RESTORATION OF DAUNOMYCIN RETENTION IN MULTIDRUG-RESISTANT P388 CELLS BY SUBMICROMOLAR CONCENTRATIONS OF SDZ PSC-833, A NONIMMUNOSUPPRESSIVE CYCLOSPORINE DERIVATIVE
RESTORATION OF DAUNOMYCIN RETENTION IN MULTIDRUG-RESISTANT P388 CELLS BY SUBMICROMOLAR CONCENTRATIONS OF SDZ PSC-833, A NONIMMUNOSUPPRESSIVE CYCLOSPORINE DERIVATIVE
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DOI：
10.1016/0014-4827(91)90452-z
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发表时间：
1991-09-01
影响因子：
3.7
通讯作者：
LOOR, F
中科院分区：
文献类型：
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作者：
BOESCH, D;MULLER, K;LOOR, F
P-糖蛋白的过表达可引起多种抗癌药物外排增加，从而导致肿瘤细胞的多药耐药。使用了两种小鼠单核细胞白血病P388细胞亚系，一种是亲本细胞（Par-P388），一种是多药耐药细胞（MDR-P388）。在体外细胞生长抑制试验中，Par-P388细胞对柔红霉素（DAU）的敏感性正常，而MDR-P388细胞对DAU的耐药率高达200倍。在细胞荧光测定中，MDR-P388细胞中的DAU保留仅达到Par-P388细胞中达到的水平的5%。该细胞系对用于比较非免疫抑制性环孢菌素类似物PSC 833与几种耐药修饰剂（RMA）的体外化学增敏活性和DAU保留的恢复。PSC 833在0.1和0.3 μg/ml（0.08和0.25 μM）浓度下分别致敏MDR-P388细胞60倍和140倍，在1.0 μg/ml PSC 833浓度下完全恢复敏感性。类似地，低至0.1 μg/ml（0.08 μM）的PSC 833足以将细胞内DAU保留恢复至Par-P388细胞中发现的水平的60%，高3倍的浓度几乎恢复了整个DAU保留。对于这两种活性，PSC 833的活性至少比CsA高一个数量级，CsA本身比维拉帕米（另一种已用于临床的RMA）强一个数量级。由于PSC 833对Par-P388细胞没有影响，既没有化学增敏作用，也没有药物滞留作用，因此推测它通过抑制P-糖蛋白泵的功能并因此恢复MDR-P388细胞的正常ACD敏感性而作用于在MDR-P388细胞膜上高度表达的P-糖蛋白。
Overexpression of P-glycoprotein may cause increased efflux of a variety of anticancer drugs (ACD) leading to multidrug resistance (MDR) of tumor cells. Two sublines of murine monocytic leukemia P388 cells were used, one parental (Par-P388) and one multidrug resistant (MDR-P388). In cell growth inhibition assaysin vitro, the Par-P388 cells showed a normal sensitivity to daunomycin (DAU) while the MDR-P388 cells were 200-fold resistant. In cellular fluorescence assays, DAU retention in MDR-P388 cells reached only 5% of the level achieved in Par-P388 cells. This cell line pair was used to compare the nonimmunosuppressive cyclosporin analog PSC 833 with several resistance-modifying agents (RMAs) for theirin vitrochemosensitizing activity and for their restoration of DAU retention. PSC 833 sensitized the MDR-P388 cells 60- and 140-fold when used at 0.1 and 0.3 μg/ml (0.08 and 0.25 μM), respectively, a complete restoration of sensitivity being obtained at 1.0 μg/ml PSC 833. Similarly as little as 0.1 μg/ml (0.08 μM) PSC 833 was sufficient to restore intracellular DAU retention to 60% of the level found in Par-P388 cells, a 3-fold higher concentration restoring virtually the whole DAU retention. For both these activities, PSC 833 was at least one order of magnitude more active than CsA, which was itself an order of magnitude stronger than verapamil, another RMA already used in clinic. Since PSC 833 had no effect on the Par-P388 cells, neither on chemosensitization nor on drug retention, it is assumed that it acts on the P-glycoprotein, which is highly expressed on the membrane of the MDR-P388 cells, by inhibiting the function of the P-glycoprotein pump and thus restoring a normal ACD-sensitivity of the MDR-P388 cells.