Preclinical evaluation of a novel ATM inhibitor, KU59403, in vitro and in vivo in p53 functional and dysfunctional models of human cancer.
Preclinical evaluation of a novel ATM inhibitor, KU59403, in vitro and in vivo in p53 functional and dysfunctional models of human cancer.
复制标题
DOI：
10.1158/1535-7163.mct-12-0707
复制
发表时间：
2013-06
影响因子：
5.7
通讯作者：
Curtin NJ
中科院分区：
文献类型：
--
作者：
Batey MA;Zhao Y;Kyle S;Richardson C;Slade A;Martin NM;Lau A;Newell DR;Curtin NJ
ATM激酶通过p53和DNA修复信号DNA双链断裂（DSB）到细胞周期停滞。ATM缺陷细胞对DSB诱导剂敏感，使ATM成为抗癌化疗和放射增敏的有吸引力的靶点。KU 59403是一种ATM抑制剂，具有用于高级临床前评价的效力、选择性和溶解性。KU 59403本身对人癌细胞系（SW 620、LoVo、HCT 116和MDA-MB-231）无细胞毒性，但显著增加拓扑异构酶I和II毒物（喜树碱、依托泊苷和多柔比星）的细胞毒性。ATM抑制的化疗和放射增敏作用不依赖于p53。小鼠给药后，KU 59403分布到组织中，并且在肿瘤异种移植物中保持超过体外活性所需浓度至少4小时。KU 59403在单独无毒且联合耐受良好的剂量下显著增强了携带人结肠癌异种移植物（SW 620和HCT 116）的小鼠中拓扑异构酶毒物的抗肿瘤活性。化疗敏感性是剂量和时间表依赖性。KU 59403代表了ATM抑制剂开发的重大进展，是第一个在人体癌症体内模型中表现出良好组织分布和显著化学增敏作用的化合物，没有重大毒性。KU 59403提供了第一个原理验证的临床前数据，以支持ATM抑制剂的未来临床开发。
ATM kinase signals DNA double strand breaks (DSB) to cell cycle arrest via p53 and DNA repair. ATM-defective cells are sensitive to DSB-inducing agents, making ATM an attractive target for anticancer chemo- and radio-sensitisation. KU59403 is an ATM inhibitor with the potency, selectivity and solubility for advanced pre-clinical evaluation. KU59403 was not cytotoxic to human cancer cell lines (SW620, LoVo, HCT116 and MDA-MB-231) per se but significantly increased the cytotoxicity of topoisomerase I and II poisons: camptothecin, etoposide and doxorubicin. Chemo- and radio-sensitisation by ATM inhibition was not p53-dependent. Following administration to mice, KU59403 distributed to tissues and concentrations exceeding those required for in vitro activity were maintained for at least 4 hr in tumour xenografts. KU59403 significantly enhanced the antitumour activity of topoisomerase poisons in mice bearing human colon cancer xenografts (SW620 and HCT116) at doses that were non-toxic alone and well tolerated in combination. Chemosensitisation was both dose and schedule-dependent. KU59403 represents a major advance in ATM inhibitor development, being the first compound to demonstrate good tissue distribution and significant chemo-sensitisation in in vivo models of human cancer, without major toxicity. KU59403 provides the first proof-of-principle pre-clinical data to support the future clinical development of ATM inhibitors.