Mutational analysis of the mitochondrial tRNA genes and flanking regions in lymphocytes from long-term pediatric cancer survivors given doxorubicin chemotherapy for acute lymphoblastic leukemia.

backgroundDoxorubicin induced cardiotoxicity in childhood cancer survivors is mediated by mitochondrial dysfunction. The aims of this research are to determine (i) the frequency of mitochondrial DNA (mtDNA) mutations in long-term survivors of childhood acute lymphoblastic leukemia (ALL), and (ii) to determine if co-administration of dexrazoxane reduces the occurrence of mutations.

methodsPatients previously treated on Dana-Farber Cancer Institute Childhood ALL protocols and at least 4 years from the date of ALL diagnosis were enrolled in this study. MtDNA was isolated from samples of peripheral blood lymphocytes. A vertical denaturing gradient gel electrophoresis method was used for detecting sequence variants in the 22 transfer RNA (tRNA) genes and flanking regions of the human mitochondrial genome. The patients were divided into two cohorts, those with mutations and those without, and compared. The patients and variants were also compared to healthy controls. Mutational status was compared with echocardiographic measurements.

resultsOf the patients who received chemotherapy, there were 51/167 (31%) children who were found to have 61 different sequence variants in mtDNA with 9 patients having more than one variant. There was no association between mutation status and cumulative doxorubicin dose, though patients receiving < 300 mg/m

conclusionsThe results of this study indicate that doxorubicin chemotherapy is associated with increases in mtDNA sequence variants in lymphocytes. The role of mtDNA mutations in late-onset cardiomyopathy of doxorubicin, and the potential antimutagenic activity of dexrazoxane, were not established but warrant further investigation.