Grey M, Borg A G, Wood P, Burgess R, Fisher A, Yin J A
University Department of Clinical Haematology, Manchester Royal Infirmary, UK.
Leuk Res. 1997 Sep;21(9):867-74. doi: 10.1016/s0145-2126(97)00059-3.
Multidrug resistance (MDR) mediated by the drug efflux pump P-glycoprotein (Pgp), may cause remission failure and relapse in patients with acute myeloid leukaemia (AML) by extruding cytotoxic agents such as anthracyclines from leukaemic cells thus allowing them to survive. Cell line data suggest that reversal of MDR is possible using modifying drugs such as cyclosporin A (CSA) and its analogue PSC 833. We have investigated the effects on cell kill of the addition of CSA and PSC 833 to daunorubicin, idarubicin, mitozantrone, etoposide and cytarabine in 52 fresh cell samples from AML patients using an MTT assay. Pgp status was determined by using monoclonal antibodies JSB-1 and MRK-16 and by assessment of rhodamine efflux. Although overall each cytotoxic-modifier combination produced significant improvements in cell kill compared to cytotoxic alone (P values ranged from P < 0.001 to P = 0.017), modifiers also produced significant cytotoxicity in their own right, and no consistent difference was seen between responses in Pgp-positive and negative groups. Up to one in three Pgp-positive samples failed to show any improvement in cell kill with the addition of CSA or PSC 833, possibly owing to co-expression of alternative resistance mechanisms not affected by the MDR modifiers. The best responses were seen when PSC 833 was added to idarubicin, with 7 out of 22 Pgp-positive cases (32%) showing five-fold improvements in cell kill or better compared to idarubicin alone. Comparison of equimolar concentrations of the two modifiers in the Pgp positive group failed to show a significant difference in cell kill, though PSC 833 was markedly superior to CSA in a minority of highly responsive samples which demonstrated clear evidence of MDR reversal. Our in vitro data suggest that MDR modifiers such as CSA and PSC 833 could play an important role in the therapy of AML and indicate the need for prospective randomised trials to assess their clinical efficacy.
由药物外排泵P-糖蛋白（Pgp）介导的多药耐药（MDR），可能通过将阿霉素等细胞毒性药物从白血病细胞中排出，从而使白血病细胞得以存活，导致急性髓系白血病（AML）患者缓解失败和复发。细胞系数据表明，使用环孢素A（CSA）及其类似物PSC 833等修饰药物有可能逆转MDR。我们使用MTT法研究了在来自AML患者的52个新鲜细胞样本中，将CSA和PSC 833添加到柔红霉素、伊达比星、米托蒽醌、依托泊苷和阿糖胞苷中对细胞杀伤的影响。通过使用单克隆抗体JSB-1和MRK-16以及评估罗丹明外排来确定Pgp状态。尽管总体而言，与单独使用细胞毒性药物相比，每种细胞毒性药物与修饰剂的组合在细胞杀伤方面都有显著改善（P值范围从P < 0.001到P = 0.017），但修饰剂本身也产生了显著的细胞毒性，并且在Pgp阳性和阴性组的反应中未观察到一致的差异。高达三分之一的Pgp阳性样本在添加CSA或PSC 833后细胞杀伤没有任何改善，这可能是由于不受MDR修饰剂影响的其他耐药机制的共表达。当将PSC 833添加到伊达比星中时观察到最佳反应，22例Pgp阳性病例中有7例（32%）与单独使用伊达比星相比，细胞杀伤提高了五倍或更好。在Pgp阳性组中比较两种修饰剂的等摩尔浓度，未显示细胞杀伤有显著差异，尽管在少数显示出MDR逆转明确证据的高反应性样本中，PSC 833明显优于CSA。我们的体外数据表明，CSA和PSC 833等MDR修饰剂可能在AML治疗中发挥重要作用，并表明需要进行前瞻性随机试验来评估它们的临床疗效。
