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 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.
van Acker
F A
FA
Department of Medical Oncology, University Hospital Vrye Universiteit, Amsterdam, The Netherlands. f.vanacker.azvu.nl.
van Acker
S A
SA
Kramer
K
K
Haenen
G R
GR
Bast
A
A
van der Vijgh
W J
WJ
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D004317:Doxorubicin / Q000009:adverse effects / Q000494:pharmacology*; D004334:Drug Administration Schedule; D004562:Electrocardiography; D005419:Flavonoids / Q000494:pharmacology; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006896:Hydroxyethylrutoside / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009206:Myocardium / Q000473:pathology; D015430:Weight Gain / Q000187:drug effects
D000970:Antineoplastic Agents; D005419:Flavonoids; D006896:Hydroxyethylrutoside; D004317:Doxorubicin