Modification of radiation sensitivity in radiation therapy by combination of molecular target therapy

结合分子靶向治疗改变放射治疗的放射敏感性

• 批准号: 16390334
• 负责人: NAKANO Takashi
• 金额: $ 9.09万
• 依托单位: Gunma University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390334/
• 关键词: Cervical cancer; Hypoxia; Radiation; Prognosis; HIF1α; p53

Correlations between radiation response and various biological parameters including oncogenes, apoptosis relating gene expressions of tumors and hypoxia relating proteins were investigated for prediction of radiation sensitivity predominantly relating local control probability following radiation therapy.Immunohistochemical study and various DNA/RNA analysis for human specimens were performed for obtaining parameters relating to radiation sensitivity as well as analysis for tumor cell lines and experimental animals as materials. Prognosis was analyzed by various parameters including p21, p27, p53 protein expression, inducible NOS (iNOS), Hypoxia-inducible factor-1α (HIF-1α) and Cyclooxygenase-2 (Cox-2).Of 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 the positive infection with HPV. There was a significant positive correlation between high HIF-1α expression and dis … More ease recurrence (p<0.05). Furthermore, HIF-1α had a significant correlation with the recurrence free survival rate (p=0.04). No statistical significance was noted between high HIF-1α expression and local control rate (p=0.17), whereas HIF-1α status predicted distant metastasis with strong significance (p=0.03). Conversely, other factors demonstrated no impact on clinical outcome of patients with stage IIIB cervical carcinoma. 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.Cyclooxygenase-2 (Cox-2) impairs treatment effects of radiotherapy for cervical cancer by inhibition of radiation-induced apoptosis.COX-2 plays a pivotal role in regulation of radiation-induced apoptosis. The relationship between COX-2 expression and postradiotherapy outcomes of patients with cervical cancer was analyzed for biopsy specimens from 47 consecutive patients who had undergone definitive radiotherapy alone or radiotherapy combined with chemotherapy. The COX-2 expression rate of the pretreatment samples was 46.1% +/- 21.0%, and the apoptotic index (AI) 1 week after start of radiotherapy was 2.1% +/- 0.9%. There was a significant negative correlation between the pretreatment COX-2 expression and the AI during radiotherapy (r=-0.52, p=0.0002). Complete response rates were 59% for COX-2 positive patients compared with 80% for COX-2 negative patients (p=0.12). The 2-year local control rate for COX-2 positive patients was 71.3%, whereas the corresponding rate for COX-2 negative patients was 96.0% (p=0.06). these results firstly prove clinically that COX-2 can make cervical squamous cell carcinomas more refractory to radiotherapy by inhibition of radiation-induced apoptosis. Furthermore, expression of COX-2 may be a good indicator to predict local tumor control after radiotherapy.Bystander responses of human lung cancer cell line induced by high LET heavy-ion irradiation.Lung cancer cells were irradiated with a collimated heavy-ion microbeam single cell irradiation system, which allows selected cells to be individually hit with defined number of heavy charged particles at JAERI-Takasaki. This system has been developed to study radiobiological processes in hit cells and bystander cells exposed to low dose and low dose-rate high-LET radiations, in ways that cannot be achieved using conventional broad-field exposures. The individual cultured cells grown in special dishes were irradiated in the atmosphere with a single or defined numbers of carbon beams. Bystander effect was induced by carbon irradiation and blocked by addition of gap inhibitor. Less

研究放射反应与各种生物参数之间的相关性，包括癌基因、肿瘤凋亡相关基因表达和缺氧相关蛋白，以预测放射敏感性，主要与放射治疗后的局部控制概率相关。对人体标本进行免疫组织化学研究和各种 DNA/RNA 分析用于获得与放射敏感性相关的参数，并以肿瘤细胞系和实验动物为材料，通过各种参数（包括p21、p27、p53蛋白表达、诱导型NOS）进行预后分析。 (iNOS)、缺氧诱导因子-1α (HIF-1α) 和环氧化酶-2 (Cox-2)。在 38 名患者中，17 名患者中发现 HIF-1α、p53、bax 和 bcl-2 高表达（45 %)、22 (58%)、15 (39%) 和 15 (39%) 名患者，以及 28 名患者(74%)显示HPV阳性感染，HIF-1α高表达与复发率呈显着正相关(p<0.05)。此外，HIF-1α与无复发生存率显着相关。 (p=0.04)。高 HIF-1α 表达与局部控制率之间没有统计学意义 (p=0.17)，而 HIF-1α 状态预测远处转移具有很强的显着性 (p=0.03)。 HIF-1α是一个重要的线下预后因素，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。环氧合酶-2（Cox-2）通过抑制辐射来损害宫颈癌放疗的治疗效果COX-2在辐射诱导细胞凋亡的调节中发挥着关键作用。 COX-2表达与细胞凋亡之间的关系。对47例连续接受单纯放疗或放疗联合化疗的宫颈癌患者的活检标本进行放疗后结果分析，治疗前样本中COX-2表达率为46.1%+/-21.0%，细胞凋亡。放疗开始后1周的AI指数为2.1%+/-0.9%，治疗前COX-2表达与期间AI呈显着负相关。 COX-2 阳性患者的完全缓解率为 59%，而 COX-2 阴性患者的完全缓解率为 80%（p=0.12）。 2 阳性患者为 71.3%，而 COX-2 阴性患者的相应率为 96.0% (p=0.06)。 COX-2可以通过抑制辐射诱导的细胞凋亡而使宫颈鳞状细胞癌对放疗更难抵抗。此外，COX-2的表达可能是预测放疗后局部肿瘤控制的良好指标。诱导人癌症肺细胞系的旁观者反应。通过高 LET 重离子照射。用准直重离子微束单细胞照射系统照射肺癌细胞，该系统允许用规定数量的重带电粒子在JAERI-Takasaki 开发了该系统，用于研究暴露于低剂量和低剂量率高 LET 辐射的命中细胞和旁观者细胞的放射生物学过程，其方式是使用传统的广场照射无法实现的。在特殊培养皿中生长的植物在大气中用单一或规定数量的碳束进行照射，通过碳照射诱导旁观者效应，并通过添加间隙抑制剂来阻止。

项目成果

CT-fluoroscopy guided interstitial brachytherapy with image-based trestment planning for unresectable locally recurrent rectal carcinoma

CT 透视引导间质近距离放射治疗和基于图像的治疗计划治疗不可切除的局部复发直肠癌

• 发表时间: 2004
• 期刊: Brachytehrapy 3・4
• 作者: Sakurai H;Mitsuhashi N;Harashima K;Muramatsu H;Hasegawa M;et al.
• 通讯作者: et al.

Expression of hypoxic-inducible factor 1α predicts metastasis-free survival after radiation therapy alone in stage IIIB cervical squamous cell carcinoma

缺氧诱导因子 1α 的表达可预测 IIIB 期宫颈鳞状细胞癌单独放疗后的无转移生存期

• 发表时间: 2004
• 期刊: Int J Radiat Oncol Biol Phys 60・2
• 作者: Ishikawa H;Sakurai H;Hasegawa M;Mitsuhashi N;Takahashi M;et al.
• 通讯作者: et al.

Oxygenated and reoxygenated tumors show better local control in radiation therapy for cervical cancer

• DOI: 10.1111/j.1525-1438.2006.00341.x
• 发表时间: 2006-01-01
• 期刊: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
• 影响因子: 4.8
• 作者: Suzuki, Y;Nakano, T;Tsujii, H
• 通讯作者: Tsujii, H

Immunohistochemical study of cell cycle associated proteins in adenocarcinoma of the uterine cervix treated with radiation therapy alone

单纯放射治疗宫颈腺癌细胞周期相关蛋白的免疫组织化学研究

• 发表时间: 2004
• 期刊: Int J Radiat Oncol Biol Phys. 60(1)
• 作者: Suzuki Y;Nakano T;Kato S;et al.
• 通讯作者: et al.

A 104-year-old woman with advanced cervical carcinoma of the uterus

104 岁女性，患有晚期宫颈癌

• 发表时间: 2004
• 期刊: Gyn Oncol 92
• 作者: Sakurai H et al.;Sakurai H et al.
• 通讯作者: Sakurai H et al.