MODIFICATION OF RADIOSENSITIVITY BY ALTERATION OF ACTIVITY OF RECEPTOR TYROSINE KINASE AND ITS SIGNAL TRANSDUCTION PATHWAYS

通过改变受体酪氨酸激酶的活性及其信号转导途径来改变放射敏感性

• 批准号: 11670867
• 负责人: AKIMOTO Tetsuo
• 金额: $ 1.79万
• 依托单位: Gunma University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670867/
• 关键词: Radiation; Survival signal transduction; Molecular-target therapy; MAP kinase; Apoptosis; p53; EGFR; 増殖因子受容体; 放射線感受性; 生存シグナル; シグナル伝達; MAPK; 細胞周期

The purpose of this study is to clarify the role of activation of receptor tyrosine kinase and its signal transduction pathways in determining radiosensitivity and enhancement of radiosensitivity. We have already reported that inverse relationship between EGFR expression and radiocurability in murine tumors, and the underline mechanism is in part attributed to activation of signal transduction pathways by radiation. In addition, we focused on "survival signal transduction pathways" that is consisted of Raf-MEK-p42/p44 ERK and PI3K-AKT/PKB, and a part of the results has already been reported. (1) Radiation activated survival signal transduction pathways, (2) Genistein, a tyrosine kinase inhibitor, enhanced radiosensitivity by inhibition of radiation-induced activation of survival signal transduction, (3) Selective inhibition of PI3K or p42/p44 ERK enhanced radiosensitivity, (4) Apoptosis induction may be involved in enhancement of radiosensitivity especially in the cell lines with wild type p53. These results indicated that survival signal transduction pathways plays an important role in determining radiosensitivity, and would be a molecular-target in improving treatment efficacy in radioresistant tumors.

本研究的目的是阐明受体酪氨酸激酶的激活及其信号转导途径在决定放射敏感性和增强放射敏感性中的作用。我们已经报道了小鼠肿瘤中EGFR表达和放射性之间的负相关关系，并且强调的机制部分归因于辐射激活信号转导途径。另外，我们还对由Raf-MEK-p42/p44 ERK和PI 3 K-AKT/PKB组成的“生存信号转导通路”进行了研究，部分结果已被报道。(1)（2）酪氨酸激酶抑制剂Genistein通过抑制辐射诱导的生存信号转导途径而增强辐射敏感性;（3）选择性抑制PI 3 K或p42/p44 ERK增强辐射敏感性;（4）凋亡诱导可能参与辐射敏感性的增强，尤其是在野生型p53的细胞系中。这些结果表明，生存信号转导通路在决定放射敏感性中起着重要作用，并将成为提高放射抗性肿瘤治疗效果的分子靶点。

项目成果

Akimoto T: "Low E-cadherin and beta-catenin correlates with increased spontaneous and artificial metastasis in murine carcinoma"Clin Exp Metastasis. 17. 171-176 (1999)

Akimoto T：“低 E-钙粘蛋白和 β-连环蛋白与小鼠癌自发性和人工转移增加相关”Clin Exp 转移。

Akimoto T et al.: "Low E-cadherin and beta-catenin correlates with increased spontaneous and artificial lung metastasis in murine carcinoma"Clin Exp Metastasis. 17. 171-176 (1999)

Akimoto T 等人：“低 E-钙粘蛋白和 β-连环蛋白与鼠癌自发性和人工肺转移增加相关”Clin Exp 转移。

Mitsuhashi N: "Is radiosensitive cell line cross-sensitive to heat? : Effect of heat on two rat yolk sac tumor cell lines with different radiosensitivity"Cancer Letters. 142. 195-200 (1999)

Mitsuhashi N：“放射敏感性细胞系对热是否交叉敏感？：热对两种具有不同放射敏感性的大鼠卵黄囊肿瘤细胞系的影响”《癌症快报》。

Akimoto T et al.: "Genistein, a tyrosine kinase inhibitor, enhanced radiosensitivity in human esophageal cancer cell line in vitro"Int J Radiat Oncol Biol Phys. (in press). (2001)

Akimoto T 等人：“金雀异黄酮，一种酪氨酸激酶抑制剂，在体外增强人食管癌细胞系的放射敏感性”Int J Radiat Oncol Biol Phys。

Akimoto T. et al.: "Potentially lethal damage repair and its inhibitory effect of caffeine in two yolk sac tumour cell lines with different radiosensitivities"Cancer Letters. 147(1-2). 199-206 (1999)

Akimoto T.等人：“咖啡因对两种具有不同放射敏感性的卵黄囊肿瘤细胞系的潜在致命损伤修复及其抑制作用”《癌症快报》。