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Preclinical evaluation of the cardiotoxicity of taxane-anthracycline combinations using the model of isolated perfused rat heart.

Paclitaxel strongly potentiates the cardiotoxicity of doxorubicin in the clinical setting. In this study, we aimed (1) to determine whether this potentiation could be reproduced in an ex vivo model and, if so, (2) to select drugs and protocols that did not cause this potentiation. The effect of paclitaxel and docetaxel on the cardiotoxicity induced by doxorubicin and epirubicin was studied using the model of isolated perfused rat heart. Cardiac performances were evaluated after several combination protocols administered every 2 days over a period of 12 days, and anthracycline concentrations in the heart and liver were determined on Day 12. When administered simultaneously, paclitaxel strongly potentiated the cardiotoxicity of doxorubicin ex vivo, and this effect was not due to Cremophor EL, the solvent used in the formulation of paclitaxel. The potentiation of anthracycline cardiotoxicity could be avoided by the replacement of doxorubicin by epirubicin, and/or of paclitaxel by docetaxel. Cardiotoxic potentiation was also avoided by the introduction of a 24-h lag time between the repetitive injections of doxorubicin and docetaxel. The concentration of doxorubicin and its cardiotoxic metabolite, doxorubicinol, in the heart and liver was not significantly altered by the taxanes, but that of epirubicin was increased twofold both in the heart and the liver. These results show that the potentiation of doxorubicin-induced cardiotoxicity by paclitaxel can be reproduced with an ex vivo model, and that it is not related to an increase in tissue concentration of the drug or active metabolite. Our model, therefore, may be useful for the selection of anthracycline-containing protocols with no increased risk of cardiotoxicity for the patients.