Nakagawa Yosuke, Kajihara Atsuhisa, Takahashi Akihisa, Kondo Natsuko, Mori Eiichiro, Kirita Tadaaki, Ohnishi Takeo
Particle Radiation Oncology Research Center, Research Reactor Institute, Kyoto University, Sennan-gun, Osaka 590-0494, Japan.
Department of Oral and Maxillofacial Surgery, School of Medicine, Nara Medical University, Kashihara, Nara 634‑8521, Japan.
Oncol Rep. 2014 May;31(5):2001-6. doi: 10.3892/or.2014.3080. Epub 2014 Mar 11.
5-Fluorouracil (5-FU) is widely used in clinical cancer therapy. It is commonly used either alone or in combination with other drugs and/or radiation for head and neck, and other types of cancers. 5-FU induces DNA double-strand breaks (DSBs). Inhibition of the repair of 5-FU-induced DSBs may improve the therapeutic response in many tumors to this anticancer agent. The aim of the present study was to further our understanding of the pathways which are involved in the repair of 5-FU-induced DSBs. Cell survival after drug treatment was examined with colony forming assays using Chinese hamster lung fibroblast cells or Chinese hamster ovary cell lines which are deficient in DSB repair pathways involving the homologous recombination repair-related genes BRCA2 and XRCC2, and the non-homologous end joining repair-related genes DNA-PKcs and Ku80. It was found that BRCA2 was involved in such repair, and may be effectively targeted to inhibit the repair of 5-FU-induced damage. Observations showed that knockdown of BRCA2 using small interference RNA suppression increased the sensitivity to 5-FU of human oral cancer cell lines (SAS and HSC3). These findings suggest that downregulation of BRCA2 may be useful for sensitizing tumor cells during 5-FU chemotherapy.
5-氟尿嘧啶（5-FU）广泛应用于临床癌症治疗。它通常单独使用或与其他药物和/或放疗联合用于头颈癌及其他类型的癌症。5-FU可诱导DNA双链断裂（DSB）。抑制5-FU诱导的DSB修复可能会改善许多肿瘤对这种抗癌药物的治疗反应。本研究的目的是进一步了解参与5-FU诱导的DSB修复的途径。使用中国仓鼠肺成纤维细胞或中国仓鼠卵巢细胞系进行集落形成试验，检测药物处理后的细胞存活率，这些细胞系在涉及同源重组修复相关基因BRCA2和XRCC2以及非同源末端连接修复相关基因DNA-PKcs和Ku80的DSB修复途径中存在缺陷。研究发现BRCA2参与了这种修复，并且可能是抑制5-FU诱导损伤修复的有效靶点。观察结果表明，使用小干扰RNA抑制敲低BRCA2可增加人口腔癌细胞系（SAS和HSC3）对5-FU的敏感性。这些发现表明，下调BRCA2可能有助于在5-FU化疗期间使肿瘤细胞敏感化。
