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Cardioprotective Properties of O-(β-Hydroxyethyl)-rutosides in Doxorubicin-pretreated BALB/c Mice¹

Department of Pharmacochemistry [S. A. B. E. V., J. d-J., A. B.], Faculty of Chemistry, Vrije Universiteit, De Boelelaan 1083, Department of Oncology [H. T. M., W. J. F. V.], Free University Hospital, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands; Department of Internal Medicine, Utrecht University Hospital, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands [E. E. V.]; Laboratory for Pathology, National Institute of Public Health and Environmental Protection, Antonie van Leeuwenhoeklaan 9, 3720 BA Bilthoven, The Netherlands [D. B. B.]

² To whom requests for reprints should be addressed.

Chronic doxorubicin-induced cardiotoxicity is believed to be caused by the formation of oxygen free radicals. Thus O-(β-hydroxyethyl)-rutosides, a standardized flavonoid mixture (Venoruton) with iron chelating and radical scavenging activity, might provide protection. Therefore, we investigated the (cardio)protective effect of Venoruton (1.5 g/kg injected i.p. on days 1-5, 8-12,15-19, and 22-26) in BALB/c mice treated with doxorubicin (4 mg/kg injected i.v. on days 1,8,15, and 22) compared with mice treated with doxorubicin alone. Saline-treated animals served as controls. No mortality was encountered in either of the groups; weight gain data suggest little general toxicity of this dose schedule. The basal frequency of the isolated right atria was increased in doxorubicin-pretreated animals as compared to control animals (468 ± 22 and 366 ± 20 beats/min, respectively). Venoruton coadministration diminished this increase (373 ± 17 beats/min). The -log of the concentration giving 50% effect of l-isoprenaline on the right atrium was changed after doxorubicin pretreatment (8.33 ± 0.04 versus 8.86 ± 0.06 for control animals). Venoruton coadministration resulted in a smaller shift in the -log of the concentration giving 50% effect (8.51 ± 0.10) than with doxorubicin alone. The extent of cardiotoxicity found in the functional studies was confirmed by histological scoring of heart ventricle damage. It can be concluded that Venoruton has the potential to protect against doxorubicin-induced cardiotoxicity.

¹ Supported by Grant IKA 92-127 awarded by the Dutch Cancer Society.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 3/31/93. Accepted 7/23/93.

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