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Impaired mitochondrial function is abrogated by dexrazoxane in doxorubicin‐treated childhood acute lymphoblastic leukemia survivors
Author(s) -
Lipshultz Steven E.,
Anderson Lynn M.,
Miller Tracie L.,
Gerschenson Mariana,
Stevenson Kristen E.,
Neuberg Donna S.,
Franco Vivian I.,
LiButti Daniel E.,
Silverman Lewis B.,
Vrooman Lynda M.,
Sallan Stephen E.
Publication year - 2016
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.29872
Subject(s) - dexrazoxane , medicine , mitochondrial dna , doxorubicin , peripheral blood mononuclear cell , mitochondrion , oxidative phosphorylation , cancer , cancer research , microbiology and biotechnology , chemotherapy , biology , biochemistry , gene , breast cancer , anthracycline , in vitro
BACKGROUND Impaired cardiac function in doxorubicin‐treated childhood cancer survivors is partly mediated by the disruption of mitochondrial energy production. Doxorubicin intercalates into mitochondrial DNA (mtDNA) and disrupts genes encoding for polypeptides that make adenosine triphosphate. METHODS This cross‐sectional study examined mtDNA copy numbers per cell and oxidative phosphorylation (OXPHOS) in peripheral blood mononuclear cells (PBMCs) in 64 childhood survivors of high‐risk acute lymphoblastic leukemia (ALL) who had been treated on Dana‐Farber Cancer Institute childhood ALL protocols and had received doxorubicin alone (42%) or doxorubicin with the cardioprotectant dexrazoxane (58%). The number of mtDNA copies per cell and the OXPHOS enzyme activity of nicotinamide adenine dinucleotide dehydrogenase (complex I [CI]) and cytochrome c oxidase (complex IV [CIV]) were measured with quantitative real‐time polymerase chain reaction immunoassays and thin‐layer chromatography, respectively. RESULTS At a median follow‐up of 7.8 years after treatment, the median number of mtDNA copies per cell for patients treated with doxorubicin alone (1106.3) was significantly higher than the median number for those who had also received dexrazoxane (310.5; P = .001). No significant differences were detected between the groups for CI or CIV activity. CONCLUSIONS Doxorubicin‐treated survivors had an increased number of PBMC mtDNA copies per cell, and concomitant use of dexrazoxane was associated with a lower number of mtDNA copies per cell. Because of a possible compensatory increase in mtDNA copies per cell to maintain mitochondrial function in the setting of mitochondrial dysfunction, overall OXPHOS activity was not different between the groups. The long‐term sustainability of this compensatory response in these survivors at risk for cardiac dysfunction over their lifespan is concerning. Cancer 2016;122:946–53 . © 2016 American Cancer Society .