Role of mtDNA lesions in anthracycline cardiotoxicity.
Doxorubicin (adriamycin) is an effective drug in the treatment of many malignancies. Its prolonged use is, however, limited by an irreversible, dose-dependent and progressive cardiomyopathy, which may become evident even years after completion of therapy. Data from rats and humans show that oxidative phosphorylation is impaired rapidly after acute doxorubicin-exposure. Such respiratory chain dysfunction is known to enhance the production of reactive oxygen species and may lead to quantitative and qualitative injury of mitochondrial DNA (mtDNA) and its encoded respiratory chain subunits. MtDNA depletion, mtDNA mutations and respiratory defects then accumulate with time also in the absence of continued anthracycline exposure. Chronic cardiotoxicity then manifests, when the bioenergetic capacity of the organelles is severely impaired. The mitochondrial damage in late-onset doxorubicin cardiomyopathy is heart specific and not found in skeletal muscle. DOXO-EMCH, a 6-maleimidocaproyl hydrazone derivative of doxorubicin has evolved from the search for less cardiotoxic anthracyclines. At equieffective antitumor doses, DOXO-EMCH has a substantially lower heart toxicity than free doxorubicin.
Lebrecht
Dirk
D
Department of Rheumatology and Clinical Immunology, Albert-Ludwigs University, Medizinische Universitätsklinik, Freiburg, Germany.
Walker
Ulrich A
UA
D000818:Animals; D018943:Anthracyclines / Q000009:adverse effects*; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D009202:Cardiomyopathies / Q000139:chemically induced / Q000473:pathology; D002908:Chronic Disease; D004272:DNA, Mitochondrial / Q000187:drug effects*; D006331:Heart Diseases / Q000139:chemically induced* / Q000473:pathology; D006801:Humans; D011355:Prodrugs / Q000633:toxicity
D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D004272:DNA, Mitochondrial; D011355:Prodrugs