7-monohydroxyethylrutoside protects against chronic doxorubicin-induced cardiotoxicity when administered only once per week

Doxorubicin is a very effective antitumor agent, but its clinical use is li mited by the occurrence of a cumulative dose-related cardiotoxicity, result ing in congestive heart failure, 7-Monohydroxyethylrutoside (monoHER), a fl avonoid belonging to the semisynthetic hydroxyethylrutoside family, has bee n shown to protect against doxorubicin-induced cardiotoxicity when administ ered i.p. at a dose of 500 mg/kg five times/week in combination with a week ly i.v. dose of doxorubicin. Such a dosing schedule would be very inconveni ent in clinical practice. We therefore investigated a dosing schedule of on e administration of monoHER just before doxorubicin. The electrocardiogram was measured telemetrically in mice after the combined treatment of doxorub icin (4 mg/kg, i.v.) with one dose of monoHER (500 mg/kg, i.p., administere d 1 h before doxorubicin) for 6 weeks. These data were compared with the Ev e times/week schedule (500 mg/kg, i.p., administered 1 h before doxorubicin and every 24 h for 4 days). The increase of the ST interval was used as a measure for cardiotoxicity. It was shown that 500 mg/kg monoHER administere d only 1 h before doxorubicin provided complete protection against the card iotoxicity. This protection was present for at least 10 weeks after the las t treatment, Because of the short half-life of monoHER, these results sugge st that the presence of monoHER is only necessary during the highest plasma levels of doxorubicin.