Santostasi G, Kutty R K, Krishna G
Section on Drug-Tissue Interaction, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892.
Toxicol Appl Pharmacol. 1991 Mar 15;108(1):140-9. doi: 10.1016/0041-008x(91)90277-l.
Calcium channel blocking drugs have been reported to reduce survival rate of laboratory animals treated with cardiotoxic antitumor anthracyclines. In order to elucidate the mechanisms of this drug 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 ([Ca2+]0) 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 anthracyclines in the cardiomyocytes was increased by calcium entry blockers (nifedipine, flunarizine, and verapamil) and by low [Ca2+]0; efflux of [3H]daunorubicin from myocardial cells was inhibited by nifedipine. At a dose that exerts only modest calcium channel activity, R-verapamil failed to affect doxorubicin accumulation in cardiomyocytes, whereas the calcium channel activator, (+/-)-Bay K-8644, reduced the retention of anthracyclines; the calcium channel activity is thus required in order to increase the accumulation of anthracyclines in myocardial cells. Calcium channel blockers are also known to increase intracellular retention and toxicity of chemotherapeutic drugs in multidrug resistant tumor cells by inhibiting the efflux of cytotoxic agents from cells; however, the ability of the interacting drugs to inhibit the efflux of chemotherapeutic agents from tumor cells is not dependent on the calcium channel blocking activity. Therefore, the mechanism(s) by which calcium channel blocking drugs increase the accumulation of anthracyclines in resistant tumor cells and myocardial cells may be different. In accordance with previous investigations, the present in vitro study confirmed that anthracycline-induced cardiotoxicity may be potentiated by calcium channel blocking drugs. This indicates that, in the association of antineoplastic drugs with agents that reverse multidrug resistance, the potential exists for enhanced damage of normal cells and tissues; further studies are needed to evaluate the relevance of this adverse interaction.
据报道，钙通道阻滞剂会降低接受心脏毒性抗肿瘤蒽环类药物治疗的实验动物的存活率。为了阐明这种药物相互作用的机制，我们在从新生大鼠分离的心肌细胞原代培养物中评估了蒽环类药物阿霉素和柔红霉素的细胞毒性。低浓度的细胞外钙（[Ca2+]0）以及添加钙通道阻滞剂（硝苯地平或氟桂利嗪）会增强蒽环类药物的心肌毒性，这可通过细胞中乳酸脱氢酶的释放来评估。钙通道阻滞剂（硝苯地平、氟桂利嗪和维拉帕米）以及低[Ca2+]0会增加蒽环类药物在心肌细胞中的蓄积；硝苯地平会抑制[3H]柔红霉素从心肌细胞中的流出。在仅发挥适度钙通道活性的剂量下，R-维拉帕米未能影响阿霉素在心肌细胞中的蓄积，而钙通道激活剂（±）-Bay K-8644会减少蒽环类药物的滞留；因此，为了增加蒽环类药物在心肌细胞中的蓄积需要钙通道活性。已知钙通道阻滞剂还会通过抑制细胞毒性药物从细胞中的流出，增加多药耐药肿瘤细胞中化疗药物的细胞内滞留和毒性；然而，相互作用的药物抑制化疗药物从肿瘤细胞中流出的能力并不依赖于钙通道阻断活性。因此，钙通道阻滞剂增加蒽环类药物在耐药肿瘤细胞和心肌细胞中蓄积的机制可能不同。与先前的研究一致，目前的体外研究证实钙通道阻滞剂可能会增强蒽环类药物诱导的心脏毒性。这表明，在抗肿瘤药物与逆转多药耐药的药物联合使用时，存在增强对正常细胞和组织损伤的可能性；需要进一步研究来评估这种不良相互作用的相关性。
