替莫唑胺的耐药性研究进展

Research progress of resistance of temozolomide

神经胶质瘤是较常见的颅内恶性肿瘤,手术、放疗及辅以替莫唑胺(TMZ)的化疗已成为欧洲的一线治疗措施。TMZ烷化DNA产生O6-甲基鸟嘌呤(O6-meG)、N7-甲基鸟嘌呤(N7-meG)、N3-甲基腺嘌呤(N3-meA)等DNA加合物而发挥抗癌作用。TMZ的抗癌作用主要是由O6-meG介导的,但肿瘤细胞DNA修复系统中O6-meG-DNA甲基转移酶(MGMT)可以修复O6-meG而导致TMZ的疗效降低,同时TMZ抗癌作用需要完整的碱基错配修复(MMR)系统参与。N7-meG主要被碱基切除修复(BER)系统修复。TMZ在临床的治疗效果有很大的个体差异,固有的或获得性耐药限制了TMZ在临床的运用。掌握TMZ的分子药理机制和耐药产生的机理可以制定有效的治疗方案延缓TMZ耐药性的产生。

Glioblastoma multiforme （GBM） is the most common aggressive adult primary brain tumour. Surgery, radiotherapy and adjuvant temozolomide （TMZ） chemotherapy have become the standard care for GBM in Europe. TMZ alkylates DNA and produces DNA adducts such as 06-methylguanine （06- meG）, N7- methylguaine （N7- meG） and N3 - methyladenine （N3 - meA）, etc. O6- meG is the primary cytotoxic lesion for anticancer effect. However, 06-meG can be repaired by methylguanine- DNA methyhransferase （MGMT） in tumours, and the anticancer effect of TMZ is greatly reduced. The anticancer effect of TMZ is also dependent on the intact mismatch repair （MMR） system. N7-meG can be repaired by base excision repair （BER） system. The clinical outcomes of TMZ are variable, contributing to MGMT and MMR diversified expression and the intrinsic and acquired resistance, which limit its clinical applications. Understanding the mechanism of action of TMZ and its resistance mechanism would help to design efficient therapeutic strategy and overcome acquired resistance in clinic.