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首页> 外文期刊>Radiotherapy and oncology: Journal of the European Society for Therapeutic Radiology and Oncology >Improvement of esophageal adenocarcinoma cell and xenograft responses to radiation by targeting cyclin-dependent kinases.
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Improvement of esophageal adenocarcinoma cell and xenograft responses to radiation by targeting cyclin-dependent kinases.

机译：通过靶向细胞周期蛋白依赖性激酶改善食管腺癌细胞和异种移植物对放射的反应。

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BACKGROUND AND PURPOSE: Concurrent chemo-radiotherapy before surgery is standard treatment protocol for esophageal cancer with a less than 30% complete response due to resistance to therapy. The aim of this study was to determine whether molecular targeting approach using an inhibitor of cyclin-dependent kinases, flavopiridol, can help overcome the resistance to radiotherapy. MATERIALS AND METHODS: SEG-1 cells (human esophageal adenocarcinoma) were exposed to gamma-rays with and without flavopiridol treatment and assayed for clonogenic survival, apoptosis, cell cycle distribution, and Western blot analysis. Efficacy of flavopiridol in enhancing tumor response to radiation was determined by tumor growth delay assay using SEG-1 tumor xenografts generated in nude mice. RESULTS: The clonogenic cell survival assay data showed that flavopiridol (300 nM, 24h), when given either before or after radiation, significantly enhanced the radiosensitivity of SEG-1 cells. The cells were accumulated at G1 phase of the cell cycle by flavopiridol that was associated with downregulation of p-cdk-1, p-cdk-2, cyclin D1 and p-Rb expression. Flavopiridol by itself induced apoptosis in SEG-1 cells and also enhanced the radiation-induced apoptosis, associated with an increase in cleaved poly ADP-ribose polymerase. Reduction in phosphorylation of RNA polymerase II by flavopiridol suggested that flavopiridol inhibited the transcriptional activity. In vivo studies with SEG-1 tumor xenografts showed that flavopiridol, either given before or after radiation, greatly enhanced the effect of tumor irradiation. CONCLUSIONS: Flavopiridol treatment significantly enhanced SEG-1 cell radiosensitivity as well as the radioresponse of SEG-1 tumor xenografts. The underlying mechanisms are multiple, including cell cycle redistribution, apoptosis, and transcriptional inhibition. These preclinical data suggest that flavopiridol has the potential to increase the radioresponse of esophageal adenocarcinomas.
机译：背景与目的：术前同时放化疗是食管癌的标准治疗方案，由于对治疗的抵抗力，其完全缓解率不足30％。这项研究的目的是确定使用细胞周期蛋白依赖性激酶抑制剂flavopiridol的分子靶向方法是否可以帮助克服对放射疗法的抵抗力。材料与方法：SEG-1细胞（人食道腺癌）在接受和不接受氟哌啶醇处理的情况下接受伽玛射线照射，并进行克隆形成存活，细胞凋亡，细胞周期分布和蛋白质印迹分析。使用在裸鼠中产生的SEG-1肿瘤异种移植物，通过肿瘤生长延迟试验确定了黄酮哌啶醇在增强肿瘤对放射线反应中的功效。结果：克隆细胞存活测定数据表明，黄酮哌啶醇（300 nM，24h）在放疗前或放疗后给予，可显着增强SEG-1细胞的放射敏感性。黄素哌啶醇在细胞周期的G1期积累细胞，其与p-cdk-1，p-cdk-2，细胞周期蛋白D1和p-Rb表达的下调有关。 Flavopiridol本身可诱导SEG-1细胞凋亡，并增强辐射诱导的凋亡，这与裂解的聚ADP-核糖聚合酶的增加有关。黄酮哌啶醇减少RNA聚合酶II的磷酸化表明黄酮哌啶醇抑制了转录活性。 SEG-1肿瘤异种移植物的体内研究表明，黄素哌啶醇在放疗前或放疗后给予，大大增强了放疗的效果。结论：黄酮哌啶醇治疗可显着增强SEG-1细胞的放射敏感性以及SEG-1肿瘤异种移植物的放射反应。潜在的机制是多种的，包括细胞周期再分布，细胞凋亡和转录抑制。这些临床前数据表明黄酮哌啶醇有可能增加食管腺癌的放射反应。

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