MGMT基因表达与人脑胶质瘤化疗耐药关系研究

Relationship Between MGMT Gene Expression and Drug Resistance in Human Gliomas

胶质瘤临床化疗效果不理想,大多对常用化疗药物不敏感,已有用肿瘤细胞系及临床观察研究发现肿瘤甲基化类抗癌药耐药与MGMT表达相关。本研究将体外药敏结果与同一病人肿瘤组织中MGMT表达水平进行相关性分析,以期进一步证实MGMT表达在胶质瘤耐药中的作用。方法:采用MTT法对34例胶质瘤病人新鲜标本,进行了3种脑肿瘤常用化疗药物的体外敏感性测定。并采用RT-PCR方法检测MGMT的表达,随后将肿瘤标本中的MGMT表达与体外药敏试验结果进行相关性分析。结果:RT-PCR结果显示MGMT在获得有效RNA的26个胶质瘤标本中的表达状况为:8例几乎不表达,相对表达值范围是0～2;有8例弱表达,相对表达值范围是2～5;有10例强表达,相对表达值均大于5。三种脑肿瘤常用化疗药物中MeCCNU对大多数胶质瘤不敏感,但DDP和VM-26相对敏感的较多。DDP和MeCCNU的IC_(50)与MGMT基因表达之间呈正相关(r=0.613、P=0.001;r=0.696、P=0.002),VM-26的IC50与MGMT表达无显著相关。结论:临床标本中,多数有MGMTmRNA的表达,其强弱有较大的差异。MeCCNU和DDP的IC50和MGMT的mRNA之间有显著的相关性,支持MGMT基因表达与胶质瘤对烷化剂类耐药相关。因此,检测MGMT的表达也可以为临床胶质瘤病人个体化化疗提供参考。

BACKGROUND & OBJECTIVES: Glioma has been considered as one of the most difficult malig-nant tumors to be cured. Most of such tumors are not sensitive to commonly used anticancer drugs and have been suggest-ed related to MGMT expression. In this investigation, in vitro sensitivity to anticancer drugs and MGMT expression of glioma tissues were determined, so as to confirm the correlation between MGMT expression and drug resistance. METH-ODS: The chemosensitivity of glioma specimens was determined by MTT assay, while MGMT expression was measured by RT-PCR assay. Then the relationship between MGMT gene expression and in vitro drug sensitivity was analyzed. RE-SULTS: Chemosensitivity of 34 glioma samples has been measured, and 26 samples that obtained intact mRNA were deter-mined MGMT expression by RT-PCR and revealed that MGMT was poorly expressed in 8 samples, with comparative expres-sion value of less than 2, and in 8 samples was weakly expressed, with expression value of between 2 and 5. However, in 10 samples MGMT expression was very strong, with comparative expression value of greater than 5. The IC_(50) of DDP and MeCCNU were significantly correlated with the MGMT gene expression (r=0.613, P= 0 . 001; r=0. 696, P=0. 002,respectively).CONCLU-SION: MGMT mRNA expression in most of the clini-cal samples could be observed, while the expression lev-els varied widely. There was a significant correlation be- tween the mRNA level of MGMT and the IC_(50) of DDP or MeCCNU. These results support that the expression of MGMT gene contributes to resistance of alkylating agents of human gliomas, and indicating that determination of MGMT expres-sion could provide reference to individual chemotherapy for the patients.