中国癌症杂志 ›› 2018, Vol. 28 ›› Issue (9): 657-664.doi: 10.19401/j.cnki.1007-3639.2018.09.000

• 专家述评与论著 • 上一篇    下一篇

评价替莫唑胺对脑胶质瘤治疗敏感性的新方法

张 雷1,刘一博2,刘继才2,刘云会1   

  1. 1. 中国医科大学附属盛京医院神经外科,辽宁 沈阳 110004 ;
    2. 胤安国际(沈阳)基因科技股份有限公司,辽宁 沈阳 110169
  • 出版日期:2018-09-30 发布日期:2018-10-26
  • 通信作者: 刘云会 E-mail: liuyh@sj-hospital.org

A novel method to predict temozolomide sensitivity for the treatment of glioblastoma

ZHANG Lei1, LIU Yibo2, LIU Jicai2, LIU Yunhui1   

  1. 1. Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China; 2. Yinan International (Shenyang) Gene Technologies, Shenyang 110169, Liaoning Province, China
  • Published:2018-09-30 Online:2018-10-26
  • Contact: LIU Yunhui E-mail: liuyh@sj-hospital.org

摘要: 背景与目的:替莫唑胺(temozolomide,TMZ)是治疗胶质母细胞瘤的唯一化疗药。O6-甲基鸟嘌呤DNA甲基转移酶(O6-methylguanine-DNA methyltransferase,MGMT)基因启动子甲基化是评价TMZ敏感性的唯一指标。但通过检测MGMT的甲基化程度来评估TMZ的敏感性是不够的,因为目前MGMT检测只是定性检测,而且这种检测只能反映DNA损伤修复的一条通路,而另两条通路的修复情况却没有反映出来。方法:该研究一方面是应用高分辨率熔解曲线(high resolution melting,HRM),对MGMT的甲基化进行定量检测,同时应用实时荧光定量聚合酶链反应(real-time fluorescent quantitative polymerase chain reaction,RTFQPCR)来探讨另外两条修复通路蛋白N-甲基化嘌呤DNA糖基化酶(N-methylpurine DNA glycosylase,MPG)和人类烷烃羟化酶基因同系物2(alkane hydroxylase gene homolog 2,ALKBH2)的mRNA表达。将MPGALKBH2的表达分为高表达和低表达。结果:结合MGMT的甲基化(阳性)和非甲基化(阴性)程度,再把MPGALKBH2结合起来评估患者对TMZ的敏感性。三阳性(MGMT非甲基化,MPG阳性和ALKBH2阳性)为化疗抵抗,两阳性为不感,两阴性为次敏感,三阴性(MGMT甲基化,MPG阴性和ALKBH2阴性)为最敏感。结合8例胶质母细胞瘤患者的检测和生存期,结果与我们的判断结果相吻合,三阴性的患者生存时间最长,三阳性的患者的生存时间最短。结论:通过定量检测MGMT同时结合MPGALKBH2可以更精准地判断TMZ的敏感性。

关键词: 替莫唑胺, O6-甲基鸟嘌呤DNA甲基转移酶, N-甲基化嘌呤DNA糖基化酶, 烷烃羟化酶基因同系物2

Abstract: Background and purpose: Temozolomide (TMZ) is the only drug available for the treatment of glioblastoma, and O6-methylguanine-DNA methyltransferase (MGMT) promotor methylation is the only gene for prediction of the sensitivity of TMZ in glioblastoma patients. However, detecting the status of MGMT gene methylation alone is not sufficient for evaluating the sensitivity to TMZ. One reason is that the current MGMT detection is qualitative and it is not quantitative. Another reason is that detection of MGMT gene methylation just reflects one of the three DNA repair pathways. The other two repair pathways are not tested. Methods: In this study, we used high resolution melting (HRM) analysis to qualify the methylation status of the patients’ samples, and then measured mRNA levels of N-methylpurine DNA glycosylase (MPG) and human alkane hydroxylase gene homolog 2 (ALKBH2) in the other two pathways by polymerase chain reaction (PCR). Furthermore, the expression levels of MPG and ALKBH2 were divided into high and low expressions, respectively. Results: We found that patients with triple positive test results were more resistant to TMZ whereas patients with triple negative test results were more sensitive to TMZ. The results were consistent with the survival data. Patients with triple negative test results survived the longest, while patients with triple positive test results survived the shortest. Conclusion: Our results suggest that this novel method may predict TMZ sensitivity more precisely in glioblastoma patients.

Key words: Temozolomide, O6-methylguanine-DNA methyltransferase, N-methylpurine DNA glycosylase, Alkane hydroxylase gene homolog 2