rutin and Weight-Loss

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

The cumulative dose-related cardiotoxicity of doxorubicin is believed to be caused by the production of oxygen- free radicals. 7-Monohydroxyethylrutoside (monoHER), a semisynthetic flavonoid and powerful antioxidant, was investigated with respect to the prevention of doxorubicin-induced cardiotoxicity in mice and to its influence on the antitumor activity of doxorubicin in vitro and in vivo. Non-tumor-bearing mice were equipped with a telemeter in the peritoneal cavity. They were given six weekly doses of 4 mg/kg doxorubicin i.v., alone or in combination with either 100 or 250 mg/kg monoHER i.p., 1 h prior to doxorubicin administration and for the following 4 days. Cardiotoxic effects were measured from electrocardiogram changes up to 2 weeks after treatment. Protection against cardiotoxicity was found to be dose dependent, with 53 and 75% protection, respectively, as calculated from the reduction in the increase in the ST interval. MonoHER and several other flavonoids with good antioxidant properties were tested for their antiproliferative effects in the absence or the presence of doxorubicin in A2780 and OVCAR-3 human ovarian cancer cells and MCF-7 human breast cancer cells in vitro. Some flavonoids were directly toxic at 50 and 100 microM, whereas others, including monoHER, did not influence the antiproliferative effects of doxorubicin at these concentrations. The influence of monoHER was further tested on the growth-inhibitory effect of 8 mg/kg doxorubicin i.v., given twice with an interval of 1 week in A2780 and OVCAR-3 cells that were grown as s.c. xenografts in nude mice. MonoHER, administered 1 h before doxorubicin in a dose schedule of 500 mg/kg i.p. 2 or 5 days per week, was not toxic and did not decrease the antitumor activity of doxorubicin. It can be concluded that monoHER showed a dose-dependent protection against chronic cardiotoxicity and did not influence the antitumor activity of doxorubicin in vitro or in vivo.

Topics: Animals; Antibiotics, Antineoplastic; Antioxidants; Breast Neoplasms; Cardiomyopathies; Catechin; Chelation Therapy; Cystadenocarcinoma, Serous; Dose-Response Relationship, Drug; Doxorubicin; Drug Interactions; Electrocardiography; Female; Flavonoids; Flavonols; Free Radical Scavengers; Free Radicals; Humans; Hydroxyethylrutoside; Iron; Iron Chelating Agents; Kaempferols; Mice; Mice, Nude; Molecular Structure; Neoplasm Transplantation; Ovarian Neoplasms; Quercetin; Razoxane; Rutin; Telemetry; Tumor Cells, Cultured; Weight Loss