替莫唑胺(TMZ)是一种甲基化剂,用作胶质母细胞瘤化疗的一线药物。然而,癌细胞最终获得抗性,需要开发TMZ增强治疗剂。TMZ诱导几种DNA碱基加合物,包括O6-MEG,3-meA,还有7-meG.TMZ的细胞毒性源于这些加合物直接(3-meA)或间接(O6-meG)损害DNA复制的能力。虽然TMZ毒性通常归因于O6-meG,其它烷基化碱基可以是同样重要的,这取决于处理的细胞的各种DNA修复途径的状态。在这篇小型综述中,我们强调了区分TMZ敏感性胶质母细胞瘤的必要性,它们不表达甲基鸟嘌呤-DNA甲基转移酶(MGMT),并被O6-meG/T对的错配修复(MMR)无效循环杀死,vs.TMZ耐药MGMT阳性或MMR阴性胶质母细胞瘤,其在治疗过程中被选择并且仅在较高TMZ剂量下被复制阻断3-meA杀死。这两种类型的细胞可以通过抑制不同的DNA修复途径而被TMZ致敏。然而,在这两种情况下,有毒的中间体似乎是ssDNA缺口,在BRCA缺陷型癌症中也发现了一种脆弱性。PARP抑制剂(PARPi),最初被开发用于通过合成致死性来治疗BRCA1/2缺陷型癌症,在临床试验中重新使用以增强TMZ的作用。我们讨论了我们对TMZ毒性的遗传决定因素的理解的最新进展如何通过抑制PARP1和其他参与烷基化损伤修复的酶(例如,APE1)。
Temozolomide (TMZ) is a methylating agent used as the first-line drug in the chemotherapy of glioblastomas. However, cancer cells eventually acquire resistance, necessitating the development of TMZ-potentiating therapy agents. TMZ induces several DNA base adducts, including O 6 -meG, 3-meA, and 7-meG. TMZ cytotoxicity stems from the ability of these adducts to directly (3-meA) or indirectly (O 6 -meG) impair DNA replication. Although TMZ toxicity is generally attributed to O 6 -meG, other alkylated bases can be similarly important depending on the status of various DNA repair pathways of the treated cells. In this mini-review we emphasize the necessity to distinguish TMZ-sensitive glioblastomas, which do not express methylguanine-DNA methyltransferase (MGMT) and are killed by the futile cycle of mismatch repair (MMR) of the O 6 -meG/T pairs, vs. TMZ-resistant MGMT-positive or MMR-negative glioblastomas, which are selected in the course of the treatment and are killed only at higher TMZ doses by the replication-blocking 3-meA. These two types of cells can be TMZ-sensitized by inhibiting different DNA repair pathways. However, in both cases, the toxic intermediates appear to be ssDNA gaps, a vulnerability also seen in BRCA-deficient cancers. PARP inhibitors (PARPi), which were initially developed to treat BRCA1/2-deficient cancers by synthetic lethality, were re-purposed in clinical trials to potentiate the effects of TMZ. We discuss how the recent advances in our understanding of the genetic determinants of TMZ toxicity might lead to new approaches for the treatment of glioblastomas by inhibiting PARP1 and other enzymes involved in the repair of alkylation damage (e.g., APE1).