抗癌治疗之间的时间依赖性相互作用。
Schedule-dependent interaction between anticancer treatments.
作者信息
Chen Sheng-Hong, Forrester William, Lahav Galit
机构信息
Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
出版信息
Science. 2016 Mar 11;351(6278):1204-8. doi: 10.1126/science.aac5610. Epub 2016 Mar 10.
Abstract
The oncogene MDMX is overexpressed in many cancers, leading to suppression of the tumor suppressor p53. Inhibitors of the oncogene product MDMX therefore might help reactivate p53 and enhance the efficacy of DNA-damaging drugs. However, we currently lack a quantitative understanding of how MDMX inhibition affects the p53 signaling pathway and cell sensitivity to DNA damage. Live cell imaging showed that MDMX depletion triggered two distinct phases of p53 accumulation in single cells: an initial postmitotic pulse, followed by low-amplitude oscillations. The response to DNA damage was sharply different in these two phases; in the first phase, MDMX depletion was synergistic with DNA damage in causing cell death, whereas in the second phase, depletion of MDMX inhibited cell death. Thus a quantitative understanding of signal dynamics and cellular states is important for designing an optimal schedule of dual-drug administration.
摘要
癌基因MDMX在许多癌症中过度表达，导致肿瘤抑制因子p53受到抑制。因此，癌基因产物MDMX的抑制剂可能有助于重新激活p53并增强DNA损伤药物的疗效。然而，我们目前缺乏对MDMX抑制如何影响p53信号通路以及细胞对DNA损伤敏感性的定量认识。活细胞成像显示，MDMX缺失在单细胞中引发了p53积累的两个不同阶段：最初的有丝分裂后脉冲，随后是低振幅振荡。这两个阶段对DNA损伤的反应截然不同；在第一阶段，MDMX缺失与DNA损伤在导致细胞死亡方面具有协同作用，而在第二阶段，MDMX的缺失抑制了细胞死亡。因此，对信号动态和细胞状态的定量理解对于设计双药联合给药的最佳方案很重要。
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