Calcium channel blocking drugs have been reported to reduce survival rate of laboratory animals treated with the cardiotoxic antitumor anthracyclines. In order to elucidate the mechanisms of this clinically relevant interaction, cell toxicity of the anthracyclines, doxorubicin and daunorubicin, was evaluated in primary cultures of cardiac myocytes, isolated from neonatal rats. Low concentrations of extracellular calcium and addition of calcium entry blockers (nifedipine or flunarizine) potentiated myocardial toxicity of anthracyclines as assessed by the release of lactate dehydrogenase from the cells. Accumulation of anthracycline in the cardiomyocytes was increased by calcium entry blockers (nifedipine, flunarizine and verapamil) and by low extracellular calcium; efflux of [3H]-daunorubicin from myocardial cells was inhibited by nifedipine. These data are consistent with the presence in myocardial cells of a membrane transporter which accelerates the efflux of anthracyclines; whether this carrier is related to the glycoprotein GP170, which induces the outward transport of chemotherapeutic drugs from tumor cells, remains to be elucidated. Calcium channel blockers are known to combine with the GP170 and prevent the efflux of cyt-otoxic agents from multi-drug resistant tumor cells. In myocardial cells, however, doxorubicin retention was not affected by R(+)-verapamil, which lacks calcium channel blocking activity, and was reduced by the calcium channel agonist, Bay K-8644. Calcium channel blocking activity is thus required in order to increase the accumulation of anthracyclines in cardiomyocytes. These data indicate that anthracycline-induced cardiotoxicity may be potentiated during the course of calcium channel blocking therapy.
