DNA Damage by Tumor Cell-Specific N-Oxides

肿瘤细胞特异性氮氧化物对 DNA 的损伤

• 批准号: 6858673
• 负责人: Kent S Gates
• 金额: $ 17.03万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-14 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6858673
• 关键词: DNA damage; DNA repair; antineoplastics; chemical reaction; chemical structure function; chemistry; cytotoxicity; gas chromatography mass spectrometry; high performance liquid chromatography; hydroxyl radical; hypoxia; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; nitrogen oxides; nuclear magnetic resonance spectroscopy; oxygen tension; tirapazamine

DESCRIPTION (provided by applicant): 3-Amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine, TPZ) is a bioreductively-activated DNA-damaging agent that selectively kills the hypoxic cells found in virtually all solid tumors. This compound shows great clinical promise and is currently being examined in more than ten different clinical trials, including several phase III studies. Importantly, TPZ damages DNA via a completely novel sequence of chemical reactions in which the one-electron reduced drug initiates radical-mediated DNA damage and then the drug or its metabolites transfer oxygen atoms from their N-oxide functional groups to the resulting DNA radicals, thus, converting them to strand cleavage sites. While the medicinal properties of TPZ have been extensively investigated, many of its biologically relevant chemical properties remain poorly understood. The growing clinical interest in TPZ provides a practical incentive to characterize the relevant chemistry of this drug. In addition, characterization of this new chemical motif that efficiently delivers cytotoxic DNA-damaging radicals to the interior of hypoxic cells may be of fundamental interest in both medicinal chemistry and toxicology. The work described in this proposal is divided into three Specific Aims: 1. How does TPZ generate radical lesions on DNA? Does the drug serve to deliver the known DNA-damaging agent hydroxyl radical to hypoxic cells? How do the conditions of low oxygen and low pH found in tumor cells combine to facilitate DNA damage by the drug? 2. What is the chemical mechanism by which TPZ and its metabolites transfer oxygen atoms from their N-oxide functional groups to DNA radicals? This unprecedented reaction allows the drug to efficiently damage DNA under hypoxic conditions and may play a central role in defining the structural nature of the final DNA lesions caused by TPZ. 3. We propose studies to characterize the structural nature of the DNA strand breaks and base damage mediated by TPZ. These studies will explore the possibility that the unusual conditions under which TPZ operates, along with the unique chemical properties of the drug, lead to a unique spectrum of DNA lesions that confront cells with social challenges to their DNA-repair systems.

描述（由申请人提供）： 3-氨基-1,2,4-苯并三嗪 1,4-二氧化物（替拉扎明，TPZ）是一种生物还原激活的 DNA 损伤剂，可选择性杀死几乎所有实体瘤中发现的缺氧细胞。该化合物显示出巨大的临床前景，目前正在十多项不同的临床试验中进行检验，其中包括几项 III 期研究。重要的是，TPZ 通过一系列全新的化学反应来损伤 DNA，其中单电子还原药物引发自由基介导的 DNA 损伤，然后药物或其代谢物将氧原子从其 N-氧化物官能团转移到产生的 DNA 自由基，从而将它们转化为链裂解位点。虽然 TPZ 的药用特性已得到广泛研究，但其许多生物学相关的化学特性仍然知之甚少。对 TPZ 日益增长的临床兴趣为表征该药物的相关化学提供了实际动力。此外，这种新的化学基序能够有效地将细胞毒性 DNA 损伤自由基传递到缺氧细胞内部，其特征可能在药物化学和毒理学中具有重要意义。本提案中描述的工作分为三个具体目标： 1. TPZ 如何对 DNA 产生根本性损伤？该药物是否可以将已知的 DNA 损伤剂羟自由基传递至缺氧细胞？肿瘤细胞中的低氧和低 pH 条件如何结合起来促进药物对 DNA 的损伤？ 2. TPZ及其代谢物将氧原子从其N-氧化物官能团转移到DNA自由基的化学机制是什么？这种前所未有的反应使得该药物能够在缺氧条件下有效地损伤 DNA，并且可能在确定 TPZ 引起的最终 DNA 损伤的结构性质方面发挥核心作用。 3. 我们提出研究来表征 TPZ 介导的 DNA 链断裂和碱基损伤的结构性质。这些研究将探讨 TPZ 运作的不寻常条件以及该药物独特的化学性质是否会导致一系列独特的 DNA 损伤，使细胞面临对其 DNA 修复系统的社会挑战。