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排序方式: 共有124条查询结果,搜索用时 328 毫秒
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Azqueta A Arbillaga L Pachón G Cascante M Creppy EE López de Cerain A 《Chemico-biological interactions》2007,168(2):95-105
Some anticancer compounds are pro-drugs which give rise to toxic species through enzymatic reduction. The quinoxaline-di-N-oxide derivative Q-85 HCl (7-chloro-3-[[(N,N-dimethylamino)propyl]amino]-2-quinoxalinecarbonitrile 1,4-di-N-oxide hydrochloride) is a bioreductive compound selectively toxic in hypoxia. Due to the possibility of secondary tumors the study of the genotoxic capability of antitumoral drugs is very important. The aim of this study was to assess the ability of Q-85 HCl to produce reactive oxygen species (ROS) and oxidative DNA damage in Caco-2 cells, both in hypoxia and in well-oxygenated conditions. Secondly, we attempted to evaluate the effect of vitamins C and E under hypoxic and normoxic conditions, in order to determine if these antioxidant substances modify Q-85 HCl effect in hypoxic cells or possibly exert a protective action in normal cells. Caco-2 cells were treated with Q-85 HCl for 2h, at high concentrations in normoxia (0.1-5 microM) and at low concentrations in hypoxia (0.002-0.1 microM). In normoxia, a dose-related significant increase in intracellular ROS level was evident; in hypoxia all the concentrations produced very high level of ROS. Just after the treatment and 24h later, oxidative DNA damage was evaluated by the modified comet assay after post-digestion of the cells with formamidopyrimidine-DNA glycosylase (FPG) and endonuclease III (Endo III). Q-85 HCl treatment evoked a significant dose-dependent increase in the total comet score of the cells both in hypoxia and normoxia, indicating that this compound or some metabolite is able to oxidize purine and pyrimidine bases. After 24h DNA damage caused by the compound was completely repaired with only one exception: cells treated with the highest concentration of Q-85 HCl in hypoxia and post-digested with FPG. Vitamin C (5-100 microM) and vitamin E (500-400 microM) did not have a pro-oxidant effect in Caco-2 cells. Treatment of cells with vitamin C (10 microM) or vitamin E (100 microM) did not significantly reduce oxidative DNA damage in hypoxia and normoxia. In conclusion, the use of these vitamins would not hinder toxicity against hypoxic cells, but a protective effect in normoxic cells was not evident. 相似文献
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Amaia Ercilla Alba Llopis Sonia Feu Sergi Aranda Patrik Ernfors Raimundo Freire Neus Agell 《Nucleic acids research》2016,44(10):4745-4762
Defects in DNA replication and repair are known to promote genomic instability, a hallmark of cancer cells. Thus, eukaryotic cells have developed complex mechanisms to ensure accurate duplication of their genomes. While DNA damage response has been extensively studied in tumour cells, the pathways implicated in the response to replication stress are less well understood especially in non-transformed cells. Here we show that in non-transformed cells, APC/CCdh1 is activated upon severe replication stress. Activation of APC/CCdh1 prevents new origin firing and induces permanent arrest in S-phase. Moreover, Rad51-mediated homologous recombination is also impaired under these conditions. APC/CCdh1 activation in S-phase occurs after replication forks have been processed into double strand breaks. Remarkably, this activation, which correlates with decreased Emi1 levels, is not prevented by ATR/ATM inhibition, but it is abrogated in cells depleted of p53 or p21. Importantly, we found that the lack of APC/CCdh1 activity correlated with an increase in genomic instability. Taken together, our results define a new APC/CCdh1 function that prevents cell cycle resumption after prolonged replication stress by inhibiting origin firing, which may act as an additional mechanism in safeguarding genome integrity. 相似文献
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Nora Fernandez-Jimenez Leticia Plaza-Izurieta Tamara Lopez-Euba Amaia Jauregi-Miguel Jose Ramon Bilbao 《Epigenetics》2012,7(12):1349-1354
Epigenetic mechanisms, including DNA methylation, are important determinants in development and disease. There is a need for technologies capable of detecting small variations in methylation levels in an accurate and reproducible manner, even if only limited amounts of DNA are available (which is the case in many studies in humans). Quantitative methylation analysis of minute DNA amounts after whole bisulfitome amplification (qMAMBA) has been proposed as an alternative, but this technique has not been adequately standardized and no comparative study against conventional methods has been performed, that includes a wide range of methylation percentages and different target assays. We designed an experiment to compare the performance of qMAMBA and bisulfite-treated genomic (non-amplified) DNA pyrosequencing. Reactions were performed in duplicate for each technique in eight different target genes, using nine artificially constructed DNA samples with methylation levels ranging between 0% and 100% with intervals of 12.5%. Cubic polynomial curves were plotted from the experimental results and the real methylation values and the resulting equation was used to estimate new corrected data points. The use of the cubic regression-based correction benefits the accuracy and the power of discrimination in methylation studies. Additionally, dispersion of the new estimated data around a y = x line (R2) served to fix a cutoff that can discriminate, with a single 9-point curve experiment, whether whole bisulfitome amplification and subsequent qMAMBA can produce accurate methylation results. Finally, even with an optimized reagent kit, DNA samples subjected to whole bisulfitome amplification enhance the preferential amplification of unmethylated alleles, and subtle changes in methylation levels cannot be detected confidently. 相似文献
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