Double-strand break repair deficiency and radiation sensitivity in BRCA2 mutant cancer cells
Double-strand break repair deficiency and radiation sensitivity in BRCA2 mutant cancer cells
复制标题
DOI：
10.1093/jnci/90.13.978
复制
发表时间：
1998-07-01
期刊：
影响因子：
--
通讯作者：
Holt, JT
中科院分区：
文献类型：
--
作者：
Abbott, DW;Freeman, ML;Holt, JT
BRCA2基因的蛋白产物介导DNA双链断裂的修复，因为许多癌症疗法通过启动双链断裂发挥细胞毒性作用，由携带BRCA2基因突变的细胞组成的癌症可能更容易接受导致这种断裂的药物治疗。方法：我们鉴定了一种缺乏BRCA2基因拷贝的人类胰腺腺癌细胞系，在其余拷贝中含有突变（6174deIT）。用该细胞系和其他基因突变相似、分化状态相似和/或癌型相似的癌细胞系进行体外和体内实验，检测双链断裂修复、对诱导双链断裂药物的敏感性和辐射敏感性。结果：brca2缺陷细胞仅不能修复电离辐射诱导的双链DNA断裂。这些细胞对米托蒽醌，amsacrine和etoposide（诱导双链断裂的药物）（双面P = 0.002）和电离辐射（双面P = 0.001）也显着敏感。将反义BRCA2脱氧核糖核内酯引入具有正常BRCA2功能的细胞导致对米托蒽醌的敏感性增加（双面P = 0.008）。将BRCA2缺陷细胞注射到裸鼠体内形成的肿瘤高度敏感（肿瘤大小减少90%）。双侧P =.002)对电离辐射和米托卡拉酮的影响，与表现出正常BRCA2功能的turner相比。与具有正常BRCA2功能的对照肿瘤相比，经放疗的BRCA2缺陷肿瘤的组织学分析显示，坏死程度较大。结论：brca2缺陷癌细胞对引起DNA双链断裂的药物高度敏感。
Background The protein product of the BRCA2 gene mediates repair of double-strand breaks in DNA, Because a number of cancer therapies exert cytotoxic effects via the initiation of double-strand breaks, cancers comprised of cells carrying BRCA2 gene mutations may be more amenable to treatment with agents that cause such breaks, Methods: We identified a hunan pancreatic adenocarcinoma cell line lacking one copy of the BRCA2 gene and containing a mutation (6174deIT) in the remaining copy. In vitro and in vivo experiments were conducted with this cell line and with ether carcinoma cell lines matched for similar genetic mutations, similar differentiation status, and/or similar carcinoma type to examine double-strand break repair, sensitivity to drugs that induce double-strand breaks, and radiation sensitivity. Results: BRCA2-defective cells mere unable to repair the double-strand DNA breaks induced by ionizing radiation. These cells were also markedly sensitive to mitoxantrone, amsacrine, and etoposide (drugs that induce double-strand breaks) (two-sided P =.002) and to ionizing radiation (two-sided P =.001), Introduction of antisense BRCA2 deoxyrilbonucleolides into cells possessing normal BRCA2 function led to increased sensitivity to mitoxantrone (two-sidled P =,008), Tumors formed by injection of BRCA2 defective cells into nude mice were highly sensitive (>90% tumor size reduction, two-sided P =.002) to both ionizing radiation and mitoxaratrone when compared with turners exhibiting normal BRCA2 function. Histologic analysis of irradiated BRCA2-defecetive tumors showed a large degree of necrosis compared with that observed for control tumors possessing normal BRCA2 function. Conclusion: BRCA2-defective cancer cells are highly sensitive to agents that cause double-strand breaks in DNA.