Oxidative DNA base damage by the antitumor agent 3-amino-1,2,4-benzotriazine 1,4-Dioxide (Tirapazamine)
In this work, base excision repair enzymes that remove oxidatively damaged DNA bases, leaving behind easily detected strand breaks, were used to provide evidence that tirapazamine causes significant amount of damage to both purine and pyrimidine residues in double-stranded DNA.
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Acknowledgements
This work was generously supported by American Cancer Society Grant RPG-00–028–01.
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Identification of one-electron reductases that activate both the hypoxia prodrug SN30000 and diagnostic probe EF5
2015, Biochemical PharmacologyCitation Excerpt :Of these, TPZ has been the most extensively studied both preclinically and in the clinic [18–20]. TPZ forms reactive free radicals upon its 1e reduction in tumour cells, resulting in oxidative DNA damage [21,22]. The hypoxia selectivity of TPZ is due to reoxidation of the initial TPZ radical by molecular oxygen [23–25].
Homologous recombination repair-dependent cytotoxicity of the benzotriazine di-N-oxide CEN-209: Comparison with other hypoxia-activated prodrugs
2012, Biochemical PharmacologyCitation Excerpt :PR-104 and TH-302, both currently undergoing clinical evaluation, are thought to act primarily by hypoxia-selective release of potent DNA cross-linking metabolites [8,9]. The most thoroughly investigated HAP is tirapazamine (TPZ), a benzotriazine di-N-oxide that undergoes oxygen-inhibited reduction to reactive free radicals [10,11] which induce oxidative DNA damage [12–14]. TPZ showed promising indications of activity in early clinical trials [15,16] but did not extend overall survival in combination with cisplatin and radiotherapy for advanced head and neck cancers in a recent phase III study [17].
DNA strand cleaving properties and hypoxia-selective cytotoxicity of 7-chloro-2-thienylcarbonyl-3-trifluoromethylquinoxaline 1,4-dioxide
2010, Bioorganic and Medicinal ChemistryOxidative DNA damage following photoexcitation of daunomycin: Direct role of oxygen
2008, Journal of Photochemistry and Photobiology A: ChemistryA quinoxaline 1,4-di-N-oxide derivative induces DNA oxidative damage not attenuated by vitamin C and E treatment
2007, Chemico-Biological InteractionsCitation Excerpt :One of the bioreductive agents that shows the highest hypoxia-selective toxicity in vitro is the tirapazamine (TPZ), a benzotriazine-di-N-oxide that has progressed to clinical use [6,13,16,17]. Under hypoxic conditions, this compound generates base damage, single strand breaks (SSB) and double strand breaks (DSB) [18–22]. Moreover, it has been demonstrated that, in hypoxia, TPZ causes oxidative DNA damage to both purine and pyrimidine residues in double-stranded DNA [22].