Dougherty Michele K, Schumaker Lisa M, Jordan V Craig, Welshons Wade V, Curran Edward M, Ellis Matthew J, El-Ashry Dorraya
Lombardi Cancer Center, Department of Oncology, Georgetown University Medical Center, Washington, DC, USA.
Cancer Biol Ther. 2004 May;3(5):460-7. doi: 10.4161/cbt.3.5.810. Epub 2004 May 18.
A retrospective analysis of CALGB trial 9344 suggested paclitaxel administration following cyclophosphamide and doxorubicin adjuvant chemotherapy is most beneficial for patients with ERalpha negative (ERalpha-) breast cancer. Since the cytotoxic effects of paclitaxel are cell cycle dependent, we postulated that the relationship between ERalpha and the effectiveness of adjuvant paclitaxel reflects the observation that ERalpha positive (ERalpha+) breast cancers proliferate more slowly than ERalpha- breast cancers. Three in vitro models (MCF-7, T47D and ZR-75) were examined to compare growth rates and paclitaxel-induced apoptosis in ERalpha+ and ERalpha- clones of the same, originally ERalpha+ cell line. For the T47D and ZR-75 cell lines, loss of ERalpha was associated with a decrease in doubling time and an increase in paclitaxel sensitivity. However, when cell culture conditions were altered to achieve equivalent cell proliferation rates, no difference in paclitaxel sensitivity was observed. Similarly, an ERalpha- clone of MCF-7 cells that did not exhibit an enhanced growth rate compared to its ERalpha+ counterpart also did not show increased paclitaxel sensitivity. The combined apoptotic effects of tamoxifen and paclitaxel on MCF-7 cells were not synergistic or even clearly additive. In these in vitro models, the effectiveness of paclitaxel correlated more closely with growth rate than ERalpha expression. These data suggest that measurements of tumor proliferation may provide more accurate predictive markers for the benefits of adjuvant paclitaxel than ERalpha analysis.
对癌症和白血病研究组B（CALGB）9344试验的回顾性分析表明，对于雌激素受体α阴性（ERα-）乳腺癌患者，在环磷酰胺和阿霉素辅助化疗后给予紫杉醇最为有益。由于紫杉醇的细胞毒性作用具有细胞周期依赖性，我们推测ERα与辅助性紫杉醇疗效之间的关系反映了以下观察结果：雌激素受体α阳性（ERα+）乳腺癌的增殖速度比ERα-乳腺癌慢。我们检测了三种体外模型（MCF-7、T47D和ZR-75），以比较同一原始ERα+细胞系的ERα+和ERα-克隆的生长速率以及紫杉醇诱导的细胞凋亡。对于T47D和ZR-75细胞系，ERα的缺失与倍增时间的缩短和紫杉醇敏感性的增加相关。然而，当改变细胞培养条件以实现等效的细胞增殖速率时，未观察到紫杉醇敏感性的差异。同样，MCF-7细胞的ERα-克隆与其ERα+对应物相比未表现出生长速率的提高，也未显示出紫杉醇敏感性的增加。他莫昔芬和紫杉醇对MCF-7细胞的联合凋亡作用并非协同作用，甚至没有明显的相加作用。在这些体外模型中，紫杉醇的疗效与生长速率的相关性比与ERα表达的相关性更密切。这些数据表明，与ERα分析相比，肿瘤增殖的测量可能为辅助性紫杉醇的益处提供更准确的预测指标。
