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7-Monohydroxyethylrutoside Protects against Chronic Doxorubicin-induced Cardiotoxicity When Administered Only Once Per Week

Department of Medical Oncology, University Hospital Vre Universiteit [F. A. A. v. A., S. A. B. E. v. A., W. J. F. v. d. V.] and Leiden/Amsterdam Center for Drug Research, Department of Pharmacochemistry, Faculty of Chemistry [F. A. A. v. A., S. A. B. E. v. A., K. K.], Vrije Universiteit, 1081 HV Amsterdam, the Netherlands, and Department of Pharmacology and Toxicology, University Maastricht, 6200 MD Maastricht, the Netherlands [G. R. M. M. H., A. B.]

Doxorubicin is a very effective antitumor agent, but its clinical use is limited by the occurrence of a cumulative dose-related cardiotoxicity, resulting in congestive heart failure. 7-Monohydroxyethylrutoside (monoHER), a flavonoid belonging to the semisynthetic hydroxyethylrutoside family, has been shown to protect against doxorubicin-induced cardiotoxicity when administered i.p. at a dose of 500 mg/kg five times/week in combination with a weekly i.v. dose of doxorubicin. Such a dosing schedule would be very inconvenient in clinical practice. We therefore investigated a dosing schedule of one administration of monoHER just before doxorubicin. The electrocardiogram was measured telemetrically in mice after the combined treatment of doxorubicin (4 mg/kg, i.v.) with one dose of monoHER (500 mg/kg, i.p., administered 1 h before doxorubicin) for 6 weeks. These data were compared with the five 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 administered only 1 h before doxorubicin provided complete protection against the cardiotoxicity. This protection was present for at least 10 weeks after the last treatment. Because of the short half-life of monoHER, these results suggest that the presence of monoHER is only necessary during the highest plasma levels of doxorubicin.

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