DNA base damage by the antitumor agent 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine)

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dc.authoridJaruga, Pawel/0000-0001-9192-6084
dc.authorwosidJaruga, Pawel/M-4378-2015
dc.contributor.authorBirincioglu, M
dc.contributor.authorJaruga, P
dc.contributor.authorChowdhury, G
dc.contributor.authorRodriguez, H
dc.contributor.authorDizdaroglu, M
dc.contributor.authorGates, KS
dc.date.accessioned2024-08-04T20:13:27Z
dc.date.available2024-08-04T20:13:27Z
dc.date.issued2003
dc.departmentİnönü Üniversitesien_US
dc.description.abstractTirapazamine is a bioreductively activated DNA-damaging agent that selectively kills the hypoxic cells found in solid tumors. This compound shows clinical promise and is currently being examined in a variety of clinical trials, including several phase III studies. It is well established that DNA is an important cellular target for tirapazamine; however, the structural nature of the DNA damage inflicted by this drug remains poorly understood. As part of an effort to understand the chemical events responsible for the hypoxia-selective cytotoxicity of this drug, the studies reported here are designed to characterize tirapazamine-mediated damage to the genetic information stored in the heterocyclic base residues of double-stranded DNA. Here, we used gas chromatography/mass spectrometry and liquid chromatography/mass spectrometry to characterize and quantify oxidative DNA base damage mediated by tirapazamine. A multiplicity of modified bases including 8,5'-cyclopurine-2'-deoxynucleoside tandem lesions were identified and quantified. The results provide the first detailed insight regarding the structural identity of the DNA base lesions caused by this drug. Interestingly, it appears that the hypoxic conditions under which tirapazamine operates, along with the unique chemical properties of the drug, yield a unique variety of DNA base damage that is dominated by formamidopyrimidine and 5-hydroxy-6-hydropyrimidine lesions. Importantly, the results suggest that tirapazamine may generate a set of poorly repaired, potentially cytotoxic DNA base lesions that block DNA transcription and replication. Overall, the results indicate that DNA base damage may contribute to the biological effects of tirapazamine in vivo.en_US
dc.description.sponsorshipNCI NIH HHS [CA100757] Funding Source: Medlineen_US
dc.identifier.doi10.1021/ja0352146
dc.identifier.endpage11615en_US
dc.identifier.issn0002-7863
dc.identifier.issue38en_US
dc.identifier.pmid13129365en_US
dc.identifier.scopus2-s2.0-0141757434en_US
dc.identifier.scopusqualityN/Aen_US
dc.identifier.startpage11607en_US
dc.identifier.urihttps://doi.org/10.1021/ja0352146
dc.identifier.urihttps://hdl.handle.net/11616/93626
dc.identifier.volume125en_US
dc.identifier.wosWOS:000185711100044en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherAmer Chemical Socen_US
dc.relation.ispartofJournal of The American Chemical Societyen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/closedAccessen_US
dc.subjectOne-Electron Reductionen_US
dc.subjectChromatography-Mass-Spectrometryen_US
dc.subjectColi Fpg Proteinen_US
dc.subjectCenter-Dot-Dgen_US
dc.subjectDi-N-Oxidesen_US
dc.subjectAqueous-Solutionen_US
dc.subjectIn-Vitroen_US
dc.subjectEscherichia-Colien_US
dc.subjectExcision-Repairen_US
dc.subjectQuinoxaline 1,4-Di-N-Oxideen_US
dc.titleDNA base damage by the antitumor agent 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine)en_US
dc.typeArticleen_US

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