Nishiyama M, Horichi N, Mazouzi Z, Bungo M, Saijo N, Tapiero H
Laboratoire de Pharmacologie Cellulaire et Molèculaire, ICIG, Hôpital Paul Brousse, Villejuif, France.
Anticancer Drug Des. 1990 Feb;5(1):135-9.
Accumulation, cytotoxicity, and DNA damages produced by doxorubicin (DOX), pirarubicin (THP-DOX), fluoro-doxorubicin (ME2303) or its isolated metabolite M1 have been investigated in human myelogenous leukemia cells, sensitive (K562) and resistant to DOX (K562/DOX). These compounds differed by lipophilicity and/or sugar moiety either with (DOX, THP-DOX) or without (ME2303, M1) amino group. In K562 cells, the cytotoxicity was correlated to DNA single-stranded breaks and the intracellular drug amount of DOX or M1. This was not true when the cells were treated with THP-DOX or ME2303. In addition, THP-DOX produced total DNA protein cross-linking. In K562 cells DNA damage was not repaired, while in K562/DOX repair of DNA damage produced by all drugs could be observed. Although in K562/DOX cells drug accumulation was much reduced, higher intracellular drug concentration was required to induce similar level of cytotoxicity and DNA damage. Thus, cytotoxicity produced by anthracycline is not always associated with DNA damage. Different level of resistance to DOX, THP-DOX, ME2303 or M1 is associated with reduced drug accumulation which varies with the structure.
已在对阿霉素（DOX）敏感的人骨髓性白血病细胞（K562）和对DOX耐药的人骨髓性白血病细胞（K562/DOX）中研究了阿霉素（DOX）、吡柔比星（THP-DOX）、氟阿霉素（ME2303）或其分离代谢物M1产生的蓄积、细胞毒性和DNA损伤。这些化合物在亲脂性和/或糖部分上存在差异，有的带有（DOX、THP-DOX）氨基，有的不带（ME2303、M1）氨基。在K562细胞中，细胞毒性与DNA单链断裂以及DOX或M1的细胞内药物量相关。当用THP-DOX或ME2303处理细胞时，情况并非如此。此外，THP-DOX会产生总DNA-蛋白质交联。在K562细胞中，DNA损伤未得到修复，而在K562/DOX细胞中，可以观察到所有药物产生的DNA损伤均得到修复。尽管在K562/DOX细胞中药物蓄积大大减少，但需要更高的细胞内药物浓度才能诱导出相似水平的细胞毒性和DNA损伤。因此，蒽环类药物产生的细胞毒性并不总是与DNA损伤相关。对DOX、THP-DOX、ME2303或M1的不同耐药水平与药物蓄积减少有关，而药物蓄积减少随结构而异。
