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Interaction of new dinuclear platinum complexes effective to cisplatin-resistant tumor cell lines with DNA.

对顺铂耐药肿瘤细胞系有效的新型双核铂配合物与 DNA 的相互作用。

基本信息

批准号：
13672265
负责人：
CHIKUMA Masahiko
金额：
$ 2.3万
依托单位：
Osaka University of Pharmaceutical Sciences
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

项目摘要

Cisplatin is one of the most widely used anticancer agents. A current challenge in platinum bioinorganic chemistry is to design effective anticancer agents overcoming cisplatin resistance, based on the detailed knowledge of apoptosis attributable to DNA lesion by platinum binding. The purpose of this research project is to elucidate the differences of the interaction mode of some new dinuclear platinum complexes and that of cisplatin.The following results have been obtained.(1)New dinuclear platinum complexes with hydroxo-and pyrazolato-bridges were prepared and they induced apoptosis in the wild-type L 1210 and its cisplatin resistant cell lines.(2)Proton-assist square-planar platinum(II) substitution reaction in the dinuclear complexes was analyzed kinetically in the presence of sodium chloride.(3)Uptake of platinum atom by tumor cells was investigated by atomic absorption spectrometry, and intracellular platinum level was higher in the dinuclear complexes than in cisplatin.(4)Since the dinuclear complexes showed not only coordination binding with DNA but also non-covalent interactions, the DNA binding mode of dinuclear complexes is different from that of cisplatin. Effectiveness of the dinuclear complexes to the cisplatin resistant tumor cells seems to be attributed to this different binding mode with DNA.This research promises to lead to the development of new generation of anticancer agents overcoming cisplatin resistance.

顺铂是最广泛使用的抗癌药物之一。目前铂生物无机化学的挑战是设计有效的抗癌剂克服顺铂耐药性，基于铂结合的DNA损伤归因于细胞凋亡的详细知识。本课题的目的是阐明一些新的双核铂配合物与顺铂作用模式的差异，得到了以下结果。（1）合成了新型的含羟基和吡唑桥的双核铂配合物，并诱导野生型L1210及其顺铂耐药细胞株凋亡。（2）在氯化钠存在下，对双核配合物中的质子辅助正方平面铂（II）取代反应进行了动力学分析。（3）用原子吸收光谱法研究了肿瘤细胞对铂原子的摄取，发现双核配合物中的细胞内铂含量高于顺铂。（4）由于双核配合物与DNA之间既有配位作用，又有非共价作用，因此双核配合物与DNA的结合方式与顺铂不同。双核配合物对顺铂耐药肿瘤细胞的有效性似乎归因于这种与DNA的不同结合模式。这项研究有望导致新一代克服顺铂耐药的抗癌药物的开发。