抗癌药与DNA相互作用的电喷雾质谱研究

Interaction between anticancer drugs and DNA studied by using electrospray ionization mass spectrometry

为了进一步阐明抗癌药与DNA结合的序列选择性和结合本质,用电喷雾质谱方法研究了抗癌药与DNA的相互作用,这些药物包括小沟结合剂(偏端霉素A,DM和纺锤霉素,NP)和嵌入剂(米托蒽醌,MT)。DM与AT富有的DNA主要形成2∶1的特异性复合物,NP只形成1∶1的特异性复合物;MT倾向与GC富有的DNA特异性结合。另外,DM与带5个A/T碱基小沟长度的DNA几乎以2∶1结合,而与带3个A/T碱基的DNA未见结合,而NP与带4个A/T碱基的DNA结合能力最强。MT还与6-mer DNA形成了1∶1特异性复合物。竞争结合实验证明,DM和NP与AT富有的DNA的键合顺序为NP>DM。这些结果为深入研究抗癌药物的作用机制和改进目标药物结构提供了依据。

To elucidate further sequence selectivity and nature of the binding of anticancer drugs to DNA, the interaction between anticancer drugs, which are minor groove ligands （distamycin A, DM and netropsin, NP） and intercalator （mitoxantrone, MT）, and DNA were studied by electrospray ionization mass spectrometry. The 2：1 specific complex of DM and AT-rich DNA were observed principally, while only 1：1 specific complex of NP and AT-rich DNA were observed. MT specifically binds to GC-rich DNA. In addition, DM binds to DNA containing 5 A/T bases minor groove almost in a 2：1 mode and does not bind to DNA containing 3 A/T bases minor groove. NP binds most strongly to DNA containing 4 A/T bases minor groove. The 1：1 specific complex of MT and 6-met DNA was also observed. The result of competitive binding experiment shows that DM binds more strongly to AT-rich DNA than NP does. These results provide bases for investigating the mechanism of interaction between the drugs and DNA and for improving the structure of target drug.