In Vivo DNA-Protein Cross-Linking by cis- and trans-Diamminedichloroplatinum(II)

Abstract When Novikoff hepatoma-bearing rats were given injections of a therapeutic dose of cis -diamminedichloroplatinum(II) ( cis -DDP) (7 mg/kg), DNA-protein cross-links could be detected by using antisera to dehistonized chromatin, nuclear matrix, or Novikoff hepatoma cytoskeletal preparation. The extent of cross-linking increased in time up to 24 h after the injection, after which time the DNA-protein cross-links were gradually repaired, with no cross-links detectable at 72 h. trans -DDP in equitoxic (40 mg/kg) dose was very efficient in forming DNA-protein cross-links. Although formed more rapidly, these trans -DDP-mediated cross-links were repaired faster, within 48 h after the injection. The repair of cross-links at equimolar trans -DDP dose (7 mg/kg) was even more rapid. The principal proteins cross-linked to the DNA by both cis - or trans -DDP were Novikoff hepatoma cytokeratins ( M r , 39,000, 49,000, 56,000, and an additional protein band reacting with the antiserum to Novikoff hepatoma cytoskeletal preparation at M r , -68,000).