Tapiero H, Nguyen-Ba G, Lampidis T J
Laboratoire de Pharmacologie Cellulaire et Moléculaire, ICIG, Hôpital Paul Brousse, Villejuif, France.
Pathol Biol (Paris). 1994 Apr;42(4):328-37.
Positively charged doxorubicin (DOX) and non-positively charged anthracyclines, aclarubicin (ACR) and morpholino-carminomycin (KRN 8602), have been investigated with respect to pharmacological parameters, cytotoxicity, DNA damage and repair in DOX-sensitive and -resistant murine and human cells. Friend leukemia cells (FLC) resistant to high concentrations of doxorubicin (DOX-RFLC3) or daunorubicin (DNR-RFLC3) (1771 and 1543 fold resistance respectively) express less than 10 fold resistance to aclarubicin (ACR). In these cells, the intracellular accumulation of ACR is similar in sensitive and resistant cells. Resistance to ACR was not observed in either DOX-RFLC1 or DNR1 with a lower level of resistance (27 fold). Increased expression of a 170,000-dalton surface antigen (gp-170) was found to be correlated with the level of resistance. However, when the selective agent in ACR, despite the low level of resistance (2.8 fold) both high expression of gp 170 and resistance to DOX (77 fold) or DNR (62 fold) are observed. It is assumed therefore that induction of multidrug resistance phenotype can be achieved by compounds which do not display cross resistance with DOX or DNR. Reduced levels or absence of cross-resistance can be related to the electrical charge of the compound. This assumption is supported by further studies on DOX-sensitive or -resistant human K562 cells exposed to another non-positively charged anthracycline, KRN 8602. In the continuous presence of drug, K562/DOX were less resistant to KRN 8602 (2.9 fold) than to DOX (31 fold). After short time exposure followed by growth in drug-free medium, absence of cross-resistance to KRN 8602 has been observed in K562/DOX. Furthermore, accumulation experiments showed that high intracellular drug concentrations were rapidly achieved (within 15 min) in both DOX-sensitive and -resistant cells. In cells exposed to DOX, DNA single-strand break (DNA-SSBs) frequencies were related to time and drug concentration while those produced by KRN 8602 or ACR were maximal after short time incubation. DNA-SSBs produced by these anthracyclines are not repaired when cells are incubated in drug free medium. In DOX resistant cells, DNA-SSBs produced by DOX were repaired whereas those produced by ACR or KRN 8602 were not. It is suggested, therefore, that absence of cross resistance to various anthracyclines is related to differences in the chemical electrical charge, which may influence drug accumulation and DNA repair in resistant cells.
针对带正电荷的阿霉素（DOX）以及不带正电荷的蒽环类药物阿柔比星（ACR）和吗啉代卡米霉素（KRN 8602），研究了它们在对DOX敏感和耐药的小鼠及人类细胞中的药理学参数、细胞毒性、DNA损伤及修复情况。对高浓度阿霉素（DOX-RFLC3）或柔红霉素（DNR-RFLC3）耐药的Friend白血病细胞（分别具有1771倍和1543倍耐药性）对阿柔比星（ACR）的耐药性小于10倍。在这些细胞中，ACR在敏感细胞和耐药细胞中的细胞内蓄积情况相似。在耐药水平较低（27倍）的DOX-RFLC1或DNR1细胞中均未观察到对ACR的耐药性。发现一种170,000道尔顿表面抗原（gp-170）的表达增加与耐药水平相关。然而，当ACR中的选择剂存在时，尽管耐药水平较低（2.8倍），但同时观察到gp 170的高表达以及对DOX（77倍）或DNR（62倍）的耐药性。因此推测，多药耐药表型的诱导可通过与DOX或DNR无交叉耐药性的化合物实现。交叉耐药性降低或不存在可能与化合物的电荷有关。对DOX敏感或耐药的人K562细胞暴露于另一种不带正电荷的蒽环类药物KRN 8602的进一步研究支持了这一推测。在持续存在药物的情况下，K562/DOX对KRN 8602的耐药性（2.9倍）低于对DOX的耐药性（31倍）。在短时间暴露后于无药培养基中生长，在K562/DOX中未观察到对KRN 8602的交叉耐药性。此外，蓄积实验表明，在DOX敏感和耐药细胞中均能迅速（15分钟内）达到高细胞内药物浓度。在暴露于DOX的细胞中，DNA单链断裂（DNA-SSBs）频率与时间和药物浓度相关，而KRN 8602或ACR产生的DNA-SSBs在短时间孵育后达到最大值。当细胞在无药培养基中孵育时，这些蒽环类药物产生的DNA-SSBs不会被修复。在DOX耐药细胞中，DOX产生的DNA-SSBs会被修复，而ACR或KRN 8602产生的则不会。因此，有人提出，对各种蒽环类药物无交叉耐药性与化学电荷差异有关，这可能会影响耐药细胞中的药物蓄积和DNA修复。
