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，癌细胞最终会产生耐药性，因此需要开发 TMZ 增强治疗剂。 TMZ 诱导多种 DNA 碱基加合物，包括 O 6 -meG、3-meA 和 7-meG。 TMZ 细胞毒性源于这些加合物直接 (3-meA) 或间接 (O 6 -meG) 损害 DNA 复制的能力。虽然 TMZ 毒性通常归因于 O 6 -meG，但其他烷基化碱基也可能同样重要，具体取决于处理细胞的各种 DNA 修复途径的状态。在这篇小综述中，我们强调区分 TMZ 敏感的胶质母细胞瘤的必要性，这些胶质母细胞瘤不表达甲基鸟嘌呤-DNA 甲基转移酶 (MGMT)，并被 O 6 -meG/T 对的错配修复 (MMR) 无效循环杀死，与 TMZ 耐药性 MGMT 阳性或 MMR 阴性胶质母细胞瘤相比，这些胶质母细胞瘤是在治疗过程中选择的，并且只有在较高 TMZ 剂量时才会被复制阻断 3-meA 杀死。这两种类型的细胞可以通过抑制不同的 DNA 修复途径而对 TMZ 敏感。然而，在这两种情况下，有毒中间体似乎都是 ssDNA 缺口，这种脆弱性在 BRCA 缺陷型癌症中也存在。 PARP 抑制剂 (PARPi) 最初是为了通过合成致死性治疗 BRCA1/2 缺陷型癌症而开发的，在临床试验中被重新调整用途以增强 TMZ 的效果。我们讨论了我们对 TMZ 毒性遗传决定因素的理解的最新进展如何通过抑制 PARP1 和其他参与修复烷基化损伤的酶（例如 APE1）来开发治疗胶质母细胞瘤的新方法。版权所有 © 2024 Miramova，加特纳和伊万诺夫。

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).Copyright © 2024 Miramova, Gartner and Ivanov.