Toremifene and its metabolites enhance doxorubicin accumulation in estrogen receptor negative multidrug resistant human breast cancer cells.
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 metabolites of toremifene were also noted to increase doxorubicin accumulation in MDA A-1 doxorubicin resistant cells. Tore XVIII (deaminocarboxytoremifene), Tore IV (4-hydroxy-N-desmethyltoremifene) and N-desmethyltoremifene all increased the accumulation of doxorubicin significantly (114%, 128% and 42% respectively). Finally, we show evidence that toremifene and its active metabolites are present in high concentrations in human plasma following a single 200 mg oral dose.(ABSTRACT TRUNCATED AT 250 WORDS)
Wiebe
V
V
Koester
S
S
Lindberg
M
M
Emshoff
V
V
Baker
J
J
Wurz
G
G
DeGregorio
M
M
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004317:Doxorubicin / Q000493:pharmacokinetics*; D004347:Drug Interactions; D004351:Drug Resistance; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D011960:Receptors, Estrogen / Q000502:physiology*; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology; D017312:Toremifene; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D011960:Receptors, Estrogen; D013629:Tamoxifen; D017312:Toremifene; D004317:Doxorubicin