title: Protectors against doxorubicin-induced cardiotoxicity: flavonoids.
abstract: Doxorubicin is a widely used anthracycline anticancer agent. Its use may cause cardiomyopathy: in fact, the development of cumulative dose-related cardiotoxicity forms the major limitation of clinical doxorubicin use. We therefore searched for protective agents that combine iron-chelating and oxygen radical-scavenging properties. Moreover, any novel protector should not interfere with the cytostatic activity of doxorubicin. After extensive in vitro screening we found that flavonoids could serve this purpose. In particular 7-monohydroxyethylrutoside almost completely protected against the negative inotropic action of doxorubicin in the electrically paced mouse left atrium model. In vivo it gave full protection at 500 mg/kg intraperitoneally against the doxorubicin-induced ST-interval lengthening in the ECG. Moreover, this protector did not influence the antitumor effect of doxorubicin either in vitro using the human ovarian cell lines A2780 and OVCAR-3 and the human breast cancer cell line MCF-7 or in vivo in A2780 and OVCAR-3 subcutaneous xenografts in nude mice. Comparison of various iron chelators suggest that iron, in contrast to the general assumption, might not play a crucial role in the oxidative stress-induced toxicity of doxorubicin. Moreover, incubation of vascular endothelial cells with doxorubicin produced overexpression of adhesion molecules, which could be inhibited by 7-monohydroxyethylrutoside. From a study in human volunteers, we conclude that an intravenous dose of 1500 mg/m(2) of 7-monohydroxyethylrutoside is feasible and is safe to be investigated as protection against doxorubicin-induced cardiotoxicity.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Medicine, Maastricht University, Maastricht, The Netherlands. a.bast@farmaco.unimaas.nl
authors.forename: A
authors.initials: A
authors.lastname: Bast
authors.forename: H
authors.initials: H
authors.lastname: Kaiserová
authors.forename: G J M
authors.initials: GJ
authors.lastname: den Hartog
authors.forename: G R M M
authors.initials: GR
authors.lastname: Haenen
authors.forename: W J F
authors.initials: WJ
authors.lastname: van der Vijgh
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D002316:Cardiotonic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000633:toxicity*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004562:Electrocardiography; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006801:Humans; D006896:Hydroxyethylrutoside / Q000031:analogs & derivatives / Q000494:pharmacology; D066298:In Vitro Techniques; D018836:Inflammation Mediators / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009200:Myocardial Contraction / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism
chemical_list: C522803:7-monohydroxyethylrutoside; D000903:Antibiotics, Antineoplastic; D002316:Cardiotonic Agents; D005419:Flavonoids; D006896:Hydroxyethylrutoside; D018836:Inflammation Mediators; D013481:Superoxides; D004317:Doxorubicin; D007501:Iron