Ionizing radiation is frequently used to treat solid tumors,as it causes DNA damage and kill cancer cells.However,damaged DNA is repaired involving poly-(ADP-ribose)polymerase-1(PARP-1)causing resistance to radiation ...Ionizing radiation is frequently used to treat solid tumors,as it causes DNA damage and kill cancer cells.However,damaged DNA is repaired involving poly-(ADP-ribose)polymerase-1(PARP-1)causing resistance to radiation therapy.Thus,PARP-1 represents an important target in multiple cancer types,including prostate cancer.PARP is a nuclear enzyme essential for single-strand DNA breaks repair.Inhibiting PARP-1 is lethal in a wide range of cancer cells that lack the homologous recombination repair(HR)pathway.This article provides a concise and simplified overview of the development of PARP inhibitors in the laboratory and their clinical applications.We focused on the use of PARP inhibitors in various cancers,including prostate cancer.We also discussed some of the underlying principles and challenges that may affect the clinical efficacy of PARP inhibitors.展开更多
The DNA damage response is critical for cells to maintain genome stability and survival. In this review, we discuss approaches to targeting critical elements of the DNA damage response for radiosensitization and chemo...The DNA damage response is critical for cells to maintain genome stability and survival. In this review, we discuss approaches to targeting critical elements of the DNA damage response for radiosensitization and chemosensitization. In addition, we also discuss strategies for targeting DNA damage response and DNA repair defects in cancer cells for synthetic lethality.展开更多
Single-strand break repair protein poly(ADP-ribose)polymerase 1(PARP1)catalyzes the poly(ADPribosyl)ation of many key proteins in vivo and thus plays important roles in multiple DNA damage response pathways,rendering ...Single-strand break repair protein poly(ADP-ribose)polymerase 1(PARP1)catalyzes the poly(ADPribosyl)ation of many key proteins in vivo and thus plays important roles in multiple DNA damage response pathways,rendering it a promising target in cancer therapy.The tumor-suppressor effects of PARP inhibitors have attracted significant interest for development of novel cancer therapies.However,recent evidence indicated that the underlying mechanism of PARP inhibitors in tumor therapy is more complex than previously expected.The present review will focus on recent progress on the role of PARP1 in the DNA damage response and PARP inhibitors in cancer therapy.The emerging resistance of BRCA-deficient tumors to PARP inhibitors is also briefly discussed from the perspective of DNA damage and repair.These recent research advances will inform the selection of patient populations who can benefit from the PARP inhibitor treatment and development of effective drug combination strategies.展开更多
聚腺苷二磷酸核糖聚合酶[poly(ADP-ribose)polymerase,PARP]抑制剂与乳腺癌易感基因1(breast cancer susceptibility gene 1,BRCA1)/BRCA2突变介导的合成致死理论,为抗癌药物的研发提供了新的方向。这是一种通过抑制肿瘤细胞DNA损伤修复...聚腺苷二磷酸核糖聚合酶[poly(ADP-ribose)polymerase,PARP]抑制剂与乳腺癌易感基因1(breast cancer susceptibility gene 1,BRCA1)/BRCA2突变介导的合成致死理论,为抗癌药物的研发提供了新的方向。这是一种通过抑制肿瘤细胞DNA损伤修复,从而杀伤肿瘤细胞的安全而有效的新型治疗方式。自研究证实PARP抑制剂可引起乳腺癌细胞的合成致死效应以来,已研发出许多选择性和敏感性均较好的PARP抑制剂,且大部分已进入临床试验阶段。尽管PARP抑制剂单药在BRCA1/BRCA2突变的乳腺癌和卵巢癌中可发挥治疗效应,但目前的PARP抑制剂在临床应用时,仍是与其他化疗药物或放射治疗联合使用。本综述对已报道的PARP抑制剂联合常用化疗药物治疗肿瘤的研究进展进行小结。展开更多
文摘Ionizing radiation is frequently used to treat solid tumors,as it causes DNA damage and kill cancer cells.However,damaged DNA is repaired involving poly-(ADP-ribose)polymerase-1(PARP-1)causing resistance to radiation therapy.Thus,PARP-1 represents an important target in multiple cancer types,including prostate cancer.PARP is a nuclear enzyme essential for single-strand DNA breaks repair.Inhibiting PARP-1 is lethal in a wide range of cancer cells that lack the homologous recombination repair(HR)pathway.This article provides a concise and simplified overview of the development of PARP inhibitors in the laboratory and their clinical applications.We focused on the use of PARP inhibitors in various cancers,including prostate cancer.We also discussed some of the underlying principles and challenges that may affect the clinical efficacy of PARP inhibitors.
基金supported in part by grants from the National Institutes of Health,USA (No.R01CA133093 and R01ES016354)the National Natural Science Foundation of China(No.81001027)
文摘The DNA damage response is critical for cells to maintain genome stability and survival. In this review, we discuss approaches to targeting critical elements of the DNA damage response for radiosensitization and chemosensitization. In addition, we also discuss strategies for targeting DNA damage response and DNA repair defects in cancer cells for synthetic lethality.
基金supported by National Natural Science Foundation of China(Grant Nos.30970588 and 31170730[C.G],Grant No.30970931[T.S.T])“One-Hundred-Talent Program”(C.G)and“Knowledge Innovation Program KSCX2-YW-R-148”(T.S.T)from Chinese Academy of Sciences,and National Basic Research Program of China(Nos.2011CB944302,2011CB965003,2012CB944702).
文摘Single-strand break repair protein poly(ADP-ribose)polymerase 1(PARP1)catalyzes the poly(ADPribosyl)ation of many key proteins in vivo and thus plays important roles in multiple DNA damage response pathways,rendering it a promising target in cancer therapy.The tumor-suppressor effects of PARP inhibitors have attracted significant interest for development of novel cancer therapies.However,recent evidence indicated that the underlying mechanism of PARP inhibitors in tumor therapy is more complex than previously expected.The present review will focus on recent progress on the role of PARP1 in the DNA damage response and PARP inhibitors in cancer therapy.The emerging resistance of BRCA-deficient tumors to PARP inhibitors is also briefly discussed from the perspective of DNA damage and repair.These recent research advances will inform the selection of patient populations who can benefit from the PARP inhibitor treatment and development of effective drug combination strategies.
文摘聚腺苷二磷酸核糖聚合酶[poly(ADP-ribose)polymerase,PARP]抑制剂与乳腺癌易感基因1(breast cancer susceptibility gene 1,BRCA1)/BRCA2突变介导的合成致死理论,为抗癌药物的研发提供了新的方向。这是一种通过抑制肿瘤细胞DNA损伤修复,从而杀伤肿瘤细胞的安全而有效的新型治疗方式。自研究证实PARP抑制剂可引起乳腺癌细胞的合成致死效应以来,已研发出许多选择性和敏感性均较好的PARP抑制剂,且大部分已进入临床试验阶段。尽管PARP抑制剂单药在BRCA1/BRCA2突变的乳腺癌和卵巢癌中可发挥治疗效应,但目前的PARP抑制剂在临床应用时,仍是与其他化疗药物或放射治疗联合使用。本综述对已报道的PARP抑制剂联合常用化疗药物治疗肿瘤的研究进展进行小结。
