一种对硫亲核试剂分解具有抗性的新型抗肿瘤双核PtII配合物修饰的DNA的构象与识别
Conformation and recognition of DNA modified by a new antitumor dinuclear PtII complex resistant to decomposition by sulfur nucleophiles.
作者信息
Zerzankova Lenka, Suchankova Tereza, Vrana Oldrich, Farrell Nicholas P, Brabec Viktor, Kasparkova Jana
机构信息
Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Kralovopolska 135, CZ-61265 Brno, Czech Republic.
出版信息
Biochem Pharmacol. 2010 Jan 15;79(2):112-21. doi: 10.1016/j.bcp.2009.08.009. Epub 2009 Aug 12.
Abstract
Reported herein is a detailed biochemical and molecular biophysics study of the molecular mechanism of action of antitumor dinuclear Pt(II) complex {PtCl(DACH)}(2)-mu-Y [DACH=1,2-diaminocyclohexane, Y=H(2)N(CH(2))(6)NH(2)(CH(2))(2)NH(2)(CH(2))(6)NH(2)] (complex 1). This new, long-chain bifunctional dinuclear Pt(II) complex is resistant to metabolic decomposition by sulfur-containing nucleophiles. The results show that DNA adducts of 1 can largely escape repair and yet inhibit very effectively transcription so that they should persist longer than those of conventional cisplatin. Hence, they could trigger a number of downstream cellular effects different from those triggered in cancer cells by DNA adducts of cisplatin. This might lead to the therapeutic effects that could radically improve chemotherapy by platinum complexes. In addition, the findings of the present work make new insights into mechanisms associated with antitumor effects of dinuclear/trinuclear Pt(II) complexes possible.
摘要
本文报道了一项关于抗肿瘤双核铂（II）配合物{PtCl(DACH)}(2)-μ-Y [DACH = 1,2 - 二氨基环己烷，Y = H(2)N(CH(2))(6)NH(2)(CH(2))(2)NH(2)(CH(2))(6)NH(2)]（配合物1）作用分子机制的详细生化和分子生物物理学研究。这种新型的长链双功能双核铂（II）配合物对含硫亲核试剂的代谢分解具有抗性。结果表明，配合物1的DNA加合物能够很大程度上逃避修复，但却能非常有效地抑制转录，因此它们应该比传统顺铂的DNA加合物持续时间更长。因此，它们可能引发一些不同于顺铂DNA加合物在癌细胞中引发的下游细胞效应。这可能会带来治疗效果，从而从根本上改善铂配合物的化疗效果。此外，本研究结果为深入了解双核/三核铂（II）配合物的抗肿瘤作用机制提供了新的见解。
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