Bachmann-Moisson N, Barberi-Heyob M, Merlin J L, Ledrich M L, Batt A M, Guillemin F
Laboratoire de recherche en oncologie, centre Alexis-Vautrin, Vandoeuvre-iès-Nancy, France.
Bull Cancer. 1996 Oct;83(10):808-15.
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.
抗雌激素药物他莫昔芬（TAM）已成功用于治疗表达雌激素和孕激素受体（ER+和PR+）的乳腺癌。然而，长期治疗的患者中经常观察到抗雌激素耐药性的出现。为了更好地理解TAM及其主要代谢产物：N-去甲基他莫昔芬（N-des-TAM）和4-羟基他莫昔芬（4-OH-TAM）的作用机制，研究了它们在5种具有不同雌激素受体水平的乳腺癌细胞系中的生长抑制作用：MDA-MB 231（ER-）、MCF-7 R（ER-）、T47D（ER+）、ZR-75/1（ER+）和MCF-7（ER+），试图重现人类乳腺肿瘤中遇到的细胞异质性。在本研究中，在有或没有雌二醇（10(-8)M）的情况下，测试了TAM、N-des-TAM和4-OH-TAM在10(-8)至10(-6)M浓度范围内对细胞生长的影响。只有4-OH-TAM显示出明显的抗雌激素剂量依赖性效应。此外，在ER-和PR-细胞系MDA-MB 231中，TAM、4-OH-TAM和N-des-TAM在最高剂量（10(-6)M）时具有抗增殖活性，这支持了TAM可能通过非ER依赖机制对ER+和ER-肿瘤均有效的假设。尽管在治疗2、4和6天后T47D细胞系具有ER+和PR+状态，但在10(-6)M的N-des-TAM作用下其生长速率增加。应该注意的是，该浓度在口服TAM（40 mg/天）的患者中N-des-TAM的血浆水平范围内（10(-6)M）。这些结果以及人类乳腺肿瘤中众所周知的细胞异质性可能是抗雌激素治疗某些失败的重要原因。
