A mechanism-based, solution-phase method for screening combinatorial mixtures of potential platinum anticancer drugs

被引：26

作者：

Sandman, KE ^{[1
]}

Fuhrmann, P ^{[1
]}

Lippard, SJ ^{[1
]}

机构：

[1] MIT, Dept Chem, Cambridge, MA 02139 USA

来源：

JOURNAL OF BIOLOGICAL INORGANIC CHEMISTRY | 1998年 / 3卷 / 01期

基金：

美国国家卫生研究院;

关键词：

molecular diversity; HMG-domain proteins; platinum amino acid complexes; platinum anticancer drugs;

D O I：

10.1007/s007750050209

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

We report a new, mechanism-based approach to the screening of pools of potential platinum antitumor drugs. A platinum complex of L-lysine, [Pt(Lys)Cl-2] or Kplatin, was selected from mixtures of platinum-amino acid compounds based on the ability of its DNA adducts to bind HMG1 in a gel mobility shift assay. Kplatin, unlike most other platinum antitumor drug candidates, is an (N,O)-chelated complex which binds DNA forming two isomeric 1,2-d(GpG) intrastrand DNA cross-links. Kplatin-modified DNA is spe cifically recognized by HMG1, HMG1 domain B, and testis-specific HMG, all of which bind to the major cisplatin-DNA adducts. Kplatin is toxic towards the human tumor cell lines HeLa and KM12 with LC50 values of 59.2+/-7.8 mu M and 74 mu M, respectively.

引用

页码：74 / 80

页数：7

共 51 条

[1] Relationship between cell-killing efficiency and number of platinum atoms binding to DNA, RNA, and protein molecules in HeLa cells treated with cis-diamine(glycolato)platinum(II) [J].