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  • 1
    Electronic Resource
    Electronic Resource
    A mechanism-based, solution-phase method for screening combinatorial mixtures of potential platinum anticancer drugs (1998)
    Springer
    JBIC 3 (1998), S. 74-80 
    Details
    ISSN: 1432-1327
    Keywords: Key words Molecular diversity ; HMG-domain proteins ; Platinum-amino acid complexes ; Platinum anticancer drugs
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract  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)Cl2] 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 specifically 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 μM and 74 μM, respectively.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s007750050209
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    Paper (German National Licenses)
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  • 2
    Electronic Resource
    Electronic Resource
    Toxicity of platinum(II) amino acid (N,O) complexes parallels their binding to DNA as measured in a new solid phase assay involving a fluorescent HMG1 protein construct readout (1999)
    Springer
    JBIC 4 (1999), S. 402-411 
    Details
    ISSN: 1432-1327
    Keywords: Key words Antitumor drug ; Green fluorescent protein ; Screening method ; Fusion protein
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract  The compound [Pt(lysine)Cl2] (Kplatin) was previously identified in a study of platinum amino acid complexes as a potential antitumor drug candidate. The DNA binding properties, high mobility group (HMG)-domain protein affinity for the platinated DNA, and cytotoxicity against HeLa cells of Kplatin and three related (N,O) chelated platinum(II) amino acid complexes, [Pt(arginine)Cl2] (Rplatin), K[Pt(Ne-acetyllysine)Cl2] (NacKplatin), and K[Pt(norleucine)Cl2] (Norplatin), are reported. The four complexes have identical PtCl2(N,O) coordination environments. A new solid phase screening methodology was devised in which platinated DNA probes are covalently attached to a nylon support and tested for their ability to bind a fluorescently labeled HMG-domain protein. The fluorescent HMG-domain protein was generated by expressing a fusion of the green fluorescent protein (GFP) with recombinant rat HMG1. Binding revealed by the solid phase method correlated well with the results of gel mobility shift and HeLa cytotoxicity assays. These results suggest that the net charge on the complex, rather than the nature of the side chain, is the most important factor underlying the DNA binding properties and toxicity of amino acid (N,O) chelated platinum complexes. This property explains why Kplatin was previously selected from the pool of platinum amino acid complexes based on the ability of its DNA adducts to bind HMG1.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s007750050326
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    Paper (German National Licenses)
    Fulltext
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