聚腺苷二磷酸核糖聚合酶（PARP）抑制剂 AG014699提高 BRCA2缺陷的胰腺癌细胞放射敏感性的体外实验研究

摘要

目的：探讨AG014699提高含BRCA2基因缺陷的胰腺癌细胞放射敏感性的作用机制。方法选择Ca-pan-1和Panc-12种胰腺癌细胞株，分成单纯药物组、单纯放疗组、药物联合放疗组，MTT法检测药物IC50，通过细胞克隆形成率分析细胞存活状态，应用免疫荧光法观察H2Ax的形成。结果单药AG014699（≤10μM）对Capan-1细胞有毒性作用，对Panc-1无效应；放疗联合药物组对Capan-1细胞克隆形成率影响最明显，与单药和单放疗组比较（P＜0．05），而该差异在Panc-1细胞中不明显（P＞0．05）；DNA损伤表现为H2Ax形式，提示DNA双链断裂是细胞死亡的主要模式。结论 AG014699对含有BRCA2基因缺陷的胰腺癌细胞Capan-1有放疗增敏作用。%Objective To investigate radiosensitization mechanism of AG 014699 in BRCA2 deficient pancreatic cancer cells.Methods Pancreatic cancer cells lines were used ,including Capan-1 with mutuated BRCA-2 and Panc-1 with BRCA1/2 wild type.Cell were treated AG014699 and /or radiotherapy (4~10 Gy) then the capability to proliferate was evaluated by colo-ny formation,cell counting and MTT assays .Flow Cytometry were utilized to assess cell respone to AG 014699 plus irradiation.Re-sults AG014699 (≤10 μM)was cytotoxic to Capan-1 cell with mutuated BRCA-2 but not to Panc-1 cell without BRCA1/2 mutations.AG014699 indued DNA double-strand break in Capan-1 cell.Combination treatment with AG014699 plus radiotherapy was more effective than drug alone .Conclusion The rationale of using a PARP inhibitor as radiosensitizer in pancreatic cancer with BRCA2 mutation has been demonstrated .