替莫唑胺治疗胶质母细胞瘤的耐药性产生机制研究进展

Research Progress of Temozolomide in the Mechanism of Drug Resistance in Glioblastoma

胶质母细胞瘤作为胶质瘤中恶性程度最高的原发性脑部肿瘤,具有治愈率低、复发率高、呈浸润性生长等特点,在不使用化疗药物的情况下,患者中位生存期仅为12.1个月。胶质母细胞瘤患者的标准治疗方法以手术切除为主,放化疗为辅,其中替莫唑胺(temozolomide,TMZ)作为一种新型的口服烷化剂,是目前用于胶质瘤化学治疗的一线药物。但经过替莫唑胺治疗后,患者中位生存期仅提高了2个月,主要原因为胶质母细胞瘤可对TMZ产生耐药性。胶质母细胞瘤对TMZ产生的耐药机制主要为DNA修复机制,其包括了O^(6)⁃甲基鸟嘌呤DNA甲基转移酶(O^(6)⁃methyl guanine DNA methyltransferase,MGMT)对药物作用位点进行的直接修复、错配修复(mismatch repair,MMR)及碱基切除修复(base excision repair,BER),这些修复机制可修复TMZ引起的DNA损伤,从而降低肿瘤细胞对TMZ敏感性。通过对近年来胶质母细胞瘤的TMZ耐药机制的研究进展进行介绍,旨在为发展新的治疗手段提供理论基础。

Glioblastoma is the most malignant primary brain tumor in glioma,which has the characteristics of low cure rate,high recurrence rate and invasive growth.Without the use of chemotherapy drugs,the median survival time of patients is only 12.1 months.The standard treatment for patients with glioblastoma is surgical resection supplemented by chemoradiotherapy.Among them,temozolomide(TMZ)as a new oral alkylating agent,is the first⁃line drug in the current chemotherapy of glioma.However,median survival improved by only 2 months after temozolomide treatment,mainly because glioblastomas can develop resistance to TMZ.Glioblastoma on TMZ resistance mechanism is mainly DNA repair mechanisms,it includes O^(6)⁃methyl guanine DNA methyltransferase(MGMT)of sites for the action of the drug directly repair,mismatch repair(MMR)and base excision repair(BER),these repair mechanisms can repair DNA damage cause by TMZ,thereby reducing tumor cell sensitivity to TMZ.The research progress on the mechanism of TMZ drug resistance of glioblastoma in recent years was reviewed,in order to provide a theoretical basis for the development of new therapeutic methods.