DNA base damage by the antitumor agent 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine)
DNA base damage by the antitumor agent 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine)
复制标题
DOI：
10.1021/ja0352146
复制
发表时间：
2003-09-24
影响因子：
15
通讯作者：
Gates, KS
中科院分区：
文献类型：
--
作者：
Birincioglu, M;Jaruga, P;Gates, KS
替拉帕明是一种生物还原激活的DNA损伤剂，它选择性地杀死实体肿瘤中发现的缺氧细胞。这种化合物显示出临床前景，目前正在进行各种临床试验，包括几项第三阶段研究。众所周知，DNA是替拉帕扎明的重要细胞靶点；然而，这种药物造成的DNA损伤的结构性质仍然知之甚少。作为了解该药物低氧选择性细胞毒性的化学事件的一部分，本文报道的研究旨在表征替拉扎明对存储在双链DNA杂环碱基残基中的遗传信息的损害。在这里，我们使用气相色谱/质谱仪和液-质联用来表征和定量替帕西明介导的DNA氧化性碱基损伤。鉴定和定量了包括8，5‘-环嘌呤-2’-脱氧核苷串联损伤在内的多种修饰碱基。这一结果为该药物引起的DNA碱基损伤的结构特征提供了第一个详细的见解。有趣的是，似乎替拉帕明在低氧条件下工作，加上药物独特的化学性质，会产生一种独特的DNA碱基损伤，以甲酰胺基嘧啶和5-羟基-6-羟基嘧啶损伤为主。重要的是，研究结果表明，替拉帕明可能会产生一系列修复不良的、潜在的细胞毒性DNA碱基损伤，阻止DNA转录和复制。总之，这些结果表明DNA碱基损伤可能与替拉扎明在体内的生物学效应有关。
Tirapazamine 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.