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

  • Karen E. Sandman
  • Peter Fuhrmann
  • S. J. Lippard
ORIGINAL ARTICLE

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.

Key words Molecular diversity HMG-domain proteins Platinum-amino acid complexes Platinum anticancer drugs 

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Copyright information

© Society of Biological Inorganic Chemistry 1998

Authors and Affiliations

  • Karen E. Sandman
    • 1
  • Peter Fuhrmann
    • 1
  • S. J. Lippard
    • 1
  1. 1.Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA Fax: +1-617-258-8150; e-mail: lippard@lippard.mit.eduUS

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