Targeting the S and G2 checkpoint to treat cancer

被引：194

作者：

Chen, Tao ^{[1
]}

Stephens, Peter A. ^{[1
]}

Middleton, Fiona K. ^{[1
]}

Curtin, Nicola J. ^{[1
]}

机构：

[1] Newcastle Univ, No Inst Canc Res, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England

来源：

DRUG DISCOVERY TODAY | 2012年 / 17卷 / 5-6期

关键词：

DNA-DAMAGE RESPONSE; DOUBLE-STRAND BREAKS; TUMOR-CELL SURVIVAL; ATR PROTEIN-KINASE; PHASE-I TRIAL; ATAXIA-TELANGIECTASIA; IONIZING-RADIATION; CHK1; INHIBITION; CARCINOMA-CELLS; REPLICATION CHECKPOINT;

D O I：

10.1016/j.drudis.2011.12.009

中图分类号：

R9 [药学];

学科分类号：

100702 [药剂学];

摘要：

Cell survival following DNA damage depends on activating checkpoints to arrest proliferation. Most cancer cells have dysregulated G1 checkpoints making them dependent on their S and G2 checkpoints, which are activated by ATR/Chk1 signalling. Thus, inhibiting ATR or Chk1 should selectively sensitise cancer cells to DNA damage. Genetic inactivation of ATR and Chk1 abrogates cell cycle arrest and enhances cytotoxicity following exposure to DNA-damaging agents. Similar effects were seen with small-molecule Chk1 inhibitors in preclinical studies, and clinical trial data are starting to emerge. Recently, potent ATR inhibitors have been identified that also sensitise cancer cells in vitro. ATR and Chk1 inhibitors might also cause 'synthetic lethality' in tumour cells defective in defined DNA repair pathways.

引用

页码：194 / 202

页数：9

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