Institute for Integrated Radiation and Nuclear Science Kyoto University, Kumatori-cho, Sennan-gun, Osaka, 590-0494, Japan.
Institute for Integrated Radiation and Nuclear Science Kyoto University, Kumatori-cho, Sennan-gun, Osaka, 590-0494, Japan.
Appl Radiat Isot. 2020 Sep;163:109204. doi: 10.1016/j.apradiso.2020.109204. Epub 2020 Apr 25.
Temozolomide (TMZ) is a DNA-alkylating agent used for chemo-radiotherapy of glioblastoma, which is also a target cancer for boron neutron capture therapy (BNCT). Although the DNA-repair enzyme O-methylguanine DNA methyltransferase (MGMT) and the tumor suppressor p53 are mutated in some glioblastoma cells, it remains unknown whether these mutations affect sensitivity to neutron irradiation. We examined sensitivity to neutron irradiation and TMZ in two glioblastoma cell lines: T98G, which is p53-mutant with high levels of MGMT activity; and A172, which is p53-wild-type and has low MGMT activity. T98G cells were more resistant to TMZ treatment than A172 cells, with a 10-fold higher LC50. In A172 cells, TMZ treatment did not change the cell-killing effect of neutron irradiation in the presence of borono-phenylalanine (BPA). By contrast, T98G cells were more resistant to neutron irradiation when BPA was present. These results indicate that DNA repair activity in T98G cells might be higher due to upregulation of MGMT after TMZ treatment. Thus, differences in the MGMT and p53 statuses of glioblastoma cells might predict the effect of combination therapy with BNCT and DNA-alkylating agent.
替莫唑胺（TMZ）是一种用于胶质母细胞瘤放化疗的 DNA 烷化剂，也是硼中子俘获治疗（BNCT）的靶向癌症。尽管一些胶质母细胞瘤细胞中存在 DNA 修复酶 O-甲基鸟嘌呤 DNA 甲基转移酶（MGMT）和肿瘤抑制因子 p53 的突变，但这些突变是否影响对中子辐射的敏感性尚不清楚。我们研究了两种胶质母细胞瘤细胞系对中子辐射和 TMZ 的敏感性：T98G，其 p53 突变且 MGMT 活性高；A172，其 p53 野生型且 MGMT 活性低。与 A172 细胞相比，T98G 细胞对 TMZ 治疗的耐药性更强，LC50 高 10 倍。在 A172 细胞中，硼苯丙氨酸（BPA）存在时，TMZ 治疗不会改变中子辐射的细胞杀伤作用。相比之下，当存在 BPA 时，T98G 细胞对中子辐射的抵抗力更强。这些结果表明，TMZ 治疗后 MGMT 的上调可能导致 T98G 细胞的 DNA 修复活性更高。因此，胶质母细胞瘤细胞中 MGMT 和 p53 状态的差异可能预测 BNCT 和 DNA 烷化剂联合治疗的效果。
