Department of Neurosurgery, Seoul National University Bundang Hospital, Seongnam-si, Republic of Korea.
Seoul National University College of Medicine, Seoul, Republic of Korea.
In Vivo. 2021 Jul-Aug;35(4):2015-2023. doi: 10.21873/invivo.12470.
BACKGROUND/AIM: Poly (ADP-ribose) polymerase (PARP) inhibition could enhance the efficacy of temozolomide and prolong survival in patients with glioblastoma. The aim of this study was to evaluate the combination of the PARP inhibitor olaparib with temozolomide in the treatment of glioblastoma.
The in vitro and in vivo antitumor effects of the PARP inhibitor olaparib together with temozolomide were evaluated. The in vitro experimental glioblastoma model involved O-methylguanine methyltransferase (MGMT) promoter-methylated (U87MG, U251MG) and MGMT promoter-unmethylated (T98G) glioblastoma cell lines using In this model cell viability and apoptosis were assessed. For the in vivo studies, nude mice bearing orthotopically xenografted glioblastoma cell lines (U87MG) were randomized to four experimental groups: i) the untreated, ii) temozolomide alone, iii) olaparib alone and iv) olaparib and temozolomide combination groups. Mice were treated daily for 4 weeks and monitored for tumor growth and survival.
In vitro we found that the combination of olaparib with temozolomide enhanced temozolomide-induced cytotoxicity in all glioblastoma cell lines regardless of the status of MGMT promoter methylation. In vivo, mice treated with temozolomide alone or in combination with olaparib showed greater survival than those untreated or with the olaparib monotherapy, as well as significantly decreased tumor volume. There was no significant difference in survival and tumor volume between temozolomide alone and the combination treatment.
The combination of the PARP inhibitor olaparib with temozolomide could be promising candidates for combination therapy of glioblastoma regardless of the MGMT promoter methylation status.
背景/目的：聚（ADP-核糖）聚合酶（PARP）抑制剂可以增强替莫唑胺的疗效并延长胶质母细胞瘤患者的生存期。本研究旨在评估 PARP 抑制剂奥拉帕利与替莫唑胺联合治疗胶质母细胞瘤的效果。
评估了 PARP 抑制剂奥拉帕利与替莫唑胺联合的体外和体内抗肿瘤作用。体外实验使用 O-甲基鸟嘌呤甲基转移酶（MGMT）启动子甲基化（U87MG、U251MG）和 MGMT 启动子未甲基化（T98G）胶质母细胞瘤细胞系构建的实验性胶质母细胞瘤模型，评估了该模型中的细胞活力和细胞凋亡。对于体内研究，将荷位移植胶质母细胞瘤细胞系（U87MG）的裸鼠随机分为四组实验：i）未治疗组，ii）替莫唑胺单独治疗组，iii）奥拉帕利单独治疗组和 iv）奥拉帕利和替莫唑胺联合治疗组。小鼠每日接受治疗 4 周，并监测肿瘤生长和生存情况。
我们发现，奥拉帕利与替莫唑胺联合使用可增强替莫唑胺在所有胶质母细胞瘤细胞系中的细胞毒性作用，而与 MGMT 启动子甲基化状态无关。在体内，与未治疗或奥拉帕利单药治疗相比，替莫唑胺单独或联合奥拉帕利治疗的小鼠的生存时间更长，肿瘤体积更小。替莫唑胺单独治疗与联合治疗的生存时间和肿瘤体积无显著差异。
PARP 抑制剂奥拉帕利与替莫唑胺的联合治疗可能是胶质母细胞瘤联合治疗的有前途的候选药物，而与 MGMT 启动子甲基化状态无关。
