Selective inhibition of BRCA2-deficient mammary tumor cell growth by AZD2281 and cisplatin
Selective inhibition of BRCA2-deficient mammary tumor cell growth by AZD2281 and cisplatin
复制标题
DOI：
10.1158/1078-0432.ccr-07-4953
复制
发表时间：
2008-06-15
影响因子：
11.5
通讯作者：
Jonkers, Jos
中科院分区：
文献类型：
--
作者：
Evers, Bastiaan;Drost, Rinske;Jonkers, Jos
目的：为了评估新的，选择性的聚（ADP-核糖）聚合酶-1（PARP-1）抑制剂AZD 2281对新建立的BRCA 2缺陷小鼠乳腺肿瘤细胞系的疗效，并确定AZD 2281和cisplatin.Experimental Design之间的潜在协同作用：我们建立了一组独立的BRCA 2缺陷小鼠乳腺肿瘤和BRCA 2-proficient对照肿瘤的克隆细胞系，并对其进行了全面表征。随后，我们评估了这些细胞系对常规细胞毒性药物和新型PARP抑制剂AZD 2281的敏感性。结果：基因、转录和功能分析证实成功分离了BRCA 2缺陷型和BRCA 2高表达型小鼠乳腺肿瘤细胞系。用11种不同的抗癌药物或γ-射线处理这些细胞系表明，AZD 2281（一种新型特异性PARP抑制剂）对BRCA 2缺陷型乳腺肿瘤细胞和BRCA 2活性型乳腺肿瘤细胞的生长抑制作用最强。最后，药物组合研究显示，AZD 2281和顺铂对BRCA 2缺陷细胞的协同细胞毒性，但对BRCA 2-proficient control cells.Conclusion：我们已经成功地建立了第一套BRCA 2缺陷乳腺肿瘤细胞系，这形成了一个重要的除了现有的BRCA突变乳腺癌的临床前模型。这些细胞对PARP抑制剂AZD 2281（单独或与顺铂联合使用）的敏感性非常高，这为AZD 2281作为一种针对BRCA缺陷型癌症的新型靶向治疗提供了强有力的支持。
Purpose: To assess efficacy of the novel, selective poly (ADP-ribose) polymerase-1 (PARP-1) inhibitor AZD2281 against newly established BRCA2-deficient mouse mammary tumor cell lines and to determine potential synergy between AZD2281 and cisplatin.Experimental Design: We established and thoroughly characterized a panel of clonal cell lines from independent BRCA2-deficient mouse mammary tumors and BRCA2-proficient control tumors. Subsequently, we assessed sensitivity of these lines to conventional cytotoxic drugs and the novel PARP inhibitor AZD2281. Finally, in vitro combination studies were done to investigate interaction between AZD2281 and cisplatin.Results: Genetic, transcriptional, and functional analyses confirmed the successful isolation of BRCA2-deficient and BRCA2-proficient mouse mammary tumor cell lines. Treatment of these cell lines with 11 different anticancer drugs or with gamma-irradiation showed that AZD2281, a novel and specific PARP inhibitor, caused the strongest differential growth inhibition of BRCA2-deficient versus BRCA2-proficient mammary tumor cells. Finally, drug combination studies showed synergistic cytotoxicity of AZD2281 and cisplatin against BRCA2-deficient cells but not against BRCA2-proficient control cells.Conclusion: We have successfully established the first set of BRCA2-deficient mammary tumor cell lines, which form an important addition to the existing preclinical models for BRCA-mutated breast cancer. The exquisite sensitivity of these cells to the PARP inhibitor AZD2281, alone or in combination with cisplatin, provides strong support for AZD2281 as a novel targeted therapeutic against BRCA-deficient cancers.