Monohydroxyethylrutoside, a dose-dependent cardioprotective agent, does not affect the antitumor activity of doxorubicin.
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.
van Acker
S A
SA
Leiden Amsterdam Center for Drug Research, Division of Molecular Pharmacology, Department of Pharmacochemistry, Faculty of Chemistry, Vrije Universiteit, Amsterdam, The Netherlands.
Boven
E
E
Kuiper
K
K
van den Berg
D J
DJ
Grimbergen
J A
JA
Kramer
K
K
Bast
A
A
van der Vijgh
W J
WJ
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D001943:Breast Neoplasms / Q000473:pathology; D009202:Cardiomyopathies / Q000139:chemically induced / Q000517:prevention & control*; D002392:Catechin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D015913:Chelation Therapy; D018284:Cystadenocarcinoma, Serous / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D004347:Drug Interactions; D004562:Electrocardiography; D005260:Female; D005419:Flavonoids / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D044948:Flavonols; D016166:Free Radical Scavengers; D005609:Free Radicals; D006801:Humans; D006896:Hydroxyethylrutoside / Q000494:pharmacology* / Q000627:therapeutic use; D007501:Iron; D007502:Iron Chelating Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D044949:Kaempferols; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000473:pathology; D011794:Quercetin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D011929:Razoxane / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D012431:Rutin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D013686:Telemetry; D014407:Tumor Cells, Cultured / Q000187:drug effects; D015431:Weight Loss / Q000187:drug effects
D000903:Antibiotics, Antineoplastic; D000975:Antioxidants; D005419:Flavonoids; D044948:Flavonols; D016166:Free Radical Scavengers; D005609:Free Radicals; D006896:Hydroxyethylrutoside; D007502:Iron Chelating Agents; D044949:Kaempferols; D011929:Razoxane; D012431:Rutin; C006552:kaempferol; D004317:Doxorubicin; D002392:Catechin; D011794:Quercetin; C003377:taxifolin; D007501:Iron