达沙替尼（BMS-35482）与多西他赛、吉西他滨、拓扑替康和阿霉素在 SRC 通路高激活和蛋白表达的卵巢癌细胞中具有协同作用。
Dasatinib (BMS-35482) interacts synergistically with docetaxel, gemcitabine, topotecan, and doxorubicin in ovarian cancer cells with high SRC pathway activation and protein expression.
机构信息
*Division of Gynecologic Oncology, †Departments of Medicine, and ‡Medical Oncology, Duke Cancer Institute, Duke University Medical Center, Durham, NC.
出版信息
Int J Gynecol Cancer. 2014 Feb;24(2):218-25. doi: 10.1097/IGC.0000000000000056.
PURPOSE
This study aimed to explore the activity of dasatinib in combination with docetaxel, gemcitabine, topotecan, and doxorubicin in ovarian cancer cells.
METHODS
Cells with previously determined SRC pathway and protein expression (SRC pathway/SRC protein IGROV1, both high; SKOV3, both low) were treated with dasatinib in combination with the cytotoxic agents. SRC and paxillin protein expression were determined pretreatment and posttreatment. Dose-response curves were constructed, and the combination index (CI) for drug interaction was calculated.
RESULTS
In the IGROV1 cells, dasatinib alone reduced phospho-SRC/total SRC 71% and p-paxillin/t-paxillin ratios 77%. Phospho-SRC (3%-33%; P = 0.002 to 0.04) and p-paxicillin (6%-19%; P = 0.01 to 0.05) levels were significantly reduced with dasatinib in combination with each cytotoxic agent. The combination of dasatinib and docetaxel, gemcitabine, or topotecan had a synergistic antiproliferative effect (CI, 0.49-0.68), whereas dasatinib combined with doxorubicin had an additive effect (CI, 1.08).In SKOV3 cells, dasatinib resulted in less pronounced reductions of phospho-SRC/total SRC (49%) and p-paxillin/t-paxillin (62%). Phospho-SRC (18%; P < 0.001) and p-paxillin levels (18%; P = 0.001; 9%; P = 0.007) were significantly decreased when dasatinib was combined with docetaxel and topotecan (p-paxillin only). Furthermore, dasatinib combined with the cytotoxics in the SKOV3 cells produced an antagonistic interaction on the proliferation of these cells (CI, 1.49-2.27).
CONCLUSIONS
Dasatinib in combination with relapse chemotherapeutic agents seems to interact in a synergistic or additive manner in cells with high SRC pathway activation and protein expression. Further evaluation of dasatinib in combination with chemotherapy in ovarian cancer animal models and exploration of the use of biomarkers to direct therapy are warranted.
目的
本研究旨在探讨达沙替尼联合多西他赛、吉西他滨、拓扑替康和阿霉素在卵巢癌细胞中的活性。
方法
对先前确定的 SRC 途径和蛋白表达（SRC 途径/SRC 蛋白 IGROV1 均高；SKOV3 均低）的细胞用达沙替尼联合细胞毒性药物进行处理。检测预处理和后处理时 SRC 和桩蛋白的表达。构建剂量-反应曲线，并计算药物相互作用的合并指数（CI）。
结果
在 IGROV1 细胞中，达沙替尼单独使用可使磷酸化 SRC/总 SRC 减少 71%，paxillin 减少 77%。达沙替尼联合每种细胞毒性药物均可显著降低磷酸化 SRC（3%-33%；P=0.002 至 0.04）和 paxillin（6%-19%；P=0.01 至 0.05）水平。达沙替尼与多西他赛、吉西他滨或拓扑替康联合具有协同的抗增殖作用（CI 值为 0.49-0.68），而达沙替尼与阿霉素联合具有相加作用（CI 值为 1.08）。在 SKOV3 细胞中，达沙替尼可使磷酸化 SRC/总 SRC 减少 49%，paxillin 减少 62%。达沙替尼与多西他赛和拓扑替康联合使用时，磷酸化 SRC（18%；P<0.001）和 paxillin 水平（18%；P=0.001；9%；P=0.007）均显著降低（paxillin 仅）。此外，达沙替尼联合 SKOV3 细胞中的细胞毒性药物对这些细胞的增殖产生拮抗相互作用（CI 值为 1.49-2.27）。
结论
在 SRC 途径激活和蛋白表达高的细胞中，达沙替尼联合复发化疗药物似乎以协同或相加的方式相互作用。有必要在卵巢癌动物模型中进一步评估达沙替尼联合化疗的效果，并探索使用生物标志物来指导治疗。
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