Improved efficacy of acylfulvene in colon cancer cells when combined with a nuclear excision repair inhibitor.
Improved efficacy of acylfulvene in colon cancer cells when combined with a nuclear excision repair inhibitor.
复制标题
与核切除修复抑制剂联合使用时，酰富烯在结肠癌细胞中的功效得到提高。
DOI：
10.1021/tx400255f
复制
发表时间：
2013
影响因子：
4.1
通讯作者：
Sturla,ShanaJ
中科院分区：
文献类型：
--
作者：
vanMidwoud,PaulM;Sturla,ShanaJ
DNA损伤性抗癌药物的功效很大程度上受细胞DNA修复能力的影响，通过抑制相关的DNA修复途径，烷化剂的功效可能会增加。因此，将 DNA 修复抑制剂与选择性靶向肿瘤组织的抗癌药物相结合应该可以改善癌症治疗。本研究的目的是检验以下假设：用酰基富烯（AF，烷化剂）和 UCN-01（DNA 修复抑制剂）共同治疗癌细胞会提高药物疗效并促进 DNA 加合物的持久性。先前有关修复良好的细胞与缺陷细胞对 AF 类似物的相对敏感性的数据表明，相应的加合物通过核切除修复 (NER) 进行修复，这是一种已被证明可以用 UCN-01 预防的细胞过程。在这项研究中，细胞用无毒水平的 UCN-01 和增加剂量的 AF 共同处理。通过测量细胞毒性和 DNA 加合物来评估 AF 的功效。此外，细胞还与无毒水平的甲氧胺（一种已知的碱基切除修复 (BER) 抑制剂）共同处理，以确定抑制 BER 是否也会促进 AF 的细胞毒性。通过使用稳定同位素标记的质谱分析，以灵敏且精确的方式测量 DNA 加合物。本研究获得的数据首次证明，DNA 修复 NER 途径的药理抑制会导致 AF 特异性加合物的持续存在，并促进 AF 细胞毒性。
The efficacy of DNA-damaging anticancer drugs is highly influenced by cellular DNA repair capacity, and by inhibiting the relevant DNA repair pathway, efficacy of alkylating agents may be increased. Therefore, combining DNA repair inhibitors with anticancer agents that selectively target tumor tissue should improve cancer treatment. The objective of this study was to test the hypothesis that cotreatment of cancer cells with acylfulvene (AF, alkylating agent) and UCN-01 (DNA repair inhibitor) would improve drug efficacy and promote the persistence of DNA adducts. Previous data regarding the relative susceptibility of repair proficient versus deficient cells toward an AF analogue suggests that corresponding adducts are repaired by nuclear excision repair (NER), a cellular process that has been shown to be prevented with UCN-01. In this study, cells were cotreated with nontoxic levels of UCN-01 together with increasing doses of AF. The efficacy of AF was assessed by measuring cytotoxicity and DNA adducts. In addition, cells were cotreated with nontoxic levels of methoxyamine, a known base excision repair (BER) inhibitor, to determine if inhibiting BER also promotes cytotoxicity of AF. DNA-adducts were measured in a sensitive and precise manner by using stable isotope-labeled mass spectrometry analysis. The data obtained in this study demonstrate for the first time that pharmacological inhibition of the NER pathway of DNA repair leads to the persistence of AF-specific adducts and promotes AF cytotoxicity.