Lamb Caroline A, Helguero Luisa A, Fabris Victoria, Lucas Colombo, Molinolo Alfredo A, Lanari Claudia
Instituto de Biología y Medicina Experimental (Consejo Nacional de Investigaciones Científicas y Técnicas--CONICET), Buenos Aires, Argentina.
Breast Cancer Res Treat. 2003 May;79(1):25-35. doi: 10.1023/a:1023324827225.
The purpose of this study was to evaluate the effect of the selective estrogen receptor modulators raloxifene and tamoxifen and of the pure antiestrogen fulvestrant on tumor growth and progesterone receptor (PR) expression in an experimental model of breast cancer. The effects of these compounds on cell proliferation were studied in primary cultures of a progestin-dependent mammary carcinoma tumor line, in the presence of medroxyprogesterone acetate (MPA) or 17-beta-estradiol (E2). In in vivo studies the tumor was inoculated subcutaneously in BALB/c female mice treated with 20 mg MPA depot. Raloxifene (12.5 mg/kg) or tamoxifen (5 mg/kg) were administered in daily doses or E2 silastic pellets (5 mg) were implanted. When the tumors reached about 25-50 mm2 MPA was removed in half of the animals. E2 induced complete tumor regressions, tamoxifen inhibited tumor growth in vivo while raloxifene disclosed proliferative effects in animals in which MPA had been removed. In vitro, E2 inhibited cell proliferation at concentrations higher than 10(-14)M. Raloxifene and fulvestrant, but not tamoxifen, partially reverted E2-induced inhibition. Fulvestrant and tamoxifen inhibited MPA-induced cell proliferation while raloxifene had a stimulatory effect. Tamoxifen and E2 increased, raloxifene induced no effect, and fulvestrant significantly decreased PR expression. In this study we provide evidence for differential effects of tamoxifen and raloxifene on experimental mammary tumors. Since raloxifene is under evaluation for use in breast cancer prevention, these results may have important clinical implications.
本研究的目的是在乳腺癌实验模型中评估选择性雌激素受体调节剂雷洛昔芬和他莫昔芬以及纯抗雌激素氟维司群对肿瘤生长和孕激素受体（PR）表达的影响。在孕激素依赖性乳腺癌肿瘤细胞系的原代培养物中，于醋酸甲羟孕酮（MPA）或17-β-雌二醇（E2）存在的情况下，研究了这些化合物对细胞增殖的影响。在体内研究中，将肿瘤皮下接种于接受20mg MPA长效制剂治疗的BALB/c雌性小鼠。每天给予雷洛昔芬（12.5mg/kg）或他莫昔芬（5mg/kg），或植入E2硅橡胶丸（5mg）。当肿瘤达到约25 - 50mm²时，将一半动物体内的MPA去除。E2可诱导肿瘤完全消退，他莫昔芬在体内抑制肿瘤生长，而雷洛昔芬在去除MPA的动物中显示出增殖作用。在体外，E2在浓度高于10⁻¹⁴M时抑制细胞增殖。雷洛昔芬和氟维司群，但不是他莫昔芬，部分逆转了E2诱导的抑制作用。氟维司群和他莫昔芬抑制MPA诱导的细胞增殖，而雷洛昔芬具有刺激作用。他莫昔芬和E2增加PR表达，雷洛昔芬无影响，氟维司群显著降低PR表达。在本研究中，我们提供了他莫昔芬和雷洛昔芬对实验性乳腺肿瘤有不同作用的证据。由于雷洛昔芬正在接受用于预防乳腺癌的评估，这些结果可能具有重要的临床意义。
