7-monohydroxyethylrutoside and Heart-Diseases

The purpose of this study was to investigate the cardioprotective effect of the semisynthetic flavonoid 7-monohydroxyethylrutoside (monoHER) on doxorubicin (DOX)-induced cardiotoxicity in a phase II study in patients with metastatic cancer. Eight patients with metastatic cancer were treated with DOX preceded by a 10 min i.v. infusion of 1500 mg m(-2) monoHER. Five patients were examined by endomyocardial biopsy after reaching a cumulative dose of 300 mg m(-2). Histopathological changes in the cardiomyocytes (Billingham score) were compared with those described in literature for patients treated with DOX only. The mean biopsy score of the patients was higher (2.7) than the mean score (1.4) of historical data of patients who received similar cumulative doses of DOX. Although there is a considerable variability in few investigated patients, it was indicative that monoHER enhanced DOX-induced cardiotoxicity. However, the antitumour activity of DOX seemed better than expected: three of the four patients with metastatic soft-tissue sarcoma had a partial remission and the fourth patient stable disease. It is likely that the relatively high dose of monoHER is responsible for the lack of cardioprotection and for the high response rate in patients with soft-tissue sarcoma possibly by depleting the glutathione defense system in both heart and tumour.

Topics: Adult; Antibiotics, Antineoplastic; Doxorubicin; Female; Heart Diseases; Humans; Hydroxyethylrutoside; Male; Middle Aged; Myocytes, Cardiac; Neoplasms

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.

Topics: Animals; Behavior, Animal; Doxorubicin; Drug Evaluation, Preclinical; Heart Diseases; Hydroxyethylrutoside; Male; Mice; Mice, Inbred BALB C; Myocardium; Time; Weight Loss