High performance liquid chromatographic separation of DNA adducts induced by cancer chemotherapeutic agents.
High performance liquid chromatographic separation of DNA adducts induced by cancer chemotherapeutic agents.
复制标题
癌症化疗药物诱导的 DNA 加合物的高效液相色谱分离。
DOI：
10.1016/0163-7258(87)90008-8
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发表时间：
1987
影响因子：
13.5
通讯作者：
Ludlum,DB
中科院分区：
文献类型：
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作者：
Ludlum,DB
许多重要的抗肿瘤药物，包括环磷酰胺、苯丁酸氮芥和其他氮芥、顺铂和卤代乙基亚硝基脲，似乎都是通过修饰DNA产生治疗作用的（Hemminki和Ludlum，1984）。这些药物在临床医学中具有重要的实际意义，但它们也具有理论意义，因为它们对肿瘤细胞比对大多数正常细胞更具毒性。显然，如果这一观察结果得到更好的理解，它可能会导致癌症化疗的进一步改善。由这些试剂引起的DNA修饰的知识是这种理解的基础。该领域的早期工作者将鸟嘌呤的N-7位鉴定为共价修饰的主要位点（Brookes和Lawley，1961），而其他人获得了磷酸烷基化的物理证据（Lett等人，1962; Ludlum，1967）。然而，这些反应的复杂性直到最近才随着更新技术的可用性而被认识到。特别地，高效液相色谱（HPLC）提供了将修饰的碱基和脱氧核苷彼此分离以及与DNA的正常成分分离所必需的分辨能力。由于DNA修饰是化学致癌的起始事件，因此该领域的专家也将注意力集中在DNA修饰和修复上。然而，本章的主要重点是使用HPLC来鉴定和定量抗肿瘤药物引起的DNA修饰。由于我们对卤代乙基亚硝基脲的兴趣，这种方法将主要通过研究这组化合物来说明，但所涉及的原理同样适用于通过修饰DNA产生作用的其他化疗药物。
Many important antitumor agents including cyclophosphamide, chlorambucil and the other nitrogen mustards, cis-platin, and the haloethylnitrosoureas all appear to produce their therapeutic effects by modifying DNA (Hemminki and Ludlum, 1984). These agents are of great practical importance in clinical medicine, but they are also of theoretical interest because they are more toxic to neoplastic cells than to most normal cells. Clearly, if this observation were better understood, it could lead to further improvements in cancer chemotherapy. A knowledge of the DNA modifications caused by such agents is basic to this understanding. Early workers in the field identified the N-7 position of guanine as a primary site of covalent modification (Brookes and Lawley, 1961) while others obtained physical evidence for phosphate alkylation (Lett et al., 1962; Ludlum, 1967). However, the complexity of these reactions has been appreciated only recently with the availability of newer technology. In particular, high performance liquid chromatography (HPLC) has provided the resolving power which is necessary to separate modified bases and deoxynucleosides from each other and from the normal constituents of DNA. At the same time, advances in ultraviolet and mass spectrometry have facilitated identification of these derivatives.Because DNA modification is an initiating event in chemical carcinogenesis, specialists in this area have also focused their attention on DNA modification and repair. The major emphasis in this chapter, however, will be on the use of HPLC to identify and quantitate DNA modifications caused by antitumor agents. Because of our interest in the haloethylnitrosoureas, this methodology will be illustrated primarily by investigations of this group of compounds, but the principles involved are equally applicable to other chemotherapeutic agents which produce their effects by modifying DNA.