[Cytotoxicity of tamoxifen and its principal metabolites in human breast cancer cell lines].
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.
Bachmann-Moisson
N
N
Laboratoire de recherche en oncologie, centre Alexis-Vautrin, Vandoeuvre-iès-Nancy, France.
Barberi-Heyob
M
M
Merlin
J L
JL
Ledrich
M L
ML
Batt
A M
AM
Guillemin
F
F
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D018931:Antineoplastic Agents, Hormonal / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity*; D001711:Biotransformation; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism; D011980:Receptors, Progesterone / Q000187:drug effects / Q000378:metabolism; D013629:Tamoxifen / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity*
D018931:Antineoplastic Agents, Hormonal; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D013629:Tamoxifen
Cytotoxicité du tamoxifène et de ses principaux métabolites sur lignées cellulaires d'adénocarcinomes mammaires humains.