Murai Junko
Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
Int J Clin Oncol. 2017 Aug;22(4):619-628. doi: 10.1007/s10147-017-1145-7. Epub 2017 Jun 22.
Approximately half of high-grade serous epithelial ovarian cancers incur alterations in genes of homologous recombination (BRCA1, BRCA2, RAD51C, Fanconi anemia genes), and the rest incur alterations in other DNA repair pathways at high frequencies. Such cancer-specific gene alterations can confer selective sensitivity to DNA damaging agents such as cisplatin and carboplatin, topotecan, etoposide, doxorubicin, and gemcitabine. Originally presumed to inhibit DNA repair, PARP inhibitors that have recently been approved by the FDA for the treatment of advanced ovarian cancer also act as DNA damaging agents by inducing PARP-DNA complexes. These DNA damaging agents induce different types of DNA lesions that require various DNA repair genes for the repair, but commonly induce replication fork slowing or stalling, also referred to as replication stress. Replication stress activates DNA repair checkpoint proteins (ATR, CHK1), which prevent further DNA damage. Hence, targeting DNA repair genes or DNA repair checkpoint genes augments the anti-tumor activity of DNA damaging agents. This review describes the rational basis for using DNA repair and DNA repair checkpoint inhibitors as single agents. The review also presents the strategies combining these inhibitors with DNA damaging agents for ovarian cancer therapy based on specific gene alterations.
大约一半的高级别浆液性上皮性卵巢癌会发生同源重组基因（BRCA1、BRCA2、RAD51C、范可尼贫血基因）的改变，其余的则高频发生其他DNA修复途径的改变。此类癌症特异性基因改变可使癌细胞对顺铂、卡铂、拓扑替康、依托泊苷、多柔比星和吉西他滨等DNA损伤剂产生选择性敏感性。PARP抑制剂最初被认为可抑制DNA修复，最近已获美国食品药品监督管理局（FDA）批准用于治疗晚期卵巢癌，它还可通过诱导PARP-DNA复合物而作为DNA损伤剂发挥作用。这些DNA损伤剂会诱导不同类型的DNA损伤，这些损伤需要各种DNA修复基因进行修复，但通常会导致复制叉减慢或停滞，也称为复制应激。复制应激会激活DNA修复检查点蛋白（ATR、CHK1），从而防止进一步的DNA损伤。因此，靶向DNA修复基因或DNA修复检查点基因可增强DNA损伤剂的抗肿瘤活性。本综述描述了将DNA修复和DNA修复检查点抑制剂作为单一药物使用的理论依据。该综述还基于特定基因改变，介绍了将这些抑制剂与DNA损伤剂联合用于卵巢癌治疗的策略。
