Preclinical development of the novel Chk1 inhibitor SCH900776 in combination with DNA-damaging agents and antimetabolites.
Preclinical development of the novel Chk1 inhibitor SCH900776 in combination with DNA-damaging agents and antimetabolites.
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DOI：
10.1158/1535-7163.mct-11-0406
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发表时间：
2012-02
影响因子：
5.7
通讯作者：
Eastman A
中科院分区：
文献类型：
--
作者：
Montano R;Chung I;Garner KM;Parry D;Eastman A
许多抗癌药物会损伤DNA并主要在细胞周期的S或G2期阻滞细胞周期进程。以前的拓扑异构酶I抑制剂SN 38的研究已经证明了Chk 1抑制剂UCN-01克服这种停滞和诱导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。SCH 900776是一种新型的、选择性更高的Chk 1抑制剂，可有效抑制Chk 1并消除SN 38诱导的细胞周期阻滞。与UCN-01一样，SN 38诱导的停滞的消除提高了细胞死亡的速率，但不增加总体细胞死亡。相比之下，SCH 900776将羟基脲的生长抑制浓度降低了20-70倍。阿糖胞苷观察到类似程度的致敏作用，吉西他滨发生5-10倍致敏作用，但顺铂、5-氟尿嘧啶或6-硫鸟嘌呤未发生致敏作用。致敏作用发生在羟基脲浓度下，该浓度略微减缓DNA复制而没有明显的Chk 1活化，但这导致对Chk 1的依赖性随时间增加。例如，当加入18小时后，羟基脲，SCH 900776诱导DNA双链断裂与复制叉的快速崩溃一致。此外，一些细胞系仅对SCH 900776高度敏感，并且这些细胞需要较低浓度的SCH 900776来使它们对羟基脲敏感。我们的结论是，一些肿瘤可能是非常敏感的SCH 900776和羟基脲的组合。SCH 900776的延迟给药可能比同时治疗更有效。SCH 900776目前处于I期临床试验阶段，这些结果为未来的临床试验提供了依据和时间表。
Many anticancer agents damage DNA and arrest cell cycle progression primarily in S or G2 phase of the cell cycle. Previous studies with the topoisomerase I inhibitor SN38 have demonstrated 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 20-70 fold. A similar magnitude of sensitization was observed with cytarabine, a 5-10 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 h 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.