Long-term effects of 7-monohydroxyethylrutoside (monoHER) on DOX-induced cardiotoxicity in mice

• Published in: Cancer chemotherapy and pharmacology Vol. 60; no. 4; pp. 509 - 514
• Main Authors: BRNYNZEEL, Anna M. E, VORMER-BONNE, Suzanne, BAST, Aalt, NIESSEN, Hans W. M, VAN DER VIJGH, Wim J. F
• Format: Journal Article
• Language: English
• Published: Berlin Springer 01.09.2007; Springer Nature B.V
• Subjects: Animals; Anticancer properties; Antioxidants; Behavior, Animal - drug effects; Biological and medical sciences; Cardiotoxicity; Congestive heart failure; Doxorubicin; Doxorubicin - adverse effects; Drug Evaluation, Preclinical; Drug toxicity and drugs side effects treatment; Flavonoids; Heart Diseases - pathology; Heart Diseases - prevention & control; Hydroxyethylrutoside - analogs & derivatives; Hydroxyethylrutoside - therapeutic use; Long-term effects; Male; Medical sciences; Mice; Mice, Inbred BALB C; Myocardium - ultrastructure; Oxidants; Oxidizing agents; Pharmacology. Drug treatments; Time; Toxicity: cardiovascular system; Weight loss; Weight Loss - drug effects; Antineoplastic agent; DNA topoisomerase (ATP-hydrolysing); Drug combination; Enzyme; Toxicity; Rodentia; Cardioprotective agent; Enzyme inhibitor; Cardiotoxicity; Doxorubicin; Flavonoid; Long term; Polyphenol; Vertebrata; Isomerases; Mammalia; Mouse; Animal; Phenols; MonoHER; Anthracyclins; Drug interaction; Monohydroxyethylrutoside; Cardioprotection, Long-term follow-up
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-006-0395-2

Doxorubicin (DOX) is a potent antitumor agent for different types of cancer, but the cumulative, dose-related cardiotoxicity limits its clinical use. The incidence of abnormal cardiac function after treatment with DOX appears to increase with time. Therefore, late cardiotoxicity is-especially in young surviving patients-a major concern. The aim of this study was to evaluate in mice whether the semisynthetic flavonoid 7-monohydroxyethylrutoside (monoHER) also protected against DOX-induced cardiotoxicity after a long period of follow-up. Four groups of 6 Balb/c mice were treated weekly during 6 weeks with saline, DOX alone (4 mg/kg i.v.), DOX preceded by monoHER (500 mg/kg i.p.), or DOX preceded by monoHER followed by long-term weekly monoHER injections during the observation period of 6 months. Half of the mice treated with DOX only developed DOX-induced heart failure and died within 6 months of observation. Two mice co-treated with monoHER showed weight loss and shortness of breath, whereas one mouse was found dead in its cage known with weight loss. The group receiving DOX plus long-term repeated doses of monoHER started to lose weight. Five out of six mice in this group developed shortness of breath and died before the end of the study with symptoms of cardiac failure induced by DOX. Statistical comparison of the histological heart damage between the different experimental groups was not possible, because the animals died at different time-points in the observation period and DOX-induced cardiotoxicity progressed with time. Nevertheless, it was clear that the initial cardioprotective effect of monoHER was not prolonged during the half-year observation period. It was even suggested that addition of repeated doses of monoHER tended to aggravate DOX-induced cardiotoxicity. It cannot be excluded that the dose and frequency of monoHER administration is crucial in obtaining an optimal antioxidant activity without a pro-oxidant activity of monoHER.