Hu X F, Slater A, Wall D M, Parkin J D, Kantharidis P, Zalcberg J R
Department of Medical Oncology and Haematology, Austin and Repatriation Medical Centre, Melbourne, Australia.
Clin Cancer Res. 1996 Apr;2(4):713-20.
We have previously demonstrated that within 24 h of exposure of the CEM/A7R cell line to epirubicin (EPI), MDR1 gene expression is induced. The aim of the current study was to investigate the role of cyclosporin A (CyA) and PSC 833, two biochemical modulators of the classical multidrug-resistant phenotype, in this model. CEM/A7R cells were exposed to EPI in the presence or absence of various concentrations of CyA or PSC 833. MDR1 expression was assessed using Northern blot analysis and quantitated using a phosphorimager. P-glycoprotein (P-gp) expression was analyzed by the determination of MRK16 binding using flow cytometry. P-gp function was measured in an assay of [3H]daunomycin accumulation. The coincubation of CyA or PSC 833 with EPI prevented the increase in MDR1 gene expression induced by EPI alone. This effect of the two modulators was dose dependent. Neither modulator alone had any significant effect on the expression of MDR1. In these experiments, changes in MDR1 expression correlated with changes in P-gp levels (based on MRK16 binding) and P-gp function. Thus, both PSC 833 and CyA appear to prevent the induction of MDR1 gene expression caused by the short-term exposure of CEM/A7R cells to EPI.
我们之前已经证明，在CEM/A7R细胞系暴露于表柔比星（EPI）24小时内，MDR1基因表达被诱导。本研究的目的是在该模型中研究环孢素A（CyA）和PSC 833这两种经典多药耐药表型的生化调节剂的作用。将CEM/A7R细胞在存在或不存在不同浓度的CyA或PSC 833的情况下暴露于EPI。使用Northern印迹分析评估MDR1表达，并使用磷光成像仪进行定量。通过流式细胞术测定MRK16结合来分析P-糖蛋白（P-gp）表达。在[3H]柔红霉素积累测定中测量P-gp功能。CyA或PSC 833与EPI共同孵育可防止单独使用EPI诱导的MDR1基因表达增加。这两种调节剂的这种作用是剂量依赖性的。单独使用任何一种调节剂对MDR1的表达均无显著影响。在这些实验中，MDR1表达的变化与P-gp水平（基于MRK16结合）和P-gp功能的变化相关。因此，PSC 833和CyA似乎都能阻止CEM/A7R细胞短期暴露于EPI引起的MDR1基因表达的诱导。
