In vitro modeling of the structure-activity determinants of anthracycline cardiotoxicity.
Doxorubicin and other anthracyclines rank among the most effective anticancer drugs ever developed. Unfortunately, the clinical use of anthracyclines is limited by a dose-related life-threatening cardiotoxicity. Understanding how anthracyclines induce cardiotoxicity is essential to improve their therapeutic index or to identify analogues that retain activity while also inducing less severe cardiac damage. Here, we briefly review the prevailing hypotheses on anthracycline-induced cardiotoxicity. We also attempt to establish cause-and-effect relations between the structure of a given anthracycline and its cardiotoxicity when administered as a single agent or during the course of multiagent chemotherapies. Finally, we discuss how the hypotheses generated by preclinical models eventually translate into phase I-II clinical trials.
Menna
P
P
Department of Drug Sciences and Center of Excellence on Aging, G. dAnnunzio University School of Medicine, Chieti, Italy. pmenna@unich.it
Minotti
G
G
Salvatorelli
E
E
D000438:Alcohols / Q000378:metabolism; D000818:Animals; D018943:Anthracyclines / Q000008:administration & dosage / Q000737:chemistry* / Q000633:toxicity*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity; D002986:Clinical Trials as Topic; D004187:Disaccharides / Q000737:chemistry / Q000633:toxicity; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000737:chemistry / Q000633:toxicity; D004353:Drug Evaluation, Preclinical; D015251:Epirubicin / Q000737:chemistry / Q000633:toxicity; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006801:Humans; D066298:In Vitro Techniques; D008955:Models, Cardiovascular; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship; D043823:Taxoids / Q000008:administration & dosage / Q000633:toxicity
D000438:Alcohols; D018943:Anthracyclines; D000970:Antineoplastic Agents; D004187:Disaccharides; D017382:Reactive Oxygen Species; D043823:Taxoids; D015251:Epirubicin; D004317:Doxorubicin; C107602:sabarubicin