A MECHANISM-BASED, SOLUTION-PHASE METHOD FOR SCREENING COMBINATORIAL MIXTURES OF POTENTIAL PLATINUM ANTICANCER DRUGS

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 antit umor drug candidates, is an (N,O)-chelated complex which binds DNA for ming two isomeric 1,2-d(GpG) intrastrand DNA cross-links. Kplatin-modi fied DNA is spe cifically recognized by HMG1, HMG1 domain B, and testi s-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.