The unintended neurologic sequelae of chemotherapy contribute to significant patient morbidity. Chemotherapy-related cognitive impairment (CRCI) is observed in up to 80% of cancer patients treated with chemotherapy and involves multiple cognitive domains including executive functioning. The pathophysiology underlying CRCI and the neurotoxicity of chemotherapy is incompletely understood, but oxidative stress and DNA damage are highly plausible mechanisms based on preclinical data. Unfortunately, validating pathways relevant to CRCI in humans is limited by an absence of relevant neuropathologic studies of patient brain tissue. In the present study, we stained sections of frontal lobe autopsy tissue from cancer patients treated with chemotherapy (n = 15), cancer patients not treated with chemotherapy (n = 10), and patients without history of cancer (n = 10) for markers of oxidative stress (nitrotyrosine, 4-hydroxynonenal) and DNA damage (pH2AX, pATM). Cancer patients treated with chemotherapy had increased staining for markers of oxidative stress and DNA damage in frontal lobe cortical neurons compared to controls. We detected no statistically significant difference in oxidative stress and DNA damage by the duration between last administration of chemotherapy and death. The study highlights the potential relevance of oxidative stress and DNA damage in the pathophysiology of CRCI and the neurotoxicity of chemotherapy.

中文翻译：

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化疗患者皮质神经元的氧化应激和 DNA 损伤升高

化疗的意外神经系统后遗症导致显着的患者发病率。在多达 80% 的接受化疗的癌症患者中观察到与化疗相关的认知障碍 (CRCI)，并且涉及多个认知领域，包括执行功能。CRCI 的病理生理学和化疗的神经毒性尚不完全清楚，但基于临床前数据，氧化应激和 DNA 损伤是高度合理的机制。不幸的是，由于缺乏对患者脑组织的相关神经病理学研究，验证与人类 CRCI 相关的途径受到限制。在本研究中，我们对接受化疗的癌症患者（n = 15）、未接受化疗的癌症患者（n = 10）的额叶尸检组织切片进行染色，和没有癌症病史的患者（n = 10）的氧化应激标志物（硝基酪氨酸，4-羟基壬烯醛）和 DNA 损伤（pH2AX，pATM）。与对照组相比，接受化疗的癌症患者额叶皮质神经元中氧化应激和 DNA 损伤标志物的染色增加。我们检测到最后一次化疗和死亡之间的持续时间在氧化应激和 DNA 损伤方面没有统计学上的显着差异。该研究强调了氧化应激和 DNA 损伤在 CRCI 的病理生理学和化疗的神经毒性中的潜在相关性。与对照组相比，接受化疗的癌症患者额叶皮质神经元中氧化应激和 DNA 损伤标志物的染色增加。我们检测到最后一次化疗和死亡之间的持续时间在氧化应激和 DNA 损伤方面没有统计学上的显着差异。该研究强调了氧化应激和 DNA 损伤在 CRCI 的病理生理学和化疗的神经毒性中的潜在相关性。与对照组相比，接受化疗的癌症患者额叶皮质神经元中氧化应激和 DNA 损伤标志物的染色增加。我们检测到最后一次化疗和死亡之间的持续时间在氧化应激和 DNA 损伤方面没有统计学上的显着差异。该研究强调了氧化应激和 DNA 损伤在 CRCI 的病理生理学和化疗的神经毒性中的潜在相关性。