EFFECT OF TAMOXIFEN ON MITOXANTRONE CYTOTOXICITY IN DRUG-SENSITIVE AND MULTIDRUG-RESISTANT MCF-7 CELLS

The influence of the antiestrogen tamoxifen (TAM) on the activity of m itoxantrone (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 (A DR), is associated with increased expression of P-glycoprotein (P-gp). In a clonogenic assay it was observed that TAM (1-10 mu M) significan tly 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 stron gly synergistic in the MDR MCF-7/ADR cells. Also, TAM (10 mu M) caused a three-fold increase in the steady-state levels (C-ss) of MXN in MCF -7/ADR cells but did not modulate MXN levels in MCF-7/WT cells. The ob served synergism in MCF-7/ADR cells was perhaps due to the increase in C-ss of MXN that may involve interaction of TAM with P-gp. The combin ation of MXN and TAM may be useful in the treatment of drug-sensitive and drug-resistant breast cancer.