Cerebrospinal Fluid Oxidative Stress During Chemotherapy of Acute Lymphoblastic Leukemia in Children

Abstract

In this study the authors addressed the question whether neurotoxicity due to the chemotherapy of acute lymphoblastic leukemia (ALL) is associated with cerebrospinal fluid (CSF) oxidative stress. Examination of 38 ALL patients revealed significant increases in 8-isoprostane concentration and important decreases in total antioxidative capacity of CSF during therapy. The mean 8-isoprostane level at diagnosis was 9.05 +/- 1.62 pg/mL, and no correlations with initial leukocytosis, organomegaly, and lactate dehydrogenase levels were noted. 8-Isoprostane concentrations were increased on the 59th day of treatment (mean level: 24.85 +/- 7.59 pg/mL [P < .01]) and remained elevated at 4 points of the consolidation phase (17.28 +/- 2.16 pg/mL [P < .05]; 22.72 +/- 6.04 pg/mL [P < .05]; 24.92 +/- 6.31 pg/mL [P < .01]; 32.32 +/- 7.94 pg/mL [P < .01]) as compared to their level at diagnosis. The mean total antioxidative capacity at diagnosis was 203.08 +/- 6.17 mumol/L and was remarkably decreased on the 59th day of treatment (189.76 +/- 1.9 mumol/L [P < .05]) and at one point of the consolidation phase (188.29 +/- 3.46 mumol/L [P < .05]) as compared to the level at diagnosis. This study indicates that neurotoxicity of standard ALL treatment may be related to oxidative stress.

Increase in Oxidative Stress as Measured by Cerebrospinal Fluid Lipid Peroxidation During Treatment for Childhood Acute Lymphoblastic Leukemia

“…In summary, the significant increase in oxidized PC and PI reported here, as well as findings from previous studies showing increased F2-isoprostanes 57, 58 provide collective evidence for oxidative stress as a mechanism associated with intrathecal and intravenous chemotherapy. Future studies are needed to investigate novel neuroprotective strategies that could protect healthy brain tissue from oxidative stress while not compromising the anti-leukemic effects of chemotherapeutic agents.…”

“…This finding supports our hypothesis that CNS treatment disrupts membrane integrity in brain tissue, and increases oxidative stress. Protas and colleagues 58 reported a significant increase in 8-isoprostane concentration (a measure of lipid peroxidation) and decrease in total antioxidant capacity in CSF samples obtained from 38 children with ALL on day 59 of treatment and at 4 time points during intensive CNS-directed treatment which also supports the role of oxidative stress in neurological injury. We reported increased CSF concentrations of F 2 -Isoprostanes during the first 18 months of treatment.…”

F2-Isoprostanes

“…Acute increases in oxidative stress measures were highest among children who received more than six doses of IT MTX during the postinduction phase of treatment. These findings are similar to those of Protas et al (2010) who observed that 8-F 2 -IsoP concentrations were elevated during leukemia treatment.…”

“…However, we were able to find only one study evaluating 8- F 2 -IsoP concentrations in children with cancer. Protas, Muszynska-Roslan, Holownia, Krawczuk-Rybak, and Braszko (2010) found elevated IsoPs in 38 children receiving chemotherapy for leukemia, indicating that neurotoxicity during treatment may be related to oxidative stress.…”

Evaluation of Biomarkers of Oxidative Stress and Apoptosis in Patients With Severe Methotrexate Neurotoxicity

“…MTX increases oxidative stress in several organs, including the brain, and white matter is particularly vulnerable to oxidative stress because of its high lipid content (Inder et al, 2002; Rajamani, Muthuvel, Senthilvelan, & Sheeladevi, 2006). Recent studies confirm an association between oxidative stress levels in the cerebrospinal fluid (CSF), MTX, and CNS injury (Caron et al, 2009; Hockenberry et al, 2013; Protas, Muszynska-Roslan, Holownia, Krawczuk-Rybak, & Braszko, 2010; Stenzel et al, 2010). This paper reports clinical presentations of three patients with severe MTX toxicity as well as CSF levels of oxidative stress and apoptosis biomarkers.…”