Weitzel Douglas H, Tovmasyan Artak, Ashcraft Kathleen A, Boico Alina, Birer Samuel R, Roy Choudhury Kingshuk, Herndon James, Rodriguiz Ramona M, Wetsel William C, Peters Katherine B, Spasojevic Ivan, Batinic-Haberle Ines, Dewhirst Mark W
Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.
Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina.
Environ Mol Mutagen. 2016 Jun;57(5):372-81. doi: 10.1002/em.22021. Epub 2016 May 25.
Combinations of radiotherapy (RT) and chemotherapy have shown efficacy toward brain tumors. However, therapy-induced oxidative stress can damage normal brain tissue, resulting in both progressive neurocognitive loss and diminished quality of life. We have recently shown that MnTnBuOE-2-PyP(5+) (Mn(III)meso-tetrakis(N-n-butoxyethylpyridinium -2-yl)porphyrin) rescued RT-induced white matter damage in cranially-irradiated mice. Radiotherapy is not used in isolation for treatment of brain tumors; temozolomide is the standard-of-care for adult glioblastoma, whereas cisplatin is often used for treatment of pediatric brain tumors. Therefore, we evaluated the brain radiation mitigation ability of MnTnBuOE-2-PyP(5+) after either temozolomide or cisplatin was used singly or in combination with 10 Gy RT. MnTnBuOE-2-PyP(5+) accumulated in brains at low nanomolar levels. Histological and neurobehavioral testing showed a drastic decrease (1) of axon density in the corpus callosum and (2) rotorod and running wheel performance in the RT only treatment group, respectively. MnTnBuOE-2-PyP(5+) completely rescued this phenotype in irradiated animals. In the temozolomide groups, temozolomide/ RT treatment resulted in further decreased rotorod responses over RT alone. Again, MnTnBuOE-2-PyP(5+) treatment rescued the negative effects of both temozolomide ± RT on rotorod performance. While the cisplatin-treated groups did not give similar results as the temozolomide groups, inclusion of MnTnBuOE-2-PyP(5+) did not negatively affect rotorod performance. Additionally, MnTnBuOE-2-PyP(5+) sensitized glioblastomas to either RT ± temozolomide in flank tumor models. Mice treated with both MnTnBuOE-2-PyP(5+) and radio-/chemo-therapy herein demonstrated brain radiation mitigation. MnTnBuOE-2-PyP(5+) may well serve as a normal tissue radio-/chemo-mitigator adjuvant therapy to standard brain cancer treatment regimens. Environ. Mol. Mutagen. 57:372-381, 2016. © 2016 Wiley Periodicals, Inc.
放射疗法（RT）和化学疗法的联合应用已显示出对脑肿瘤的疗效。然而，治疗引起的氧化应激会损害正常脑组织，导致进行性神经认知功能丧失和生活质量下降。我们最近发现，MnTnBuOE-2-PyP(5+)（三价锰中-四（N-正丁氧基乙基吡啶鎓-2-基）卟啉）可挽救头部受照射小鼠的放疗引起的白质损伤。放射疗法并非单独用于治疗脑肿瘤；替莫唑胺是成人间变性星形细胞瘤的标准治疗药物，而顺铂常用于治疗儿童脑肿瘤。因此，我们评估了在单独使用或与10 Gy放疗联合使用替莫唑胺或顺铂后，MnTnBuOE-2-PyP(5+)对脑辐射的缓解能力。MnTnBuOE-2-PyP(5+)以低纳摩尔水平在脑中蓄积。组织学和神经行为测试表明，仅放疗治疗组的胼胝体轴突密度和转棒及跑步轮性能分别急剧下降。MnTnBuOE-2-PyP(5+)完全挽救了受照射动物的这种表型。在替莫唑胺组中，替莫唑胺/放疗治疗导致转棒反应比单独放疗进一步降低。同样，MnTnBuOE-2-PyP(5+)治疗挽救了替莫唑胺±放疗对转棒性能的负面影响。虽然顺铂治疗组未给出与替莫唑胺组相似的结果，但加入MnTnBuOE-2-PyP(5+)并未对转棒性能产生负面影响。此外，在侧腹肿瘤模型中，MnTnBuOE-2-PyP(5+)使胶质母细胞瘤对放疗±替莫唑胺敏感。本文中接受MnTnBuOE-2-PyP(5+)和放疗/化疗联合治疗的小鼠表现出脑辐射缓解。MnTnBuOE-2-PyP(5+)很可能可作为标准脑癌治疗方案的正常组织放疗/化疗缓解辅助疗法。《环境与分子突变》57:372 - 381，2016年。© 2016威利期刊公司
