Spencer Damian M S, Bilardi Rebecca A, Koch Tad H, Post Glen C, Nafie Jordan W, Kimura Ken-Ichi, Cutts Suzanne M, Phillips Don R
Department of Biochemistry, La Trobe University, Victoria 3086, Australia.
Mutat Res. 2008 Feb 1;638(1-2):110-21. doi: 10.1016/j.mrfmmm.2007.09.005. Epub 2007 Sep 16.
Doxorubicin, a widely used anthracycline anticancer agent, acts as a topoisomerase II poison but can also form formaldehyde-mediated DNA adducts. This has led to the development of doxorubicin derivatives such as doxoform, which can readily form adducts with DNA. This work aimed to determine which DNA repair pathways are involved in the recognition and possible repair of anthracycline-DNA adducts. Cell lines lacking functional proteins involved in each of the five main repair pathways, mismatch repair (MMR), base excision repair (BER), nucleotide excision repair (NER), homologous recombination (HR) and non-homologous end-joining (NHEJ) were examined for sensitivity to various anthracycline adduct-forming treatments. The treatments used were doxorubicin, barminomycin (a model adduct-forming anthracycline) and doxoform (a doxorubicin-formaldehyde conjugate). Cells with deficiencies in MMR, BER and NHEJ were equally sensitive to adduct-forming treatments compared to wild type cells and therefore these pathways are unlikely to play a role in the repair of these adducts. Some cells with deficiencies in the NER pathway (specifically, those lacking functional XPB, XPD and XPG), displayed tolerance to adducts induced by both barminomycin and doxoform and also exhibited a decreased level of apoptosis in response to adduct-forming treatments. Conversely, two HR deficient cell lines were shown to be more sensitive to barminomycin and doxoform than HR proficient cells, indicating that this pathway is also involved in the repair response to anthracycline-DNA adducts. These results suggest an unusual damage response pathway to anthracycline adducts involving both NER and HR that could be used to optimise cancer therapy for tumours with either high levels of NER or defective HR. Tumours with either of these characteristics would be predicted to respond particularly well to anthracycline-DNA adduct-forming treatments.
阿霉素是一种广泛使用的蒽环类抗癌药物，它作为一种拓扑异构酶II毒药，但也能形成甲醛介导的DNA加合物。这导致了阿霉素衍生物如多氧仿的开发，其能轻易地与DNA形成加合物。这项工作旨在确定哪些DNA修复途径参与了蒽环类-DNA加合物的识别和可能的修复。对缺乏参与五条主要修复途径（错配修复（MMR）、碱基切除修复（BER）、核苷酸切除修复（NER）、同源重组（HR）和非同源末端连接（NHEJ））中每一条途径的功能蛋白的细胞系进行了检测，以观察其对各种蒽环类加合物形成处理的敏感性。所使用的处理方法是阿霉素、巴米诺霉素（一种形成加合物的蒽环类模型药物）和多氧仿（一种阿霉素-甲醛共轭物）。与野生型细胞相比，MMR、BER和NHEJ缺陷的细胞对加合物形成处理同样敏感，因此这些途径不太可能在这些加合物的修复中起作用。一些NER途径缺陷的细胞系（具体来说，那些缺乏功能性XPB、XPD和XPG的细胞系），对巴米诺霉素和多氧仿诱导的加合物表现出耐受性，并且在对加合物形成处理的反应中凋亡水平也降低。相反，两个HR缺陷的细胞系对巴米诺霉素和多氧仿比HR功能正常的细胞更敏感，这表明该途径也参与了对蒽环类-DNA加合物的修复反应。这些结果表明，对蒽环类加合物存在一种不寻常的损伤反应途径，涉及NER和HR，这可用于优化对具有高水平NER或有缺陷HR的肿瘤的癌症治疗。具有这两种特征之一的肿瘤预计对蒽环类-DNA加合物形成处理反应特别良好。
