Exploring the mechanism of cell proliferation and the novel molecular target therapy of endometriosis

探索细胞增殖机制及子宫内膜异位症新型分子靶向治疗

• 批准号: 17390451
• 负责人: TERAKAWA Naoki
• 金额: $ 8.88万
• 依托单位: Tottori University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17390451/
• 关键词: Endometrinsis; TNFα; IL-8; dienogest; NFkB pathway; ovarian endometrioma; GnRH antagonist; Cetrorelix; 酢酸セトロレリックス; 臨床試験; 疼痛症状; 血中CA-125濃度; 血中IL-6濃度; 血中IL-8濃度; GrRHアンタゴニスト; 培養間質細胞; 増殖・進展; サイトカインファミリー; 転写因子NF-κB

We previous reported that the proinflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin (IL)-8 are elevated in the peritoneal fluid of women with endometriosis. In addition, TNFα enhances the mitogenic activity and upregulates IL-8 expression through NF-κB activation in endometriotic stromal cells from ovarian endometrioma (ESCs). Endometriotic tissue growth depends on ovarian steroid hormones, especially estrogen. TNFα induced-IL-8 production via estrogen action may be involved in the molecular mechanisms for development of endometriosis.The chocolate cysts linings of the ovaries of patients with endometriosis were the source of endometriotic tissues. Adding TNFα together with E2 markedly enhanced cell proliferation and IL-8 expression via NFκB pathway. In contrast, P4, dienogest, or danazol attenuated NFκB activation and IL-8 expression. These data suggest that a possible molecular mechanism of hormone therapy for controlling the growth of endometriosis.Next, we performed the clinical trial regarding a GnRH antagonist, Cetrorelix Acetate. We analyzed that serum IL-6 and IL-8 concentration of the patients with endometriosis.By the injection of Cetrorelix to the patients, the score of pain and of clinical symptoms were decreased. Cetrorelix therapy significantly suppressed the serum IL-6 concentration.We demonstrated for the first time that a GnRH antagonist, Cetrorelix improved the clinical symptoms and decreased serum IL-6 concentration, suggesting this novel drug may be effective for the therapy of endometriosis.

我们先前报道，子宫内膜异位症患者腹腔液中的促炎细胞因子，如肿瘤坏死因子-α和白介素8水平升高。此外，肿瘤坏死因子α通过激活核因子-κB，增强卵巢子宫内膜异位内膜间质细胞的有丝分裂活性，上调IL-8的表达。子宫内膜异位症组织的生长依赖于卵巢类固醇激素，尤其是雌激素。肿瘤坏死因子α通过雌激素作用诱导IL-8的产生可能参与了子宫内膜异位症发生的分子机制。联合应用肿瘤坏死因子α和雌激素E_2，可通过核因子κB途径显著促进细胞增殖和IL-8的表达。相反，P4、Dienogest或Danazol可减弱NF-κB的激活和IL-8的表达。这些数据提示激素治疗控制子宫内膜异位症生长的可能分子机制。接下来，我们进行了关于促性腺激素释放激素拮抗剂醋酸西曲列酯的临床试验。通过对子宫内膜异位症患者血清IL-6、IL-8水平的分析，发现西曲瑞克能明显降低患者的疼痛评分和临床症状积分。西曲利司治疗可显著降低血清IL-6浓度，首次证实GnRH拮抗剂西曲利司可改善临床症状，降低血清IL-6浓度，提示该新药对子宫内膜异位症的治疗可能是有效的。

项目成果

Small bowel perforation from a thermal burn caused by contact with the end of a laparoscope during ovarian cystectomy.

卵巢囊肿切除术期间与腹腔镜末端接触造成热烧伤导致小肠穿孔。

• 发表时间: 2006
• 期刊: J. Obstet. Gynaecol. Res. 32
• 作者: 早川智;相澤志保子;早川智・相澤(小峯)志保子;早川智;Y. Ohama;F. Taniguchi;Y. Ohama;F. Taniguchi;F. Taniguchi;Y. Ohama;N. Miura;T. Shoji;N. Miura;T. Shoji;M.Izawa;M. Ito
• 通讯作者: M. Ito

Low-dose oral contraceptive pill for dysmenorrheal associated with endometriosis: A placebo-controlled, double-blind, randomized trial.

低剂量口服避孕药治疗与子宫内膜异位症相关的痛经：一项安慰剂对照、双盲、随机试验。

• 期刊: Fertil . Steril. (in press)
• 作者: 早川智;相澤志保子;早川智・相澤(小峯)志保子;早川智;Y. Ohama;F. Taniguchi;Y. Ohama;F. Taniguchi;F. Taniguchi;Y. Ohama;N. Miura;T. Shoji;N. Miura;T. Shoji;M.Izawa;M. Ito;M. Mitsunari;M. Izawa;M. Ito;M. Mitsunari;M.Izawa;I. Deura;S. Horie;I. Deura;S. Horie;I.Deura;S.Horie;M. Izawa;Y. Ohata;T. Harada
• 通讯作者: T. Harada

IL-10 attenuates TNFa-induced IL-6 production in endometriotic stromal cells.

IL-10 减弱子宫内膜异位基质细胞中 TNFa 诱导的 IL-6 产生。

• 发表时间: 2008
• 作者: 早川智;相澤志保子;早川智・相澤(小峯)志保子;早川智;Y. Ohama;F. Taniguchi;Y. Ohama;F. Taniguchi;F. Taniguchi;Y. Ohama;N. Miura;T. Shoji;N. Miura;T. Shoji;M.Izawa;M. Ito;M. Mitsunari;M. Izawa;M. Ito;M. Mitsunari;M.Izawa;I. Deura;S. Horie;I. Deura;S. Horie;I.Deura;S.Horie;M. Izawa;Y. Ohata;T. Harada;T. Harada;Y. Tagashira;M. Izawa;Y. Ohata;T. Harada;T. Harada;Y. Tagashira;T. Iwabe
• 通讯作者: T. Iwabe

卵巣チョコレート嚢胞に対する腹腔鏡下手術の予後

腹腔镜卵巢巧克力囊肿手术的预后

• 发表时间: 2007
• 作者: 早川智;相澤志保子;早川智・相澤(小峯)志保子;早川智;Y. Ohama;F. Taniguchi;Y. Ohama;F. Taniguchi;F. Taniguchi;Y. Ohama;N. Miura;T. Shoji;N. Miura;T. Shoji;M.Izawa;M. Ito;M. Mitsunari;M. Izawa;M. Ito;M. Mitsunari;M.Izawa;I. Deura;S. Horie;I. Deura;S. Horie;I.Deura;S.Horie;M. Izawa;Y. Ohata;T. Harada;T. Harada;Y. Tagashira;M. Izawa;Y. Ohata;T. Harada;T. Harada;Y. Tagashira;T. Iwabe;I. Deura;A. Ikeda;T. Iwabe;I. Deura;A. Ikeda;寺川直樹;寺川直樹;谷口文紀
• 通讯作者: 谷口文紀

子宮内膜症細胞のIL-6産生に対するIL-10の影響

IL-10 对子宫内膜异位症细胞 IL-6 产生的影响

• 发表时间: 2007
• 作者: 早川智;相澤志保子;早川智・相澤(小峯)志保子;早川智;Y. Ohama;F. Taniguchi;Y. Ohama;F. Taniguchi;F. Taniguchi;Y. Ohama;N. Miura;T. Shoji;N. Miura;T. Shoji;M.Izawa;M. Ito;M. Mitsunari;M. Izawa;M. Ito;M. Mitsunari;M.Izawa;I. Deura;S. Horie;I. Deura;S. Horie;I.Deura;S.Horie;M. Izawa;Y. Ohata;T. Harada;T. Harada;Y. Tagashira;M. Izawa;Y. Ohata;T. Harada;T. Harada;Y. Tagashira;T. Iwabe;I. Deura;A. Ikeda;T. Iwabe;I. Deura;A. Ikeda;寺川直樹;寺川直樹;谷口文紀;田頭由紀子
• 通讯作者: 田頭由紀子