Selective reversal of vinblastine resistance in multidrug-resistant cell lines by tamoxifen, toremifene and their metabolites.
In this study we describe the effects of tamoxifen, toremifene and their 4-hydroxy and N-desmethyl metabolites on the toxicity of a range of drugs to human breast and lung cancer and to Chinese hamster ovary cell lines, determined using a tetrazolium-based semi-automated colorimetric assay. Vinblastine resistance was completely abolished in an mdr1-transfected lung cancer cell line (S1/1.1), indicating that P-glycoprotein-mediated multidrug resistance can be fully reversed by anti-oestrogens. A substantial (14- to 39-fold) enhancement of vinblastine toxicity to highly multidrug-resistant (MCF-7Adr) cells expressing P-glycoprotein was also observed in the presence of tamoxifen, toremifene and their metabolites, while m-amsacrine, cisplatin and melphalan toxicity was unaffected.
ICRF Laboratories, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford.
J
J
Kirk
S
S
Houlbrook
N S
NS
Stuart
I J
IJ
Stratford
A L
AL
Harris
J
J
Carmichael
D000677:Amsacrine / Q000627:therapeutic use; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy; D016466:CHO Cells / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000627:therapeutic use; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D008558:Melphalan / Q000627:therapeutic use; D013629:Tamoxifen / Q000494:pharmacology*; D017312:Toremifene / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014747:Vinblastine / Q000627:therapeutic use*
D000677:Amsacrine; D013629:Tamoxifen; D014747:Vinblastine; D017312:Toremifene; D002945:Cisplatin; D008558:Melphalan