Protectors against doxorubicin-induced cardiotoxicity: flavonoids.

Full 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.

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Author information

Author/s: Bast, A (A); Kaiserová, H (H); den Hartog, G J M (GJ); Haenen, G R M M (GR); van der Vijgh, W J F (WJ);

Affiliation: Department of Pharmacology and Toxicology, Faculty of Medicine, Maastricht University, Maastricht, The Netherlands. a.bast(-atsign-)farmaco.unimaas.nl

Journal and publication information

Publication Type: In Vitro; Journal Article

Journal: Cell biology and toxicology (Cell Biol Toxicol), published in Netherlands. (Language: eng)

Reference: 2007-Jan; vol 23 (issue 1) : pp 39-47

Dates: Created 2006/12/12; Completed 2007/10/11;

PMID: 17063376, status: MEDLINE (last retrieval date: 12/26/2008)

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Animals
Antibiotics, Antineoplastic - toxicity
Cardiotonic Agents - pharmacology
Cell Line, Tumor
Doxorubicin - toxicity
Drug Evaluation, Preclinical - methods
Electrocardiography
Female
Flavonoids - pharmacology
Heart - drug effects; physiopathology

Humans
Hydroxyethylrutoside - analogs & derivatives; pharmacology
Inflammation Mediators - metabolism
Iron - metabolism
Male
Mice
Mice, Inbred BALB C
Mice, Nude
Myocardial Contraction - drug effects
Superoxides - metabolism

Associated Chemicals: 7-monohydroxyethylrutoside (0) ; Antibiotics, Antineoplastic (0) ; Cardiotonic Agents (0) ; Flavonoids (0) ; Hydroxyethylrutoside (0) ; Inflammation Mediators (0) ; Superoxides (11062-77-4) ; Doxorubicin (23214-92-8) ; Iron (7439-89-6)

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