Protectors against doxorubicin-induced cardiotoxicity: Flavonoids.

Bast, A.; Kaiserová, H.; den Hartog, G. J. M.; Haenen, G. R. M. M.; van der Vijgh, W. J. F.

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/m2 of 7-monohydroxyethylrutoside is feasible and is safe to be investigated as protection against doxorubicin-induced cardiotoxicity.

DOXORUBICIN; ANTHRACYCLINES; CARDIOMYOPATHIES; DOSE-response relationship in poisons; FLAVONOIDS; PROTECTIVE groups (Chemistry); PATHOLOGICAL physiology; CARDIOVASCULAR diseases risk factors; THERAPEUTICS

Cell Biology & Toxicology, 2007, Vol 23, Issue 1, p39

0742-2091

Academic Journal

10.1007/s10565-006-0139-4