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首页> 外文期刊>Molecular cancer therapeutics >Preclinical development of the novel Chk1 inhibitor SCH900776 in combination with DNA-damaging agents and antimetabolites
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Preclinical development of the novel Chk1 inhibitor SCH900776 in combination with DNA-damaging agents and antimetabolites

机译：新型Chk1抑制剂SCH900776与DNA破坏剂和抗代谢物联合的临床前开发

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Many anticancer agents damage DNA and arrest cell-cycle progression primarily in S or G 2 phase of the cell cycle. Previous studies with the topoisomerase I inhibitor SN38 have shown the efficacy of the Chk1 inhibitor UCN-01 to overcome this arrest and induce mitotic catastrophe. UCN-01 was limited in clinical trials by unfavorable pharmacokinetics. SCH900776 is a novel and more selective Chk1 inhibitor that potently inhibits Chk1 and abrogates cell-cycle arrest induced by SN38. Like UCN-01, abrogation of SN38-induced arrest enhances the rate of cell death but does not increase overall cell death. In contrast, SCH900776 reduced the growth-inhibitory concentration of hydroxyurea by 20- to 70-fold. A similar magnitude of sensitization was observed with cytarabine. A 5- to 10-fold sensitization occurred with gemcitabine, but no sensitization occurred with cisplatin, 5-fluorouracil, or 6-thioguanine. Sensitization occurred at hydroxyurea concentrations that marginally slowed DNA replication without apparent activation of Chk1, but this led to dependence on Chk1 that increased with time. For example, when added 18 hours after hydroxyurea, SCH900776 induced DNA double-strand breaks consistent with rapid collapse of replication forks. In addition, some cell lines were highly sensitive to SCH900776 alone, and these cells required lower concentrations of SCH900776 to sensitize them to hydroxyurea. We conclude that some tumors may be very sensitive to the combination of SCH900776 and hydroxyurea. Delayed administration of SCH900776 may be more effective than concurrent treatment. SCH900776 is currently in phase I clinical trials, and these results provide the rationale and schedule for future clinical trials.
机译：许多抗癌剂主要在细胞周期的S或G 2期破坏DNA并阻止细胞周期进程。以前使用拓扑异构酶I抑制剂SN38进行的研究表明，Chk1抑制剂UCN-01克服了这种停滞并引发有丝分裂灾难的功效。 UCN-01在临床试验中受到不利的药代动力学的限制。 SCH900776是一种新型的，选择性更高的Chk1抑制剂，可有效抑制Chk1并消除SN38诱导的细胞周期停滞。像UCN-01一样，废除SN38诱导的逮捕可提高细胞死亡率，但不会增加整体细胞死亡。相反，SCH900776将羟基脲的生长抑制浓度降低了20到70倍。用阿糖胞苷观察到相似的敏化程度。吉西他滨发生5至10倍的致敏作用，而顺铂，5-氟尿嘧啶或6-硫鸟嘌呤则不致敏作用。敏化作用发生在羟基脲浓度上，该浓度在不明显激活Chk1的情况下略微降低了DNA复制的速度，但这导致对Chk1的依赖性随时间增加。例如，当在羟基脲中加入18小时后，SCH900776诱导的DNA双链断裂与复制叉的快速塌陷相一致。此外，某些细胞系对单独的SCH900776高度敏感，而这些细胞需要较低浓度的SCH900776才能使其对羟基脲敏感。我们得出结论，某些肿瘤可能对SCH900776和羟基脲的组合非常敏感。 SCH900776的延迟给药可能比同时治疗更有效。 SCH900776目前正在进行I期临床试验，这些结果为将来的临床试验提供了依据和时间表。

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