Chourpa I, Morjani H, Riou J F, Manfait M
Laboratoire de Spectroscopie Biomoléculaire, UFR de Pharmacie, Université de Reims, France.
FEBS Lett. 1996 Nov 11;397(1):61-4. doi: 10.1016/s0014-5793(96)01141-6.
Cytotoxicity of several classes of antitumor DNA intercalators is thought to result from disturbance of DNA metabolism following trapping of the nuclear enzyme DNA topoisomerase II as a covalent complex on DNA. Here, molecular interactions of the potent antitumor drug amsacrine (m-AMSA), an inhibitor of topoisomerase II, within living K562 cancer cells have been studied using surface-enhanced Raman (SER) spectroscopy. The work is based on data of the previously performed model SER experiments dealing with amsacrine/DNA, drug/topoisomerase II and drug/DNA/topoisomerase II complexes in aqueous buffer solutions. The SER data indicated two kinds of amsacrine interactions in the model complexes with topoisomerase II alone or within ternary complex: non-specific (via the acridine moiety) and specific to the enzyme conformation (via the side chain of the drug). These two types of interactions have been both revealed by the micro-SER spectra of amsacrine within living K562 cancer cells. Our data suppose the specific interactions of amsacrine with topoisomerase II via the side chain of the drug (particular feature of the drug/topoisomerase II and ternary complexes) to be crucial for its inhibitory activity.
几类抗肿瘤DNA嵌入剂的细胞毒性被认为是由于核酶DNA拓扑异构酶II作为共价复合物被困在DNA上后干扰了DNA代谢所致。在此，使用表面增强拉曼（SER）光谱研究了强效抗肿瘤药物安吖啶（m-AMSA，一种拓扑异构酶II抑制剂）在活的K562癌细胞内的分子相互作用。这项工作基于先前在水性缓冲溶液中进行的涉及安吖啶/DNA、药物/拓扑异构酶II和药物/DNA/拓扑异构酶II复合物的模型SER实验数据。SER数据表明，在仅与拓扑异构酶II形成的模型复合物中或在三元复合物中，安吖啶存在两种相互作用：非特异性相互作用（通过吖啶部分）和对酶构象特异性的相互作用（通过药物的侧链）。活的K562癌细胞内安吖啶的显微SER光谱揭示了这两种相互作用类型。我们的数据表明，安吖啶通过药物侧链与拓扑异构酶II的特异性相互作用（药物/拓扑异构酶II和三元复合物的独特特征）对其抑制活性至关重要。
