COMPARISON OF CYTOTOXICITY IN HEART-CELLS AND TUMOR-CELLS EXPOSED TO DNA INTERCALATING AGENTS INVITRO
COMPARISON OF CYTOTOXICITY IN HEART-CELLS AND TUMOR-CELLS EXPOSED TO DNA INTERCALATING AGENTS INVITRO
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DOI：
10.1097/00001813-199102000-00003
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发表时间：
1991-02-01
影响因子：
2.3
通讯作者：
LEE, KM
中科院分区：
文献类型：
--
作者：
DORR, RT;SHIPP, NG;LEE, KM
利用体外肿瘤细胞和心脏细胞的细胞毒性试验，评价了一种新的抗肿瘤类似物选择方法。8种蒽环类抗生素和5种非蒽环类DNA插入剂分别体外暴露于人8226骨髓瘤细胞和新生大鼠心肌细胞。肿瘤细胞用MTT染色法和心脏细胞用ATP含量法测定培养6天后的存活率。50%细胞中的抑制药物浓度（IC50）通过对数线性剂量-反应曲线测定。肿瘤细胞的IC50值从阿霉素的0.002 μ g/ml到阿霉素的主要代谢产物阿霉素醇的3.5 μ g/ml不等。相比之下，蒽环类药物在大鼠心脏细胞中的IC50值平均约为肿瘤细胞的357倍。母体蒽环类阿霉素的心脏细胞/肿瘤IC50比为114.4。对肿瘤细胞具有较差细胞毒性选择性的化合物包括阿霉素、氨奈德、阿沙林和双戊二烯。降低心脏毒性的化合物包括蒽环类药物柔红霉素（IC50比550）、柔红霉素（IC50比1500）和蒽衍生物米托蒽酮（IC50比500）。这些结果表明，同时比较心脏细胞和肿瘤细胞的细胞毒性可以识别出在体内产生较少心脏毒性的药物，如柔红霉素和米托蒽醌。通过进一步的测试，该方法可能适用于临床前筛选程序，以选择具有低心脏毒性潜力的活性DNA插入剂。
A new approach to antitumor analog selection was evaluated using in vitro cytotoxicity assays in tumor cells and heart cells. Eight anthracycline antibiotics and five nonanthracycline DNA intercalating agents were separately exposed to human 8226 myeloma cells and neonatal rat heart myocytes in vitro. Survival was measured after six days of culture by the MTT dye method for tumor cells and by ATP content for heart cells. Inhibitory drug concentrations in 50% of cells (IC50) were determined from log-linear dose-response curves for each agent. The IC50 values in the tumor cells ranged from 0.002-mu-g/ml for idarubicin to 3.5-mu-g/ml for the primary metabolite of doxorubicin, doxorubicinol. In contrast, IC50 values for anthracyclines in rat heart cells averaged approximately 357-fold higher than in the tumor cells. The heart cell/tumor IC50 ratio was 114.4 for the parent anthracycline doxorubicin. Compounds with poor cytotoxic selectivity for tumor cells included doxorubicinol, amonafide, amsacrine and bisantrene. Compounds with reduced cardiotoxicity included the anthracyclines daunorubicin (IC50 ratio of 550), esorubicin (IC50 ratio of 1500) and the anthracene derivative mitoxantrone (IC50 ratio of 500). These results show that simultaneous comparisons of cytotoxicity in heart cells and tumor cells can identify agents such as daunorubicin and mitoxantrone which are known to produce less cardiac toxicity in vivo. With further testing, this methodology may be applicable to preclinical screening programs to select active DNA intercalating agents with low cardiotoxic potential.