PARP抑制剂对Lewis肺癌细胞及移植瘤放疗增敏作用及其机制

背景与目的受电离辐射的肿瘤细胞DNA损伤主要为单链断裂（single strand break,SSB）与双链断裂（double strand break,DSB）,其中SSBs发生的频率数十倍于DSBs,而SSBs多能通过聚腺苷二磷酸核糖聚合酶[Poly（ADP-Ribose）polymerase,PARP]等因子进行修复。相关新药Olaparib（PARP1/PARP2/PARP3抑制剂）靶向作用于细胞SSBs损伤修复,其联合化疗的临床研究取得令人鼓舞结果。本实验旨在研究Olaparib对Lewis肺癌细胞及移植瘤放疗增敏作用,初步探讨其可能机制。方法采用MTT法检测Olaparib对Le...

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Bibliographic Details
Published in中国肺癌杂志 Vol. 19; no. 1; pp. 16 - 23
Main Author 王维 段碧霞 曾丽
Format Journal Article
LanguageChinese
Published 重庆医科大学附属永川医院肿瘤科,重庆,402160 2016
Subjects
DNA损伤修复
凋亡
放疗增敏
聚腺苷二磷酸核糖聚合酶抑制剂
放疗增敏
聚腺苷二磷酸核糖聚合酶抑制剂
Radiosensitization
Repair of radiation damage
Poly (ADP-Ribose) polymerase inhibitors
凋亡
DNA损伤修复
Apoptosis
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ISSN1009-3419
1999-6187
DOI10.3779/j.issn.1009-3419.2016.01.02

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Summary:背景与目的受电离辐射的肿瘤细胞DNA损伤主要为单链断裂（single strand break,SSB）与双链断裂（double strand break,DSB）,其中SSBs发生的频率数十倍于DSBs,而SSBs多能通过聚腺苷二磷酸核糖聚合酶[Poly（ADP-Ribose）polymerase,PARP]等因子进行修复。相关新药Olaparib（PARP1/PARP2/PARP3抑制剂）靶向作用于细胞SSBs损伤修复,其联合化疗的临床研究取得令人鼓舞结果。本实验旨在研究Olaparib对Lewis肺癌细胞及移植瘤放疗增敏作用,初步探讨其可能机制。方法采用MTT法检测Olaparib对Lewis细胞10%抑制浓度（10%inhibitory concentration,IC10）值,克隆形成实验验证Olaparib联合放疗的体外增敏作用;成瘤小鼠分为空白对照、Olaparib、放疗（radiotherapy,RT,2 Gy×5 d）、Olaparib＋RT组,动态测量各组移植瘤体积变化;流式细胞术比较各组细胞体外凋亡率,TUNEL法比较移植瘤细胞凋亡;Western blot检测各组DNA损伤相关蛋白γH2AX,凋亡相关蛋白Bax/Bcl-2、Caspase-3表达。结果 Olaparib对Lewis细胞IC10值为4.4μmol/L,克隆形成实验测得Olaparib放疗增敏比为1.211;移植瘤初体积（处理前）增长4倍所需天数,Olaparib＋RT组显著高于单纯RT组（P〈0.001）;流式及TUNEL法检测Lewis细胞体内外凋亡率均Olaparib＋RT组高于RT组（P〈0.05）;Olaparib＋RT组细胞及移植瘤中γH2AX、Bax、Caspase-3显著高于RT组,Bcl-2显著低于RT组（均P〈0.05）。结论 Olaparib对Lewis肺癌细胞及移植瘤起到显著放疗增敏作用,其机制可能与增加受照肿瘤细胞DNA双链断裂形成,上调Bax/Bcl-2促凋亡体系蛋白有关。
Bibliography:Background and objective The DNA damage of the irradiated tumor cells is mainly single strand breaks（SSBs） and double strand breaks（DSBs）, in which the frequency of occurrence of SSBs is dozens of times than DSBs. However, most of the SSBs could be repaired by the Poly（ADP-Ribose） Polymerase（PARP） and other related factors. Recently listed drug-Olaparib（PARP1/PARP2/PARP3 inhibitor） could target the repair pathways of single strand breaks, and recent clinical trials of PARP inhibitors combined with chemotherapy obtained encouraging results. The aim of this study is to investigate the effect and potential mechanism of radiosensitization of Poly（ADP-Ribose） polymerase inhibitor-Olaparib on lewis cells and xenografts. Methods The inhibition concentration 10% inhibitory concentration（IC10） of Olaparib to Lewis cells was detected by methyl thiazolyltetrazolium（MTT） assay. The radiosensitization effect of Olaparib on Lewis cells was determined by classical colony forming assay. Lewis xenografts models were establish
ISSN:1009-3419
1999-6187
DOI:10.3779/j.issn.1009-3419.2016.01.02