Moore Ida M Ki, Koerner Kari M, Gundy Patricia M, Montgomery David W, Insel Kathleen C, Harris Lynnette L, Taylor Olga A, Hockenberry Marilyn J
1 College of Nursing, The University of Arizona, Tucson, AZ, USA.
2 The University of Arizona, Tucson, AZ, USA.
Biol Res Nurs. 2018 Jul;20(4):393-402. doi: 10.1177/1099800418763124. Epub 2018 Mar 7.
Aggressive central nervous system (CNS)-directed treatment for acute lymphoblastic leukemia (ALL), the most prevalent cancer among children and adolescents, prevents metastasis of leukemia cells into the brain. Up to 60% of survivors experience cognitive problems, but knowledge about risk factors for and mechanisms of neurologic injury is lacking. Objectives of the present study were to (1) quantify changes in oxidant defense and apoptosis over the course of ALL therapy and (2) elucidate risk factors for long-term cognitive problems. The sample included 71 children with ALL. Cerebrospinal fluid (CSF) samples were collected at diagnosis and during intrathecal chemotherapy administration. Oxidant defense was measured by reduced glutathione (GSH), oxidized glutathione (GSSG), and the ratio of GSH:GSSG. Apoptosis was measured by activity of several cysteine-dependent aspartate-specific protease (abbreviated as caspase) enzymes that initiate (caspases 8 and 9) or execute (caspases 3/7) apoptosis. Cognitive abilities were assessed by standardized measures of short-term memory, visual-motor integration, and attention 3 years after ALL diagnosis. GSH and GSSG concentration increased significantly during ALL therapy, and a low GSH:GSSG ratio was indicative of an oxidized extracellular environment. Caspase enzyme activity increased significantly, and caspases 3/7 activity was significantly and negatively associated with performance on measures of cognitive abilities. Younger age at time of ALL diagnosis was associated with some measures of attention. Efflux of glutathione into CSF maintains oxidant defense by scavenging free radicals and other reactive oxygen species and is an early event in apoptosis. These mechanisms may be involved in neurologic injury associated with CNS-directed treatment and subsequent cognitive problems.
侵袭性中枢神经系统（CNS）导向治疗急性淋巴细胞白血病（ALL），这是儿童和青少年中最常见的癌症，可防止白血病细胞转移至脑部。高达60%的幸存者会出现认知问题，但缺乏关于神经损伤的危险因素及机制的相关知识。本研究的目的是：（1）量化ALL治疗过程中氧化防御和细胞凋亡的变化；（2）阐明长期认知问题的危险因素。样本包括71名ALL患儿。在诊断时及鞘内化疗期间采集脑脊液（CSF）样本。通过还原型谷胱甘肽（GSH）、氧化型谷胱甘肽（GSSG）以及GSH:GSSG比值来测定氧化防御。通过几种启动（半胱天冬酶8和9）或执行（半胱天冬酶3/7）细胞凋亡的半胱氨酸依赖性天冬氨酸特异性蛋白酶（简称为半胱天冬酶）的活性来测定细胞凋亡。在ALL诊断3年后，通过短期记忆、视觉运动整合和注意力的标准化测量来评估认知能力。在ALL治疗期间，GSH和GSSG浓度显著升高，低GSH:GSSG比值表明细胞外环境处于氧化状态。半胱天冬酶活性显著增加，且半胱天冬酶3/7活性与认知能力测量指标的表现显著负相关。ALL诊断时年龄较小与某些注意力测量指标相关。谷胱甘肽向CSF的外流通过清除自由基和其他活性氧来维持氧化防御，并且是细胞凋亡的早期事件。这些机制可能与CNS导向治疗相关的神经损伤及随后的认知问题有关。
