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Study on radioresistence of the cells under a hypoxic condition

缺氧条件下细胞的放射抗性研究

基本信息

批准号：
16591229
负责人：
MITSUHASHI Norio
金额：
$ 2.24万
依托单位：
Tokyo Women's Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16591229/
关键词：
Hypoxic cell Survival signals HIF-1α Radiosensitivity TKR Inhibitor HIF1-α 子宮頸癌

项目摘要

1) Enhancement of Radiosensitivity by Dual Inhibition of HER family with ZD1839 ('Iressa') and Trastuzumab ('Herceptin')Radiation-induced activation of EGFR and HER2/neu was inhibited with ZD 1839 and/or trastuzumab. Radiation in combination with HER family inhibitors also inhibited the activation of Akt and MEK1/2, the downstream survival signaling of HER family. ZD1839 enhanced radiosensitivity with a DMF (SF3) of 1.45 and trastuzumab with a DMF (SF3) of 1.11. Simultaneous blockade of HER2 family by ZD 1839 and trastuzumab induced synergistic radiosensitizing effect with a DMF (SF3) of 2.29. A dual inhibition of HER family enhanced radiosensitivity synergistically by inhibiting activation of survival signal transduction pathway. Our study suggests that HER family in combination with radiation therapy may be one of the potent candidates for molecular therapeutic targets.2) Modification of cell growth and radiosensitivity under a hypoxic conditionReduction of radiosensitivity under the … More hypoxia (5% O_2 and 1% O_2) was investigated by using A549 cell in vitro. The cell growth was significantly inhibited under the condition with 1% O_2 hypoxia but not under the condition with 5% O_2 hypoxia. Plating efficiency under the condition with 1% O_2 hypoxia was the same as that under an oxic condition. Increase in radioresistance was not observed under a hypoxic condition although the sizes of colonies were smaller under the condition with 1% O_2 hypoxia compared with those under an oxic condition.3) Expression of hypoxic-inducible factor 1α predicts metastasis-free survival after radiation therapy alone in stage IIIB cervical squamous cell carcinomaOf 38 patients, high expression of HIF-1α, p53, bax, and bcl-2 were seen in 17 (45%), 22 (58%), 15 (39%), and 15 (39%) patients, respectively, and 28 patients (74%) showed positive infection with HPV. There was a significant positive correlation between high HIF-1α expression and disease recurrence (p < 0.05). Furthermore, HIF-1α had a significant correlation with the recurrence-free survival rate (p = 0.04). No statistical correlation was noted between high HIF-1α expression and the local control rate (p = 0.17), whereas the HIF-1α status predicted distant metastasis with strong significance (p = 0.03). Conversely, other factors demonstrated no impact on the clinical outcome. The present results suggest that HIF-1α is an important prognostic factor, especially for predicting future metastasis after radiation therapy for patients with Stage IIIB squamous cell carcinoma of the cervix. Less

1)通过用ZD1839（“易瑞莎”）和曲妥珠单抗（“赫赛汀”）双重抑制HER家族增强放射敏感性用ZD 1839和/或曲妥珠单抗抑制放射诱导的EGFR和HER2/neu激活。放射与 HER 家族抑制剂相结合还抑制了 Akt 和 MEK1/2（HER 家族下游生存信号）的激活。 ZD1839 增强了放射敏感性，DMF (SF3) 为 1.45，而曲妥珠单抗的 DMF (SF3) 为 1.11。 ZD 1839 和曲妥珠单抗同时阻断 HER2 家族可诱导协同放射增敏作用，DMF (SF3) 为 2.29。 HER家族的双重抑制通过抑制生存信号转导途径的激活来协同增强放射敏感性。我们的研究表明，HER家族与放射治疗相结合可能是分子治疗靶点的有力候选者之一。2）缺氧条件下细胞生长和放射敏感性的改变通过使用体外A549细胞研究了缺氧（5％O_2和1％O_2）下放射敏感性的降低。 1%O_2缺氧条件下细胞生长受到明显抑制，而5%O_2缺氧条件下细胞生长不受抑制。 1%O_2缺氧条件下的电镀效率与有氧条件下相同。尽管1%O_2缺氧条件下的集落大小较有氧条件下更小，但在缺氧条件下未观察到放射抗性增加。 3）缺氧诱导因子1α的表达预测IIIB期宫颈鳞状细胞癌仅放疗后的无转移生存期38例患者中，HIF-1α、p53、bax和bcl-2的高表达分别有 17 名（45%）、22 名（58%）、15 名（39%）和 15 名（39%）患者出现 HPV 感染，其中 28 名患者（74%）显示 HPV 阳性感染。 HIF-1α高表达与疾病复发呈显着正相关（p < 0.05）。此外，HIF-1α 与无复发生存率显着相关（p = 0.04）。 HIF-1α 高表达与局部控制率之间没有统计学相关性 (p = 0.17)，而 HIF-1α 状态预测远处转移具有很强的意义 (p = 0.03)。相反，其他因素对临床结果没有影响。目前的结果表明，HIF-1α 是一个重要的预后因素，特别是对于预测 IIIB 期宫颈鳞状细胞癌患者放疗后的未来转移而言。较少的