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

为了预测放射治疗后局部控制率主要相关的辐射敏感性，研究了辐射反应与癌基因、肿瘤细胞凋亡相关基因表达和低氧相关蛋白等生物学参数的相关性。对人体标本进行免疫组织化学研究和各种DNA/RNA分析，以获得与辐射敏感性相关的参数，并以肿瘤细胞系和实验动物为材料进行分析。用p21、p27、P53蛋白表达、诱导型一氧化氮合酶、缺氧诱导因子-1α、环氧合酶-2等指标分析预后。38例患者中，HIF-1α高表达17例(45%)，P53高表达22例(58%)，bax高表达15例(39%)，bcl2高表达15例(39%)，28例(74%)HPV感染阳性。HIF-1α高表达与…异常呈显著正相关更容易复发(p&lt；0.05)。此外，低氧诱导因子-1α与无复发生存率显著相关(p=0.0 4)。HIF-1α高表达与局部控制率差异无统计学意义(P=0.17)，而HIF-1α高表达预测远处转移有显著意义(P=0.03)。相反，其他因素对IIIB期宫颈癌患者的临床结果没有影响。低氧诱导因子-1α是预测宫颈鳞癌放疗后转移的重要预后因子，环氧合酶-2(COX-2)通过抑制放射诱导的细胞凋亡而影响放射治疗的疗效，COX-2在辐射诱导的细胞凋亡调节中起关键作用。采用连续47例单纯放疗或放疗联合化疗的宫颈癌患者的活检标本，分析COX-2表达与宫颈癌放疗后疗效的关系。放疗前COX-2阳性率为46.1%+/-21.0%，放疗后1周细胞凋亡率为2.1%+/-0.9%。放疗前COX-2表达与放疗中AI呈显著负相关(r=-0.52，p=0.0002)。COX-2阳性患者完全缓解率为59%，COX-2阴性患者完全缓解率为80%(p=0.12)。COX-2阳性患者的2年局控率为71.3%，而COX-2阴性患者的2年局控率为96.0%(P=0.06)。这些结果首次在临床上证明了COX-2可以通过抑制放射诱导的细胞凋亡而使宫颈鳞癌对放射治疗的耐受性增加。此外，COX-2的表达可能是预测放射治疗后局部肿瘤控制的一个很好的指标。高LET重离子照射诱发的人肺癌细胞株的旁观者反应。采用准直重离子微束单细胞照射系统，在JAERI-Takasaki用一定数量的重离子粒子单独照射选定的细胞。开发该系统是为了研究低剂量和低剂量率高LET辐射下HIT细胞和旁观者细胞的放射生物学过程，这是使用常规广域照射无法实现的。在特殊的培养皿中生长的单个培养细胞在大气中被单一或规定数量的碳束照射。碳辐射诱导旁观者效应，加入GAP抑制剂可阻断旁观者效应。较少

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