Study for the development of molecular therapy targeting the signal transduction pathway through epidermal growth factor receptor

表皮生长因子受体信号转导通路分子治疗的发展研究

• 批准号: 17390445
• 负责人: KURACHI Hirohisa
• 金额: $ 10.72万
• 依托单位: Yamagata 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-17390445/
• 关键词: ovanan cancer; molecular tareeted therapy; EGF receptor; sienal transduction; anti cancer drug; EGF受容体(EGFR); DNA損傷

Treatment with gefitinib increased the efficacy of the cisplatin-induced inhibition in the intraabdominal dissemination and production of ascites in athymic nude mice inoculated intraperitoneally with cisplatin-resistant Caov-3cells. Immunofluorescent reactivity for phosphorylated EGFR in tumors treated with gefitinib alone and combination of cisplatin + gefitinib was clearly reduced compared with that in tumors treated with vehicle and cisplatin alone. Similar Results were found for the phosphorylation of ERK and Akt.We next investigated the expression of DNA-PK by immunofluorescent staining with anti-DNA-PK antibody. Treatment with cisplatin significantly increased the expression of DNA-PK in nuclei compared with that in tumors treated with vehicle. Treatment with combination of cisplatin + gefitinib significantly reduced the expression of DNA-PK compared with treatment with cisplatin alone. These results suggested that inhibition of DNA repair by gefitinib enhanced the efficacy of cisplatin.Moreover, we investigated the effects of platinum-based chemotherapy on the signaling cascades and apoptosis before and after chemotherapy in patients with ovarian cancers using specimens obtained during surgical procedures. The increase in ERK phosphorylation was more consistent than that of Akt. Increases in apoptotic marker expression were observed in all patients exposed to chemotherapy. Activation of ERK by chemotherapy may be associated with apoptosis of tumor cells in patients with ovarian cancers.

在腹腔接种顺铂耐药caov -3细胞的胸腺裸小鼠中，吉非替尼治疗增加了顺铂诱导的抑制腹腔内传播和腹水产生的效果。与单用载体和单用顺铂治疗的肿瘤相比，单用吉非替尼和顺铂联合治疗的肿瘤中磷酸化EGFR的免疫荧光反应性明显降低。在ERK和Akt的磷酸化中发现了类似的结果。接下来，我们用抗DNA-PK抗体免疫荧光染色检测DNA-PK的表达。顺铂治疗与载药治疗相比，显著提高肿瘤细胞核DNA-PK的表达。与单用顺铂治疗相比，顺铂+吉非替尼联合治疗显著降低了DNA-PK的表达。这些结果表明，吉非替尼抑制DNA修复可增强顺铂的疗效。此外，我们研究了铂类化疗对卵巢癌患者化疗前后信号级联和细胞凋亡的影响，使用手术过程中获得的标本。与Akt相比，ERK磷酸化的增加更为一致。所有接受化疗的患者均观察到凋亡标记物表达增加。化疗激活ERK可能与卵巢癌患者肿瘤细胞凋亡有关。

项目成果

血管拡張剤fasudilはVEGFにより誘導される血管新生を抑制する.

血管扩张剂法舒地尔抑制 VEGF 诱导的血管生成。

• 发表时间: 2007
• 作者: Ohta T;Ohmichi M;Hayasaka T;Mabuchi S;Saitoh M;Kawagoe J;Takahashi K;Igarashi H;Du B;Doshida M;Mirei IG;Motoyama T;Tasaka K;Kurachi H.;尹麗梅;Yin L;尹 麗梅
• 通讯作者: 尹 麗梅

Inhibition of phosphatidylinositol 3-kinase increases efficacy of cisplatin in in vivo ovarian cancer models

• DOI: 10.1210/en.2005-1450
• 发表时间: 2006-04-01
• 期刊: ENDOCRINOLOGY
• 影响因子: 4.8
• 作者: Ohta, T;Ohmichi, M;Kurachi, H
• 通讯作者: Kurachi, H

Clinical outcome and risk factors for recurrence in borderline ovarian tumours.

• DOI: 10.1038/sj.bjc.6603139
• 发表时间: 2006-06-05
• 期刊: BRITISH JOURNAL OF CANCER
• 影响因子: 8.8
• 作者: Yokoyama, Y.;Moriya, T.;Takano, T.;Shoji, T.;Takahashi, O.;Nakahara, K.;Yamada, H.;Yaegashi, N.;Okamura, K.;Izutsu, T.;Sugiyama, T.;Tanaka, T.;Kurachi, H.;Sato, A.;Tase, T.;Mizunuma, H.
• 通讯作者: Mizunuma, H.

Fasudil inhibits vascular endothelial growth factor -: induced angiogenesis in vitro and in vivo

• DOI: 10.1158/1535-7163.mct-06-0689
• 发表时间: 2007-05-01
• 期刊: MOLECULAR CANCER THERAPEUTICS
• 影响因子: 5.7
• 作者: Yin, Limei;Morishige, Ken-ichirou;Kurachi, Hirohisa
• 通讯作者: Kurachi, Hirohisa

Raloxifene improves the ovariectomy-induced impairment in endothelium-dependent vasodilation.

雷洛昔芬改善卵巢切除术引起的内皮依赖性血管舒张损伤。

• 发表时间: 2007
• 期刊: Menopause 14
• 作者: Takahashi;K
• 通讯作者: K