Zabludoff Sonya D, Deng Chun, Grondine Michael R, Sheehy Adam M, Ashwell Susan, Caleb Benjamin L, Green Stephen, Haye Heather R, Horn Candice L, Janetka James W, Liu Dongfang, Mouchet Elizabeth, Ready Shannon, Rosenthal Judith L, Queva Christophe, Schwartz Gary K, Taylor Karen J, Tse Archie N, Walker Graeme E, White Anne M
AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
Mol Cancer Ther. 2008 Sep;7(9):2955-66. doi: 10.1158/1535-7163.MCT-08-0492.
Insights from cell cycle research have led to the hypothesis that tumors may be selectively sensitized to DNA-damaging agents resulting in improved antitumor activity and a wider therapeutic margin. The theory relies on the observation that the majority of tumors are deficient in the G1-DNA damage checkpoint pathway resulting in reliance on S and G2 checkpoints for DNA repair and cell survival. The S and G2 checkpoints are regulated by checkpoint kinase 1, a serine/threonine kinase that is activated in response to DNA damage; thus, inhibition of checkpoint kinase 1 signaling impairs DNA repair and increases tumor cell death. Normal tissues, however, have a functioning G1 checkpoint signaling pathway allowing for DNA repair and cell survival. Here, we describe the preclinical profile of AZD7762, a potent ATP-competitive checkpoint kinase inhibitor in clinical trials. AZD7762 has been profiled extensively in vitro and in vivo in combination with DNA-damaging agents and has been shown to potentiate response in several different settings where inhibition of checkpoint kinase results in the abrogation of DNA damage-induced cell cycle arrest. Dose-dependent potentiation of antitumor activity, when AZD7762 is administered in combination with DNA-damaging agents, has been observed in multiple xenograft models with several DNA-damaging agents, further supporting the potential of checkpoint kinase inhibitors to enhance the efficacy of both conventional chemotherapy and radiotherapy and increase patient response rates in a variety of settings.
细胞周期研究的见解引发了一种假说，即肿瘤可能对DNA损伤剂产生选择性敏感，从而提高抗肿瘤活性并扩大治疗窗口。该理论基于以下观察结果：大多数肿瘤在G1-DNA损伤检查点通路中存在缺陷，导致依赖S期和G2期检查点进行DNA修复和细胞存活。S期和G2期检查点由检查点激酶1调节，这是一种丝氨酸/苏氨酸激酶，在DNA损伤时被激活；因此，抑制检查点激酶1信号传导会损害DNA修复并增加肿瘤细胞死亡。然而，正常组织具有功能正常的G1检查点信号通路，可实现DNA修复和细胞存活。在此，我们描述了AZD7762的临床前概况，它是一种在临床试验中的强效ATP竞争性检查点激酶抑制剂。AZD7762已在体外和体内与DNA损伤剂联合进行了广泛研究，并已证明在几种不同情况下具有增效作用，即抑制检查点激酶会导致DNA损伤诱导的细胞周期停滞被消除。当AZD7762与DNA损伤剂联合给药时，在多个异种移植模型中使用多种DNA损伤剂均观察到了抗肿瘤活性的剂量依赖性增强，这进一步支持了检查点激酶抑制剂在增强传统化疗和放疗疗效以及提高各种情况下患者反应率方面的潜力。
