Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase
Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase
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DOI：
10.1038/nature03443
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发表时间：
2005-04-14
期刊：
影响因子：
64.8
通讯作者：
Helleday, T
中科院分区：
文献类型：
--
作者：
Bryant, HE;Schultz, N;Helleday, T
聚（ADP-核糖）聚合酶（PARP 1）通过结合DNA断裂并将DNA修复蛋白吸引到损伤部位来促进DNA修复（1-3）。然而，PARP 1（-/-）小鼠是可行的，可生育的，不会发生早发性肿瘤（4）。在这里，我们表明PARP抑制剂会触发γ-H2 AX和RAD 51灶的形成。我们认为，在PARP 1缺失的情况下，自发的单链断裂会使复制叉崩溃，并引发同源重组进行修复。此外，我们表明，BRCA 2缺陷细胞，由于其在同源重组的缺陷，是急性敏感的PARP抑制剂，大概是因为所得的崩溃复制叉不再修复。因此，PARP 1活性在同源重组缺陷型BRCA 2突变细胞中是必需的。我们利用这一要求，以杀死BRCA 2缺陷的肿瘤，通过单独的PARP抑制。PARP抑制剂治疗可能具有高度的肿瘤特异性，因为只有BRCA 2（+/-）患者的肿瘤（BRCA 2（-/-））在同源重组方面存在缺陷。在不存在外源性DNA损伤剂的情况下，单独使用DNA修复酶抑制剂选择性杀死肿瘤，代表了癌症治疗的新概念。
Poly( ADP-ribose) polymerase (PARP1) facilitates DNA repair by binding to DNA breaks and attracting DNA repair proteins to the site of damage(1-3). Nevertheless, PARP1(-/-) mice are viable, fertile and do not develop early onset tumours(4). Here, we show that PARP inhibitors trigger gamma-H2AX and RAD51 foci formation. We propose that, in the absence of PARP1, spontaneous single-strand breaks collapse replication forks and trigger homologous recombination for repair. Furthermore, we show that BRCA2-deficient cells, as a result of their deficiency in homologous recombination, are acutely sensitive to PARP inhibitors, presumably because resultant collapsed replication forks are no longer repaired. Thus, PARP1 activity is essential in homologous recombination-deficient BRCA2 mutant cells. We exploit this requirement in order to kill BRCA2-deficient tumours by PARP inhibition alone. Treatment with PARP inhibitors is likely to be highly tumour specific, because only the tumours ( which are BRCA2(-/-)) in BRCA2(+/-) patients are defective in homologous recombination. The use of an inhibitor of a DNA repair enzyme alone to selectively kill a tumour, in the absence of an exogenous DNA-damaging agent, represents a new concept in cancer treatment.