Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Gynecol Oncol. 2010 Dec;119(3):579-85. doi: 10.1016/j.ygyno.2010.08.025. Epub 2010 Sep 21.
Our goal was to evaluate the effect of rapamycin, an mTOR inhibitor, in type I and II human endometrial cancer tumor explants.
Short-term tissue culture with fresh endometrial cancer tumor explants was performed. Cell proliferation was assessed by MTS assay after treatment with rapamycin. Akt and PTEN status were documented by Western blotting. The effect of rapamycin on phosphorylated-S6 and 4E-BP-1 was also assessed by Western blotting. Real-time RT-PCR was used to quantify hTERT mRNA expression. Telomere length was determined by terminal restriction fragment Southern blotting.
Thirteen fresh endometrial cancer tumor explants (nine Type I, four Type II) were placed in short-term culture and treated with rapamycin. Nine of the endometrial cancer tumors responded to rapamycin, with a median IC₅₀ of 11.4 nM. Sensitivity to rapamycin was independent of PTEN and Akt status. Tumors (13/13) had a reduction in phosphorylated-S6 and 10/13 had a reduction in phosphorylated 4E-BP-1. Rapamycin decreased hTERT mRNA expression in all of the endometrial cancer tumors. Telomere length did not correspond with responsiveness to this drug.
Rapamycin demonstrated activity in fresh endometrial tumor explants independent of PTEN and Akt status. Some tumors demonstrated a reduction in phosphorylated-S6 and 4E-BP-1 without a significant change in cellular proliferation, suggesting that additional pathways may modulate cellular proliferation. Thus, mTOR inhibitors may be a useful targeted therapy for both type I and type II endometrial cancers, but the search remains for a predictive biomarker of sensitivity to this therapy.
我们的目的是评估雷帕霉素（mTOR 抑制剂）对 I 型和 II 型人子宫内膜癌肿瘤标本的作用。
进行短期组织培养，使用新鲜的子宫内膜癌肿瘤标本。用 MTS 法检测雷帕霉素处理后细胞增殖情况。用 Western blot 法记录 Akt 和 PTEN 状态。还通过 Western blot 法评估雷帕霉素对磷酸化-S6 和 4E-BP-1 的影响。用实时 RT-PCR 法定量 hTERT mRNA 表达。通过末端限制性片段 Southern 印迹法测定端粒长度。
13 个新鲜的子宫内膜癌肿瘤标本（9 个 I 型，4 个 II 型）被置于短期培养中并接受雷帕霉素治疗。9 个子宫内膜癌肿瘤对雷帕霉素有反应，其 IC₅₀ 的中位数为 11.4 nM。对雷帕霉素的敏感性与 PTEN 和 Akt 状态无关。肿瘤（13/13）中磷酸化-S6 减少，10/13 中磷酸化 4E-BP-1 减少。雷帕霉素降低了所有子宫内膜癌肿瘤中的 hTERT mRNA 表达。端粒长度与对该药物的反应性不一致。
雷帕霉素在新鲜的子宫内膜肿瘤标本中表现出活性，与 PTEN 和 Akt 状态无关。一些肿瘤显示磷酸化-S6 和 4E-BP-1 减少，而细胞增殖没有明显变化，这表明其他途径可能调节细胞增殖。因此，mTOR 抑制剂可能是治疗 I 型和 II 型子宫内膜癌的一种有用的靶向治疗方法，但仍需寻找对这种治疗敏感的预测生物标志物。
