title: Impaired mitochondrial function is abrogated by dexrazoxane in doxorubicin-treated childhood acute lymphoblastic leukemia survivors.
abstract: 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.
authors.affiliation: Wayne State University School of Medicine, Department of Pediatrics, Children's Hospital of Michigan, Detroit, Michigan.|Karmanos Cancer Institute, Detriot, Michigan.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Lipshultz
authors.affiliation: Department of Cell and Molecular Biology Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawaii.
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Anderson
authors.affiliation: Department of Pediatrics, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Tracie L
authors.initials: TL
authors.lastname: Miller
authors.affiliation: Department of Cell and Molecular Biology Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawaii.
authors.forename: Mariana
authors.initials: M
authors.lastname: Gerschenson
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Stevenson
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Donna S
authors.initials: DS
authors.lastname: Neuberg
authors.affiliation: Wayne State University School of Medicine, Department of Pediatrics, Children's Hospital of Michigan, Detroit, Michigan.
authors.forename: Vivian I
authors.initials: VI
authors.lastname: Franco
authors.affiliation: Department of Cell and Molecular Biology Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawaii.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: LiButti
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Department of Pediatrics, Harvard Medical School, Boston, Massachusetts.|Department of Medicine, Divison of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Lewis B
authors.initials: LB
authors.lastname: Silverman
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Department of Pediatrics, Harvard Medical School, Boston, Massachusetts.|Department of Medicine, Divison of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Lynda M
authors.initials: LM
authors.lastname: Vrooman
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Department of Pediatrics, Harvard Medical School, Boston, Massachusetts.|Department of Medicine, Divison of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Sallan
mesh_terms: D000293:Adolescent; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D002855:Chromatography, Thin Layer; D003430:Cross-Sectional Studies; D056915:DNA Copy Number Variations / Q000187:drug effects*; D004272:DNA, Mitochondrial / Q000187:drug effects*; D064730:Dexrazoxane / Q000627:therapeutic use*; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects*; D042967:Electron Transport Complex I / Q000187:drug effects / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D010766:Phosphorylation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D012737:Sex Factors; D017741:Survivors
chemical_list: D000903:Antibiotics, Antineoplastic; D002316:Cardiotonic Agents; D004272:DNA, Mitochondrial; D064730:Dexrazoxane; D004317:Doxorubicin; D003576:Electron Transport Complex IV; D042967:Electron Transport Complex I
keywords: childhood cancer survivors; dexrazoxane; doxorubicin; mitochondrial DNA; mitochondrial function