Tirapazamine is a bioreductively activated DNA-damaging agent that selectively kills the hypoxic cells found in solid tomors. This compound shows great clinical promise and is currently being examined in a variety of clinical trails, 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 tirapazamine, the studies reported here are designed to characterize this drug's ability to damage 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 and 8,5'-cyclopurine-2'-deoxynucleosides 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 strongly indicate that DNA base damage may contribute to the biological effects of tirapazamine in vivo.
Citation: Journal of the American Chemical Society
Pub Type: Journals
8c5'-cyclopurine-2-'-deoxynucleosides, antitumor agent, canercer therapy, formamidopyrimidines, hypoxia-selective cyctotoxicity, mutagenesis, oxidative DNA damage