CHRONIC CARDIOTOXICITY OF DOXORUBICIN
MEASURED BY TELEMETRY IN MICE

K. Kramer, S.A.B.E. van Acker, J.A. Grimbergen, W.J.F. van der Vijgh and A. Bast. Leiden/Amsterdam Center for Drug Research, Division of Molecular Pharmacology, Department of Pharmacochemistry, Vrije Universiteit, Amsterdam, The Netherlands.

Oxygen free radicals play a role in the cardiotoxicity of doxorubicin (Dox). The clinical use of Dox is limited by a cumulative dose-related cardiotoxicity. In laboratory animals, histology is most commonly used to study Dox-induced cardiotoxicity, in combination with biological and functional parameters. However, for monitoring during treatment, a large number of animals is needed. In literature, there are several reports on electrocardiogram (ECG) changes after chronic Dox-administration in anaesthetized laboratory animals. Recently, we developed a new method to measure ECG in freely moving mice by telemetry (1). With this model, we investigated the effect of chronic Dox administration on the ECG of freely moving Balb/c mice equipped with a telemeter and the efficacy of ICRF-187 as a protecting agent. The mice were given 6 weekly doses of 4 mg/kg doxorubicin intravenously and, when appropriate, 50 mg/kg ICRF-187 intraperitoneally one hour prior to Dox administration. After 6 weeks the ST-interval in Dox-treated mice had widened significantly, however in ICRF-187 co-mediated mice there was no significant difference in the ST-interval compared with the control animals. These data were confirmed by histology since it was found that the histological scores per individual mouse correlated very well with the increase in ST-interval (r=0.902). In conclusion, the ECG measured by telemetry can be considered as a valuable and sensitive tool for measuring cardiotoxic effects of anticancer agents and the effect of protectors by monitoring the animal during treatment. In addition, telemetry makes it possible to monitor without introducing interfering factors and saves animals and time compared with histology.

References
1. Kramer et al., J. Pharmacol. Toxicol. Meth. 1993, 30(4), 209-215.