗猕猴（每只 n = 5） 5个月。 其中三组每天还注射 3 不同剂量的 ZK211 (0. 01、0.05 和 0.25 mg/kg)。 P 已知 对抗E2在子宫内膜中的增殖作用。 所以， 为了进行比较，1 组接受 E2 加低剂量 P（2 cm P 植入物），一组接受 E2 加高剂量 P（6 cm P 植入物）。 对照动物（第6组）仅接受雌激素。 ZK211治疗导致子宫内膜严重减少 质量，这与剂量依赖性抑制有关 上皮细胞增殖。 在较高剂量的 ZK211 下，这种效应 导致腺体上部退化并被捕获 分泌物质。 这些较高的剂量导致形成中度 大小的子宫内膜囊肿，其中似乎含有滞留的分泌物 材料。 没有证据表明子宫内膜增生或 化生。 正如预期的那样，长期 E2 + P 治疗导致 剂量依赖性蜕膜化反应，其特征是广泛 螺旋动脉肥大。 这种对螺旋动脉的影响是 与 ZK 211 的反应相反，ZK 211 抑制 血管发育。 我们的结论是抑制血管 ZK 211的开发可能是其背后的关键因素 抑制和阻断雌激素依赖性子宫内膜的退行性变 这种抗孕激素诱导增殖。 资助合同 Schering AG，德国柏林 出版物 无