*Department of Obstetrics and Gynecology, Tottori University School of Medicine, and †Tottori University Hospital Cancer Center, Yonago, Japan.
Int J Gynecol Cancer. 2014 Jan;24(1):61-9. doi: 10.1097/IGC.0000000000000014.
Checkpoint kinase (Chk) inhibitors are thought to increase the cytotoxic effects of DNA-damaging agents and are undergoing clinical trials. The present study was aimed to assess the potential to use the Chk1 and Chk2 inhibitor, AZD7762, with other anticancer agents in chemotherapy to treat ovarian clear cell carcinoma.
Four ovarian clear cell carcinoma cell lines were used in this study. We treated the cells with AZD7762 and anticancer agents, then assessed cell viability, cell cycle distribution, apoptosis, and the expression of protein in apoptotic pathways and molecules downstream of the Chk signaling pathways. We also investigated the effects of these drug combinations on tumor growth in a nude mouse xenograft model.
Synergistic effects from the combination of AZD7762 and cisplatin were observed in all 4 cell lines. However, we observed additive effects when AZD7762 was combined with paclitaxel on all cell lines tested. AZD7762 effectively suppressed the Chk signaling pathways activated by cisplatin, dramatically enhanced expression of phosphorylated H2A.X, cleaved caspase 9 and PARP, decreased the proportion of cells in the gap 0/ gap 1 phase and the synthesis-phase fraction, and increased apoptotic cells. Combinations of small interfering RNA against Chk 1 and small interfering RNA against Chk2 enhanced the cytotoxic effect of cisplatin in both RMG-I and KK cells. Finally, treating mice-bearing RMG-I with AZD7762 and cisplatin significantly suppressed growth of tumors in a xenograft model.
The present study indicates that chemotherapy with AZD7762 and cisplatin should be explored as a treatment modality for women with ovarian clear cell carcinoma.
细胞周期检查点激酶（Chk）抑制剂被认为能增强 DNA 损伤药物的细胞毒性作用，目前正在进行临床试验。本研究旨在评估使用 Chk1 和 Chk2 抑制剂 AZD7762 与其他抗癌药物联合化疗治疗卵巢透明细胞癌的潜力。
本研究使用了 4 种卵巢透明细胞癌细胞系。我们用 AZD7762 和抗癌药物处理细胞，然后评估细胞活力、细胞周期分布、细胞凋亡以及细胞凋亡途径和 Chk 信号通路下游分子的蛋白表达。我们还研究了这些药物组合对裸鼠异种移植模型中肿瘤生长的影响。
在所有 4 种细胞系中，AZD7762 与顺铂联合使用均观察到协同作用。然而，当在所有测试的细胞系中 AZD7762 与紫杉醇联合使用时，观察到相加作用。AZD7762 能有效抑制顺铂激活的 Chk 信号通路，显著增强磷酸化 H2AX、cleaved caspase 9 和 PARP 的表达，降低 0/ G1 期和合成期细胞比例，增加凋亡细胞。Chk1 和 Chk2 的小干扰 RNA 组合增强了顺铂对 RMG-I 和 KK 细胞的细胞毒性作用。最后，用 AZD7762 和顺铂治疗携带 RMG-I 肿瘤的小鼠，显著抑制了异种移植模型中肿瘤的生长。
本研究表明，AZD7762 和顺铂联合化疗可能是治疗卵巢透明细胞癌的一种治疗方法。
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