DNA interactions of antitumor platinum(IV) complexes.

Abstract

Modifications of natural DNA and synthetic double-stranded oligodeoxyribonucleotides by cis-diamminedichloro-trans-dihydroxyplatinum(IV) (oxoplatin) were studied by means of ELISA, Maxam-Gilbert footprinting techniques, HPLC of enzymically digested DNA, and transcription assay. It was found that oxoplatin can bind DNA directly without addition of a reducing agent. In addition, the antibodies elicited against DNA modified by cisplatin were not competitively inhibited by DNA modified by oxoplatin. However, DNA containing the adducts of oxoplatin became a strong inhibitor of these antibodies, if it was subsequently treated with ascorbic acid, which is a reducing agent. These results were interpreted to mean that oxoplatin can form DNA adducts containing the platinum moiety in the quadrivalent state. The direct irreversible binding of the platinum(IV) drug is, however, slow as compared to the reaction of its platinum(II) counterpart. It was also found that oxoplatin preferentially binds to guanine residues and can form DNA intrastrand and interstrand cross-links containing platinum(IV). The DNA adducts containing platinum(IV) can inhibit in vitro transcription by a prokaryotic DNA-dependent RNA polymerase. We find that the platinum(IV) complex binds to DNA at similar sites as its platinum(II) counterpart. On the other hand, the DNA adducts containing the platinum(II) or platinum(IV) analogues differ in the number of ligands and the formal charge on their platinum center. We suggest that these differences could be responsible for distinct conformational features and stability of DNA modified by platinum(II) or platinum(IV) complexes.