Differential modulation of doxorubicin toxicity to multidrug and intrinsically drug resistant cell lines by anti-oestrogens and their major metabolites.
The ability of the anti-oestrogens tamoxifen, toremifene and their 4-hydroxy and N-desmethyl metabolites to modify doxorubicin (dox) toxicity to intrinsically resistant and multidrug resistant cell lines was compared, using human breast and lung cancer, and Chinese hamster ovary cell lines. The anti-oestrogens significantly enhanced dox toxicity to multidrug resistant, P-glycoprotein-positive cell lines, but did not affect toxicity to intrinsically resistant, P-glycoprotein-negative cells. Modification was observed at clinically achievable anti-oestrogen concentrations. Toremifene and tamoxifen would therefore appear to be good candidates for in vivo studies as MDR modulating agents in selected patients with P-glycoprotein-positive tumours.
Kirk
J
J
ICRF Laboratory, John Radcliffe Hospital, Headington, Oxford, UK.
Houlbrook
S
S
Stuart
N S
NS
Stratford
I J
IJ
Harris
A L
AL
Carmichael
J
J
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D000911:Antibodies, Monoclonal; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016466:CHO Cells; D002352:Carrier Proteins / Q000032:analysis / Q000276:immunology; D002455:Cell Division / Q000187:drug effects; D006224:Cricetinae; D004317:Doxorubicin / Q000633:toxicity*; D004347:Drug Interactions; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D000939:Epitopes / Q000032:analysis; D004965:Estrogen Antagonists / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000032:analysis / Q000276:immunology; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D017312:Toremifene / Q000378:metabolism / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000911:Antibodies, Monoclonal; D002352:Carrier Proteins; D000939:Epitopes; D004965:Estrogen Antagonists; D008562:Membrane Glycoproteins; D013629:Tamoxifen; C016601:afimoxifene; D017312:Toremifene; D004317:Doxorubicin; C028787:N-desmethyltamoxifen; C062262:4-hydroxytoremifene