title: An introduction to the metabolic determinants of anthracycline cardiotoxicity.
abstract: Antitumor therapy with doxorubicin and other anthracyclines is limited by the possible development of cardiomyopathy upon chronic administration. Several lines of evidence suggest that a close link exists between cardiotoxicity and the amount of anthracycline that accumulates in the heart and then undergoes one- or two- electron reduction to toxic metabolites or by-products. Alternative metabolic pathways lead to an oxidative degradation of anthracyclines, possibly counteracting anthracycline accumulation and reductive bioactivation; unfortunately, however, the actual role of anthracycline oxidation is only partially characterized. Here, we briefly review the biochemical foundations of reductive versus oxidative anthracycline metabolism. We show that multiple links exist between one pathway of toxic biactivation and another, limiting the search and clinical development of "better anthracyclines" that retain antitumor activity but induce less cardiotoxicity than the available analogues.
authors.affiliation: Department of Drug Sciences and Center of Excellence on Aging, G. d'Annunzio University School of Medicine, Chieti, Italy.
authors.forename: Pierantonio
authors.initials: P
authors.lastname: Menna
authors.forename: Stefania
authors.initials: S
authors.lastname: Recalcati
authors.forename: Gaetano
authors.initials: G
authors.lastname: Cairo
authors.forename: Giorgio
authors.initials: G
authors.lastname: Minotti
mesh_terms: D000818:Animals; D018943:Anthracyclines / Q000009:adverse effects* / Q000378:metabolism*; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects* / Q000378:metabolism*; D004583:Electrons; D006331:Heart Diseases / Q000139:chemically induced* / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000009:adverse effects; D009206:Myocardium / Q000378:metabolism; D010084:Oxidation-Reduction
chemical_list: D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D007501:Iron