PMID: 1386843Jul 1, 1992Paper

Toremifene and its metabolites enhance doxorubicin accumulation in estrogen receptor negative multidrug resistant human breast cancer cells

Investigational New Drugs
V J WiebeM DeGregorio


The enhanced accumulation of doxorubicin by agents known to reverse multidrug resistance provides a good functional test for evaluating modulating activity. In the present study, the non-steroidal triphenylethylene toremifene selectively increased doxorubicin accumulation in multidrug resistant estrogen receptor negative MDA A-1 human breast cells compared to the MDA 231 wild type cells. MDA A-1 cells were noted to be 1,000 fold resistant to doxorubicin (IC 50 = less than 0.1 microgram/ml MDA 231; IC 50 = 100 micrograms/ml MDA A-1). Total accumulation of doxorubicin, expressed as area under the time concentration curve (AUC), was increased significantly in doxorubicin resistant cells (156% increase) versus wild type MDA 231 cells (6% increase). Correction of the accumulation defect to doxorubicin in drug resistant cells required a 18-20 hour pre-incubation with toremifene. The effects of toremifene on cell cycle in MDA A-1 cells was analyzed by flow cytometric techniques. Toremifene had a dose response relationship in blocking cells in G0-G1 reducing the number of cells entering S phase of the cell cycle. This effect was maximal at concentrations which increased the accumulation of doxorubicin in MDA A-1 cells. Several metaboli...Continue Reading


Sep 1, 1989·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·M W DeGregorioV J Wiebe
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