Activity of tamoxifen and its metabolites on endocrine-dependent and endocrine-independent breast cancer cells.
To better understand the mechanism of action of antiestrogens, the growth-inhibitory effect of tamoxifen and its main metabolites N-desmethyltamoxifen and 4-hydroxytamoxifen, was studied in 6 breast cancer cell lines characterized by different steroid receptor contents. On the basis of the results, our cell lines could be classified into three groups: a first group, including 734B and ZR-75.1 cell lines, characterized by a clear endocrine-dependent behavior, in which cells were sensitive to antiestrogens although to different degrees; a second group, including MDA-MB 231 and BT20 cell lines, characterized by a clear endocrine-insensitive behavior, in which cells were affected only by the highest (10(-6) M) antiestrogen concentration; a third group, including MCF7 and T47D cell lines, characterized by a peculiar behavior. The T47D cell line displayed an increased growth rate after treatment with all three antiestrogens considered. Despite the positive receptor content in the MCF7 cell line, only 4-hydroxytamoxifen showed a clear antiestrogen dose-dependent effect, whereas tamoxifen decreased the cell growth rate only at lower concentrations (10(-8) and 10(-7) M). These results and the well-known heterogeneity of human breast tumors explain the failure of antiestrogen treatment in a certain percentage of patients with breast cancer with a positive estrogen receptor status.
Coradini
D
D
Oncologia Sperimentale C, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano, Italia.
Cappelletti
V
V
Granata
G
G
Di Fronzo
G
G
D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D004273:DNA, Neoplasm / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D004967:Estrogens; D006801:Humans; D007700:Kinetics; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000473:pathology; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D004965:Estrogen Antagonists; D004967:Estrogens; D013629:Tamoxifen; C016601:afimoxifene; D004958:Estradiol; C028787:N-desmethyltamoxifen