Perspectives on the combination of radiotherapy and targeted therapy with DNA repair inhibitors in the treatment of pancreatic cancer

作     者：Shih-Hung Yang Ting-Chun Kuo Hsu Wu Jhe-Cyuan Guo Chiun Hsu Chih-Hung Hsu Yu-Wen Tien Kun-Huei Yeh Ann-Lii Cheng Sung-Hsin Kuo 

作者机构：Department of Oncology National Taiwan University Hospital and National Taiwan University Cancer Center Taipei 100 Taiwan Department of Internal Medicine National Taiwan University Hospital and National Taiwan University Cancer Center Taipei 100 Taiwan Institute of Clinical Medicine National Taiwan University Hospital and National Taiwan University Cancer Center Taipei 100 Taiwan Department of Traumatology National Taiwan University Hospital and National Taiwan University Cancer Center Taipei 100 Taiwan Department of Oncology National Taiwan University Hospital Yun-Lin Branch Yunlin 655 Taiwan Graduate Institute of Oncology National Taiwan University College of Medicine Taipei 100 Taiwan Department of Surgery National Taiwan University Hospital and National Taiwan University Cancer Center Taipei 100 Taiwan 

出 版 物：《World Journal of Gastroenterology》 (世界胃肠病学杂志（英文版）)

年 卷 期：2016年第22卷第32期

页      面：7275-7288页

核心收录：

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

主　　题：Radiotherapy Pancreatic cancer DNA damage DNA repair Molecular targets 

摘      要：Pancreatic cancer is highly lethal. Current research that combines radiation with targeted therapy may dramatically improve prognosis. Cancerous cells are characterized by unstable genomes and activation of DNA repair pathways, which are indicated by increased phosphorylation of numerous factors, including H2 AX, ATM, ATR, Chk1, Chk2, DNA-PKcs, Rad51, and Ku70/Ku80 heterodimers. Radiotherapy causes DNA damage. Cancer cells can be made more sensitive to the effects of radiation(radiosensitization) through inhibition of DNA repair pathways. The synergistic effects, of two or more combined non-lethal treatments, led to coadministration of chemotherapy and radiosensitization in BRCA-defective cells and patients, with promising results. ATM/Chk2 and ATR/Chk1 pathways are principal regulators of cell cycle arrest, following DNA doublestrand or single-strand breaks. DNA double-stranded breaks activate DNA-dependent protein kinase, catalytic subunit(DNA-PKcs). It forms a holoenzyme with Ku70/Ku80 heterodimers, called DNA-PK, which catalyzes the joining of nonhomologous ends. This is the primary repair pathway utilized in human cells after exposure to ionizing radiation. Radiosensitization, induced by inhibitors of ATM, ATR, Chk1, Chk2, Wee1, PP2 A, or DNA-PK, has been demonstrated in preclinical pancreatic cancer studies. Clinical trials are underway. Development of agents that inhibit DNA repair pathways to be clinically used in combination with radiotherapy is warranted for the treatment of pancreatic cancer.