甲基转移酶与肿瘤耐药预见性、个体化化疗的研究

Study on MGMT Assay and Tumor Individual Predictable Chemotherapy

如何预见和克服肿瘤细胞对化疗药物的耐药性是肿瘤化疗急需解决的问题。我们通过对中国人肿瘤细胞系、裸鼠移植瘤及肿瘤患者的组织分子水平的研究,探讨肿瘤细胞中O6-甲基鸟嘌呤DNA甲基转移酶(O6-methylguanine-DNAmethyl-transferase,MGMT)活性和蛋白水平高低与细胞对烷化剂、特别是对亚硝脲化疗药物耐药的关系。研究证明,肿瘤细胞的MGMT蛋白水平高,对烷化剂耐药;MGMT蛋白水平低对烷化剂敏感。在研究工作基础上,我们提出了以分析MGMT蛋白为依据,合理使用烷化剂、特别是使用亚硝脲类药物的预见性、个体化治疗方案。并进一步采用制备MGMT单抗的技术途径,研制出MGMT免疫组化检测试剂盒。本文结合文献和我们的研究工作,对甲基转移酶与肿瘤耐药预见性、个体化化疗的研究,从理论依据到实验研究作一全面的介绍。

How to predict and surmount the cell resistance in tumor chemothera py is a prompt problem. We have observed that there were close correlation among O6-Methylguanine-DNA methyltransferase (MGMT) enzyme activity, protein expres sion and cell resistance to alkylating agents especially to nitrosourea anti-tu mor compounds by a series of experiments including cell survival, xenografts in nude mice, tumor patient biopsy and molecule biology assay. We found that those tumors with high MGMT activity and abundance of MGMT protein were resistant to a lkylating agents killing effect, while those with low MGMT activity and little M GMT protein were sensitive to alkylating anti-tumor drugs. We proposed a new ta ctics for tumor predictable chemotherapy treated with alkylating agents based on MGMT protein detection. By means of preparing MGMT monoclone antibody, we have succeeded in developing MGMT immunohistochemistry diagnostic kit.