Effect of tamoxifen on cell lines displaying the multidrug-resistant phenotype

We examined the effect of tamoxifen (Tmx), verapamil, and daunorubicin (DNR) in two cell lines that displayed the multidrug-resistant (MDR) phenotype and used laser flow cytometry to quantitate intracellular DNR content. In the vinblastine-resistant human lymphoblastic lymphoma cell line CEM-VBL, simultaneous incubation of DNR with Tmx 10 μmol/L or Tmx 50 μmol/L increased intracellular DNR fluorescence in a dose-dependent manner and demonstrated an uptake pattern similar to that seen with DNR and verapamil. Similar results were obtained in the vincristine-resistant human myeloid leukemia cell line HL-60/RV+. Cellular retention of DNR was also measured in both cell lines and results suggested that continuous exposure of the cells to Tmx resulted in higher intracellular DNR content compared with cells resuspended in fresh medium. No effect of Tmx or verapamil was observed in the drug-sensitive parent cell lines CEM or HL-60. Clonogenic experiments were then performed to determine whether Tmx was itself inhibitory to cell growth or whether Tmx potentiated DNR cytotoxicity. Tmx 10 μmol/L did not significantly inhibit either CEM-VBL or HL-60/RV+ cells after a 3-hour exposure followed by culture in methylcellulose. Tmx 50 μmol/L was significantly more inhibitory in both cell lines. However, cells that had been incubated with DNR and Tmx 10 μmol/L demonstrated a marked increment in growth inhibition compared with cells that had been incubated with DNR alone or Tmx 10 μmol/L alone. Based on the data presented here, we suggest that clinical testing of Tmx and DNR be pursued in the setting where MDR may play a role.