Desai P B, Bhardwaj R, Damle B
Division of Medicinal Chemistry and Pharmaceutics, School of Pharmacy, Northeast Louisiana University, Monroe 71209-0470, USA.
Cancer Chemother Pharmacol. 1995;36(5):368-72. doi: 10.1007/BF00686184.
The influence of the antiestrogen tamoxifen (TAM) on the activity of mitoxantrone (MXN), was evaluated against wild-type MCF-7/WT and their multidrug-resistant variant MCF-7/ADR cells. Multidrug resistance (MDR) in this cell line which was selected for resistance to Adriamycin (ADR), is associated with increased expression of P-glycoprotein (P-gp). In a clonogenic assay it was observed that TAM (1-10 microM) significantly enhanced the activity of MXN in the MCF-7/ADR but not in the drug-sensitive cell line. Isobologram analysis indicated that the effect of the combination was additive in the parental MCF-7/WT cells and strongly synergistic in the MDR MCF-7/ADR cells. Also, TAM (10 microM) caused a three-fold increase in the steady-state levels (Css) of MXN in MCF-7/ADR cells but did not modulate MXN levels in MCF-7/WT cells. The observed synergism in MCF-7/ADR cells was perhaps due to the increase in Css of MXN that may involve interaction of TAM with P-gp. The combination of MXN and TAM may be useful in the treatment of drug-sensitive and drug-resistant breast cancer.
评估了抗雌激素他莫昔芬（TAM）对米托蒽醌（MXN）活性的影响，实验对象为野生型MCF-7/WT细胞及其多药耐药变体MCF-7/ADR细胞。该细胞系对阿霉素（ADR）具有耐药性，其多药耐药性（MDR）与P-糖蛋白（P-gp）表达增加有关。在克隆形成试验中观察到，TAM（1-10微摩尔）显著增强了MXN在MCF-7/ADR细胞中的活性，但在药物敏感细胞系中未观察到这种增强作用。等效线图分析表明，该组合在亲本MCF-7/WT细胞中的作用是相加的，而在MDR MCF-7/ADR细胞中具有强烈的协同作用。此外，TAM（10微摩尔）使MCF-7/ADR细胞中MXN的稳态水平（Css）增加了三倍，但未调节MCF-7/WT细胞中MXN的水平。在MCF-7/ADR细胞中观察到的协同作用可能是由于MXN的Css增加，这可能涉及TAM与P-gp的相互作用。MXN与TAM的组合可能对治疗药物敏感型和耐药型乳腺癌有用。
