Sensitization of human cancer cells to gemcitabine by the Chk1 inhibitor MK-8776: cell cycle perturbation and impact of administration schedule in vitro and in vivo.
Sensitization of human cancer cells to gemcitabine by the Chk1 inhibitor MK-8776: cell cycle perturbation and impact of administration schedule in vitro and in vivo.
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DOI：
10.1186/1471-2407-13-604
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发表时间：
2013-12-21
期刊：
影响因子：
3.8
通讯作者：
Eastman A
中科院分区：
文献类型：
--
作者：
Montano R;Thompson R;Chung I;Hou H;Khan N;Eastman A
Chk 1抑制剂已成为有前途的抗癌治疗剂，特别是当与抗代谢药如吉西他滨、阿糖胞苷或羟基脲组合时。在这里，我们解决的重要性，适当的药物调度时，吉西他滨与Chk 1抑制剂MK-8776相结合，并在时间表依赖性的机制。在多种癌细胞系中评估了吉西他滨+MK-8776诱导的生长抑制。实验使用两种药物的临床相关“推注”给药，而不是连续药物暴露。我们在体外和异种移植肿瘤模型中评估了不同治疗方案对细胞周期扰动和肿瘤细胞生长的影响。MK-8776在16种癌细胞系中诱导了对吉西他滨平均7倍的致敏性。MK-8776给药时间显著影响肿瘤细胞对吉西他滨的反应。虽然吉西他滨诱导快速细胞周期停滞，停滞的复制叉最初并不依赖于Chk 1的稳定性。到18小时，RAD 51被加载到指示同源重组的DNA上。在18 h时抑制Chk 1可使RAD 51迅速解离，导致复制叉崩溃和细胞死亡。与吉西他滨孵育6小时后，在18-24小时加入MK-8776，诱导的致敏作用远大于两种药物同时孵育6小时。由于MK-8776在患者血浆中的半衰期较短，因此与MK-8776的短暂孵育致敏细胞的能力至关重要。还在小鼠中的人胰腺肿瘤异种移植物中评估了细胞周期扰动。吉西他滨给药后18 h，S/G2期细胞大量聚集，但42 h细胞开始恢复。与单独给药或两种药物仅间隔30分钟给药相比，吉西他滨后18小时给予MK-8776可显著延迟肿瘤生长。延迟添加MK-8776可增强对吉西他滨的敏感性，原因有二：首先，S期阻滞的细胞数量增加;其次，阻滞的细胞有足够的时间启动重组，从而成为Chk 1依赖性细胞。这些结果对使用这种药物组合的临床试验设计具有重要意义。
Chk1 inhibitors have emerged as promising anticancer therapeutic agents particularly when combined with antimetabolites such as gemcitabine, cytarabine or hydroxyurea. Here, we address the importance of appropriate drug scheduling when gemcitabine is combined with the Chk1 inhibitor MK-8776, and the mechanisms involved in the schedule dependence. Growth inhibition induced by gemcitabine plus MK-8776 was assessed across multiple cancer cell lines. Experiments used clinically relevant “bolus” administration of both drugs rather than continuous drug exposures. We assessed the effect of different treatment schedules on cell cycle perturbation and tumor cell growth in vitro and in xenograft tumor models. MK-8776 induced an average 7-fold sensitization to gemcitabine in 16 cancer cell lines. The time of MK-8776 administration significantly affected the response of tumor cells to gemcitabine. Although gemcitabine induced rapid cell cycle arrest, the stalled replication forks were not initially dependent on Chk1 for stability. By 18 h, RAD51 was loaded onto DNA indicative of homologous recombination. Inhibition of Chk1 at 18 h rapidly dissociated RAD51 leading to the collapse of replication forks and cell death. Addition of MK-8776 from 18–24 h after a 6-h incubation with gemcitabine induced much greater sensitization than if the two drugs were incubated concurrently for 6 h. The ability of this short incubation with MK-8776 to sensitize cells is critical because of the short half-life of MK-8776 in patients’ plasma. Cell cycle perturbation was also assessed in human pancreas tumor xenografts in mice. There was a dramatic accumulation of cells in S/G2 phase 18 h after gemcitabine administration, but cells had started to recover by 42 h. Administration of MK-8776 18 h after gemcitabine caused significantly delayed tumor growth compared to either drug alone, or when the two drugs were administered with only a 30 min interval. There are two reasons why delayed addition of MK-8776 enhances sensitivity to gemcitabine: first, there is an increased number of cells arrested in S phase; and second, the arrested cells have adequate time to initiate recombination and thereby become Chk1 dependent. These results have important implications for the design of clinical trials using this drug combination.
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影响因子：
4.8
作者：
Kohn, EA;Ruth, ND;Eastman, A
通讯作者：
Eastman, A
影响因子：
5.7
作者：
Parsels LA;Morgan MA;Tanska DM;Parsels JD;Palmer BD;Booth RJ;Denny WA;Canman CE;Kraker AJ;Lawrence TS;Maybaum J
通讯作者：
Maybaum J
影响因子：
8
作者：
Levesque, AA;Kohn, EA;Eastman, A
通讯作者：
Eastman, A
影响因子：
8
作者：
Bahassi, E. M.;Ovesen, J. L.;Stambrook, P. J.
通讯作者：
Stambrook, P. J.
DOI：
10.1016/j.bbrc.2008.10.119
发表时间：
2008-12-26
影响因子：
3.1
作者：
Ikegami, Yosuke;Goto, Hidemasa;Inagaki, Masaki
通讯作者：
Inagaki, Masaki