Circumvention of doxorubicin resistance in multi-drug resistant human leukaemia and lung cancer cells by the pure antioestrogen ICI 164384.
ICI 164384, a new steroidal antioestrogen, entirely devoid of oestrogenic activity, modulates doxorubicin resistance in vitro. At non-cytotoxic concentrations, ICI 164384 potentiated the cytotoxicity of doxorubicin in a dose-dependent manner in both the classical multi-drug resistant (MDR) human leukaemia cell lines CEM/VLB 100 and CEM/VLB 1000 and the human small cell lung cancer cell line H69 LX4. ICI 164384 had no effect on the two respective parental cell lines, CEM/CCRF and H69 P. None of these cell lines expressed the oestrogen receptor. In comparative studies at concentrations ranging from 1.25 to 10 mumols/l, ICI 164384 was significantly more effective (1.2-6-fold) than tamoxifen in reducing the IC50 of doxorubicin in the CEM/VLB 100 line. In resistant cells, ICI 164384 increased 3H-daunomycin accumulation in a dose-dependent manner and was significantly more effective than tamoxifen at concentrations ranging from 2.5 to 10 mumol/l. ICI 164384 reduced the efflux of daunomycin from resistant cells more effectively than tamoxifen. These studies suggest that ICI 164384 is an effective modulator of MDR.
Hu
X F
XF
Repatriation General Hospital, Heidelberg West, Australia.
Nadalin
G
G
De Luise
M
M
Martin
T J
TJ
Wakeling
A
A
Huggins
R
R
Zalcberg
J R
JR
D018288:Carcinoma, Small Cell / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003630:Daunorubicin / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology*; D004351:Drug Resistance; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology*; D006801:Humans; D015458:Leukemia, T-Cell / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000473:pathology; D053284:Polyunsaturated Alkamides; D014407:Tumor Cells, Cultured / Q000187:drug effects*
D004965:Estrogen Antagonists; D053284:Polyunsaturated Alkamides; D004958:Estradiol; D004317:Doxorubicin; C051781:ICI 164384; D003630:Daunorubicin