Approximately half of glioblastoma and more than two-thirds of grade II and III glioma tumors lack the DNA repair protein O 6 -methylguanine methyl transferase (MGMT). MGMT-deficient tumors respond initially to the DNA methylation agent temozolomide (TMZ) but frequently acquire resistance through loss of the mismatch repair (MMR) pathway. We report the development of agents that overcome this resistance mechanism by inducing MMR-independent cell killing selectively in MGMT-silenced tumors. These agents deposit a dynamic DNA lesion that can be reversed by MGMT but slowly evolves into an interstrand cross-link in MGMT-deficient settings, resulting in MMR-independent cell death with low toxicity in vitro and in vivo. This discovery may lead to new treatments for gliomas and may represent a new paradigm for designing chemotherapeutics that exploit specific DNA repair defects.

中文翻译：

---

基于机制的选择性靶向耐药神经胶质瘤的药物设计

大约一半的胶质母细胞瘤和超过三分之二的 II 级和 III 级胶质瘤肿瘤缺乏 DNA 修复蛋白 O6个-甲基鸟嘌呤甲基转移酶 (MGMT)。MGMT 缺陷型肿瘤最初对 DNA 甲基化剂替莫唑胺 (TMZ) 有反应，但经常通过错配修复 (MMR) 通路的缺失获得耐药性。我们报告了通过在 MGMT 沉默的肿瘤中选择性地诱导 MMR 非依赖性细胞杀伤来克服这种耐药机制的药物的开发。这些药物沉积动态 DNA 损伤，可被 MGMT 逆转，但在 MGMT 缺陷环境中缓慢演化为链间交联，导致 MMR 非依赖性细胞死亡，体外和体内毒性低。这一发现可能会导致神经胶质瘤的新疗法，并可能代表设计利用特定 DNA 修复缺陷的化学疗法的新范例。