Reaction of Zn7Metallothionein with cis- and trans-[Pt(N-donor)2Cl2] anticancer complexes:: trans-PtII complexes retain their N-donor ligands
Reaction of Zn7Metallothionein with cis- and trans-[Pt(N-donor)2Cl2] anticancer complexes:: trans-PtII complexes retain their N-donor ligands
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DOI：
10.1021/jm070271l
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发表时间：
2007-08-23
影响因子：
7.3
通讯作者：
Vasak, Milan
中科院分区：
文献类型：
--
作者：
Knipp, Markus;Karotki, Andrei V.;Vasak, Milan
以铂为基础的癌症治疗的主要缺点是内在和获得性耐药。富含半胱氨酸和锌的蛋白质超家族金属硫蛋白(MT)可以有效地灭活这些抗肿瘤药物，因为铂化合物与S供体分子具有很强的反应活性。本文研究了十二种顺式/反式[铂(N-给体)(2)氯-2]化合物和[铂(二烯)氯]氯与新一代药物的反应，并对产物进行了表征。反应动力学比较表明，反式-铂-II化合物与Zn7MT-2的反应速度快于顺式-铂-II化合物。产物的表征表明，虽然顺式-铂-II化合物中的所有配体都被半胱氨酸硫酸酯取代，但反式-铂-II化合物保留了它们的N-给体配体，从而保持了潜在的活性形式。这些结果加深了人们对MT在铂类抗癌药物获得性耐药中的作用的理解。
Intrinsic and acquired resistance are major drawbacks of platinum-based cancer therapy. The protein superfamily of cysteine- and Zn-II-rich proteins, metallothioneins (MT), efficiently inactivate these antitumor drugs because of the strong reactivity of platinum compounds with S-donor molecules. In this study the reactions of human Zn7MT-2 with twelve cis/trans-[Pt(N-donor)(2)Cl-2] compounds and [Pt(dien)Cl]Cl, including new generation drugs, were investigated and the products characterized. A comparison of reaction kinetics revealed that trans-Pt-II compounds react faster with Zn7MT-2 than cis-Pt-II compounds. The characterization of the products showed that while all ligands in cis-Pt-II compounds were replaced by cysteine thiolates, trans-Pt-II compounds retained their N-donor ligands, thus remaining in a potentially active form. These results provide an increased understanding of the role of MT in the acquired resistance to platinum-based anticancer drugs.