Berstein Lev M, Wang Ji-Ping, Zheng Hong, Yue Wei, Conaway Mark, Santen Richard J
Laboratory of Oncoendocrinology, N N Petrov Research Institute of Oncology, Pesochny, St Petersburg, Russia.
Clin Cancer Res. 2004 Feb 15;10(4):1530-4. doi: 10.1158/1078-0432.ccr-0433-03.
In women with hormone-dependent breast cancer, tamoxifen (TAM) frequently induces tumor regression, but regrowth occurs with continuation of antiestrogen therapy. Studies of breast xenografts in nude mice suggest that this secondary resistance to TAM may reflect the development of enhanced sensitivity to the estrogenic properties of TAM. In the current study, we examined the hypothesis that TAM could also induce a state of hypersensitivity to estradiol (E(2)) itself. Oophorectomized nude mice with MCF-7 cell xenografts received 25-mg implants of TAM [long-term TAM treated (LTTT) mice] or cholesterol (C-MCF-7) over a 5-month period (phase 1). The LTTT group regressed to a lesser extent than did C-MCF-7 tumors. After 4 months of TAM exposure, the LTTT tumors begin to regrow, as did the C-MCF-7, as assessed by slope analysis. At 5 months, TAM or vehicle implants were removed, and the LTTT and C-MCF-7 subgroups were given vehicle or two doses of E(2) to test estrogen sensitivity (phase 2). We used our "E(2) clamp" technique to maintain levels of plasma E(2) at either 1.25 or 20 pg/ml. Neither group responded to the very low concentrations of E(2) (1.25 pg/ml) or vehicle. The LTTT tumors but not C-MCF-7 tumors exhibited a growth response on exposure to 20 pg/ml E(2) during 7 weeks, as demonstrated with mixed models analysis. These studies provide evidence that long-term TAM exposure enhances sensitivity to the estrogenic effects of TAM and also to E(2) itself.
在激素依赖性乳腺癌女性患者中，他莫昔芬（TAM）常可诱导肿瘤消退，但抗雌激素治疗持续进行时肿瘤会复发。对裸鼠乳腺异种移植瘤的研究表明，这种对TAM的继发性耐药可能反映出对TAM雌激素特性的敏感性增强。在本研究中，我们检验了TAM也可诱导对雌二醇（E₂）自身超敏状态的假说。将接种MCF-7细胞的去卵巢裸鼠在5个月期间（第1阶段）植入25 mg的TAM [长期TAM治疗（LTTT）小鼠] 或胆固醇（C-MCF-7）。LTTT组肿瘤消退程度小于C-MCF-7肿瘤。通过斜率分析评估，在TAM暴露4个月后，LTTT肿瘤开始像C-MCF-7肿瘤一样复发。5个月时，取出TAM或赋形剂植入物，给予LTTT和C-MCF-7亚组赋形剂或两剂E₂以测试雌激素敏感性（第2阶段）。我们使用“E₂钳夹”技术将血浆E₂水平维持在1.25或20 pg/ml。两组对极低浓度的E₂（1.25 pg/ml）或赋形剂均无反应。混合模型分析显示，在7周内，LTTT肿瘤而非C-MCF-7肿瘤在暴露于20 pg/ml E₂时出现生长反应。这些研究提供了证据，表明长期暴露于TAM会增强对TAM雌激素效应以及对E₂自身的敏感性。
