| A quinoxaline 1,4-di-N-oxide derivative induces DNA oxidative damage not attenuated by vitamin C and E treatment. | |
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MedLine Citation:
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PMID: 17420013 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Amaia Azqueta; Leire Arbillaga; Gisela Pachón; Marta Cascante; Edmond E Creppy; Adela López de Cerain |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2007-03-04 |
Journal Detail:
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Title: Chemico-biological interactions Volume: 168 ISSN: 0009-2797 ISO Abbreviation: Chem. Biol. Interact. Publication Date: 2007 Jun |
Date Detail:
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Created Date: 2007-06-18 Completed Date: 2007-08-09 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0227276 Medline TA: Chem Biol Interact Country: Ireland |
Other Details:
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Languages: eng Pagination: 95-105 Citation Subset: IM |
Affiliation:
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Centro de Investigación en Farmacobiología Aplicada, University of Navarra, C/Irunlarrea 1, Pamplona, Spain. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Anoxia
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metabolism Ascorbic Acid / pharmacology* Caco-2 Cells DNA Damage* DNA Glycosylases / metabolism DNA-Formamidopyrimidine Glycosylase / metabolism Humans Prodrugs / pharmacology* Quinoxalines / pharmacology* Reactive Oxygen Species / metabolism Vitamin E / pharmacology* |
| Chemical | |
Reg. No./Substance:
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0/7-chloro-3-(((N,N-dimethylamino)propyl)amino)-2-quinoxalinecarbonitrile-1,4-di-N-oxide; 0/Prodrugs; 0/Quinoxalines; 0/Reactive Oxygen Species; 1406-18-4/Vitamin E; 50-81-7/Ascorbic Acid; EC 3.2.2.-/DNA Glycosylases; EC 3.2.2.23/DNA-Formamidopyrimidine Glycosylase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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