[Cytotoxicity of tamoxifen and its principal metabolites in human breast cancer cell lines].
Fiche publication
Date publication
octobre 1996
Journal
Bulletin du cancer
Auteurs
Membres identifiés du Cancéropôle Est :
Pr BARBERI-HEYOB Muriel, Pr MERLIN Jean-Louis
Tous les auteurs :
Bachmann-Moisson N, Barberi-Heyob M, Merlin JL, Ledrich ML, Batt AM, Guillemin F
Lien Pubmed
Résumé
The antiestrogen tamoxifen (TAM) has been successfully used to treat breast cancer expressing estrogen and progesterone receptors (ER+ and PR+). However, the development of antiestrogen resistance is frequently observed in patients following long-term treatment. To better understand the mechanism of action of TAM and its main metabolites: N-desmethyltamoxifen (N-des-TAM) and 4-hydroxytamoxifen (4-OH-TAM), their growth inhibitory effect was studied in 5 breast cancer cell lines characterized by different estrogen receptor levels: MDA-MB 231 (ER-), MCF-7 R (ER-), T47D (ER+), ZR-75/1 (ER+) and MCF-7 (ER+) trying to reproduce a cellular heterogeneity encountered in human breast tumors. In this study, the effects of TAM, N-des-TAM and 40-H-TAM on the cell growth were tested at concentrations ranging from 10(-8) to 10(-6)M with or without estradiol (10(-8)M). Only 4-OH-TAM showed a clear antiestrogen dose-dependent effect. Moreover, the finding of an antiproliferative activity at the highest dose (10(-6)M) for TAM, 4-OH-TAM and N-des-TAM in the ER- and PR- cell line MDA-MB 231 supports the hypothesis that TAM could be effective on ER+ as well as ER- tumors by an ER-independent mechanism. Despite ER+ and PR+ status after 2, 4 and 6 days of treatment, the T47D cell line displayed an increased growth rate with N-des-TAM at 10(-6)M. It should be noted that such concentration is within the range of the plasma level of N-des-TAM (10(-6)M) in patients receiving TAM per os (40 mg/day). These results and the well-known cell heterogeneity of human breast tumors may significantly account for some failure of antiestrogen treatment.
Mots clés
Adenocarcinoma, metabolism, Antineoplastic Agents, Hormonal, metabolism, Biotransformation, Breast Neoplasms, metabolism, Cell Division, drug effects, Cell Line, Drug Resistance, Neoplasm, Drug Screening Assays, Antitumor, Female, Humans, In Vitro Techniques, Receptors, Estrogen, drug effects, Receptors, Progesterone, drug effects, Tamoxifen, metabolism
Référence
Bull Cancer. 1996 Oct;83(10):808-15