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

辐射反应与包括癌基因在内的各种生物学参数之间的相关性，肿瘤细胞凋亡相关基因和缺氧相关蛋白的表达被用来预测放射敏感性，主要与放射治疗后的局部控制概率有关。对人样本进行RNA分析以获得与辐射敏感性相关的参数以及对肿瘤细胞系的分析，实验动物为材料。结果：38例患者中，17例（45%）、22例（58%）、15例（39%）、22例（58%）、23例（58%）、24例（58%）、25例（58%）、22例（58%）、23例（58%）、22例（58%）HPV阳性28例（74%）。HIF-1α的高表达与肿瘤的分化程度呈显著正相关。 ...更多信息 减少复发（P<0.05）。此外，HIF-1α与无复发生存率显著相关（p=0.04）。HIF-1α高表达与局部控制率之间无统计学意义（p=0.17），而HIF-1α状态预测远处转移具有显著意义（p=0.03）。相反，其他因素对IIIB期宫颈癌患者的临床结局无影响。HIF-1α是预测IIIB期宫颈鳞癌放疗后是否发生转移的重要预后因子，而环氧化酶2（考克斯-2）通过抑制放疗诱导的细胞凋亡而影响放疗效果，考克斯-2在调节放疗诱导的细胞凋亡中起关键作用。分析了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中考克斯-2表达与放疗后结局的关系。放疗前标本的考克斯-2表达率为46.1% ± 21.0%，放疗开始后1周的凋亡指数（AI）为2.1% ± 0.9%。放疗前考克斯-2表达与放疗期间AI呈显著负相关（r=-0.52，p =0.0002）。考克斯-2阳性患者的完全缓解率为59%，而考克斯-2阴性患者的完全缓解率为80%（p=0.12）。考克斯-2阳性患者的2年局部控制率为71.3%，而考克斯-2阴性患者的相应率为96.0%（p=0.06）。这些结果首次在临床上证明了考克斯-2通过抑制放射诱导的细胞凋亡而使宫颈鳞状细胞癌对放射治疗更难治。考克斯-2的表达可能是预测放疗后局部肿瘤控制的良好指标。高LET重离子照射诱导的人肺癌细胞系的旁观者反应。该系统已被开发用于研究低剂量和低剂量率高LET辐射下的击中细胞和旁观者细胞的放射生物学过程，这是使用常规宽场照射无法实现的。在特殊培养皿中生长的单个培养细胞在大气中用单个或限定数量的碳束照射。旁观者效应由碳辐射诱导，并被gap抑制剂阻断。少

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