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

顺铂是目前应用最广泛的抗癌药物之一。目前铂生物无机化学的一个挑战是设计有效的抗癌药物来克服顺铂耐药，基于对铂结合引起的DNA损伤所致的细胞凋亡的详细了解。本研究的目的是阐明一些新的双核铂配合物与顺铂的相互作用方式的不同。获得了以下结果：(1)合成了新型羟基和吡唑桥双核铂配合物，并诱导了野生型L 1210及其顺铂耐药细胞系的凋亡。(2)在氯化钠存在下，对双核配合物中质子辅助的正方形平面铂(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。并且双核配合物的细胞内铂水平高于顺铂。(4)由于双核配合物不仅与DNA发生配位结合，而且还存在非共价相互作用，因此双核配合物与顺铂的DNA结合方式不同。双核复合体对顺铂耐药肿瘤细胞的作用可能归因于这种与DNA的不同结合方式。本研究有望为开发克服顺铂耐药的新一代抗癌药物奠定基础。

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.