CYTOTOXICITY OF TAMOXIFEN AND ITS MAJOR M ETABOLITES IN BREAST-CANCERCELL-LINES

Citation
N. Bachmannmoisson et al., CYTOTOXICITY OF TAMOXIFEN AND ITS MAJOR M ETABOLITES IN BREAST-CANCERCELL-LINES, Bulletin du cancer, 83(10), 1996, pp. 809-815
Citations number
37
Categorie Soggetti
Oncology
Journal title
ISSN journal
00074551
Volume
83
Issue
10
Year of publication
1996
Pages
809 - 815
Database
ISI
SICI code
0007-4551(1996)83:10<809:COTAIM>2.0.ZU;2-I
Abstract
The antiestrogen tamoxifen (TAM) has been successfully used to treat b reast cancer expressing estrogen and progesterone receptors (ER+ and P R+). However, the development of antiestrogen resistance is frequently observed in patients following long-ten treatment. To better understa nd the mechanism of action of TAM and its main metabolites: N-desmethy ltamoxifen (N-des-TAM) and 4-hydroxytamoxifen (COH-TAM), their growth inhibitory effect was studied in 5 breast cancer cell lines characteri zed 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 stu dy, the effects of TAM, N-des-TAM and 4OH-TAM on the cell growth were tested at concentrations ranging from 10(-8) to 10(-6) M with or witho ut estradiol (10(-8) M). Only 4-OH-TAM showed a clear antiestrogen dos e-dependent effect Moreover, the finding of an antiproliferative activ ity 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 m echanism. Despite ER+ and PR+ status after 2, 4 and 6 days of treatmen t, the T47D cell fine displayed an increased growth rate with N-des-TA M at 10(-6) M. Ii should be noted that such concentration is within th e range of the the plasma level of N-des-TAM (10(-6) M) in patients re ceiving TAM per os (40 mg/day). These results and the well-known cell heterogeneity of human breast tumors may significantly account for som e failure of antiestrogen treatment.