Abstract
IntroductionCentral nervous system (CNS) treatment using intrathecal chemotherapy and cranial radiation to enable long-term disease-free survival from childhood acute lymphoblastic leukemia (ALL) comes at the cost of neurotoxic side effects and long-term sequelae. We investigated oxidative stress as a possible mechanism of chemotherapy-induced neurotoxicity in children with ALL.Materials and methodsIn this case-control study, we estimated the cerebrospinal fluid (CSF) levels of 8-hydroxy-deoxyguanosine (8-OH-dG), a DNA damage product, in children with B-cell ALL and control children. CSF samples were collected at diagnosis, at end of Induction 1, Induction 2, and Induction 2A - consolidation phase. CSF 8-OH-dG levels were compared in children with and without neurotoxicity.ResultsChildren with ALL (n=23) at diagnosis had significantly higher median (interquartile range, IQR) CSF 8-OH-dG levels (ng/mL) compared to controls (n=19) [1.97 (1.59-2.56) Vs 0.65 (0.59-0.82), P<0.001]. CSF 8-OH-dG levels at the end of four weeks, eight weeks, and 16 weeks of chemotherapy were [3.96 (2.85-5.44) ng/mL], 1.00 (0.89-1.09), and 3.73 (2.80-4.39) ng/mL, respectively. Out of 23 children with ALL, 12 developed neurotoxicity; the CSF levels of 8-OH-dG in them were only marginally higher compared to those who did not develop neurotoxicity. The CSF 8-OH-dG levels did not show a significant correlation with the number of doses of methotrexate or vincristine received.ConclusionChemotherapy increases the CNS oxidative stress as measured by CSF 8-OH-dG levels, with the levels being proportional to the intensity of chemotherapy. Children with neurotoxicity had only marginally higher CSF 8-OH-dG levels as compared to children without neurotoxicity.
Highlights
Central nervous system (CNS) treatment using intrathecal chemotherapy and cranial radiation to enable long-term disease-free survival from childhood acute lymphoblastic leukemia (ALL) comes at the cost of neurotoxic side effects and long-term sequelae
Chemotherapy increases the CNS oxidative stress as measured by cerebrospinal fluid (CSF) 8-OH-dG levels, with the levels being proportional to the intensity of chemotherapy
It has been shown that flavoproteins transfer electrons from nicotinamide adenine dinucleotide hydrogen (NADH) and flavin adenine dinucleotide hydrogen (FADH) to chemotherapeutic drugs like doxorubicin, a drug commonly used in the treatment of hematological malignancies including leukemia
Summary
In this case-control study, we estimated the cerebrospinal fluid (CSF) levels of 8-hydroxy-deoxyguanosine (8-OH-dG), a DNA damage product, in children with B-cell ALL and control children. CSF 8OH-dG levels were compared in children with and without neurotoxicity. This pilot study was conducted in the division of pediatric hematology-oncology of a tertiary hospital in Delhi, India, between February 2018 and April 2019. We included children (≤12 years) with newly diagnosed B-cell acute lymphoblastic leukemia in the study. Children with CNS involvement at diagnosis of ALL, and any child receiving anti-oxidants or multivitamin supplements in the preceding four weeks were excluded. The control group included children presenting with complex febrile seizures or seizures triggered by fever, in whom a diagnostic lumbar puncture was indicated to exclude meningitis; none of them had any serious illness, septicemia, or malignant disease. Informed written consent was obtained from all caregivers of participants and prior approval from the institutional ethics committee was obtained
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