The formation of DNA interstrand cross-links by a novel Bis-[Pt2Cl4(diminazene aceturate)(2)]Cl-4 center dot 4H(2)O complex inhibits the B to Z transition

We present data demonstrating that the cytotoxic compound [Pt2Cl4(diminazen e aceturate)(2)]Cl-4. 4H(2)O (Pt-berenil) circumvents cisplatin resistance in ovarian carcinoma cells. The analysis of the interaction of Pt-berenil w ith linear and supercoiled DNA indicates that this compound induces the for mation of a large number of covalent interstrand cross-links on DNA and tha t this number is significantly higher than that produced by cis-diamminedic hlouoplatinum(II) (cis-DDP). Renaturation experiments, interstrand cross-li nk assays, and electron microscopy indicate that the kinetics of DNA inters trand cross-link formation caused by Pt-berenil binding is faster than that caused by cis-DDP at similar levels of platinum bound to DNA. Furthermore, the number of DNA interstrand cross-links in Pt-berenil-DNA complexes is i nfluenced by supercoiling. Circular dichroism experiments show that Pt-bere nil strongly inhibits the B-DNA-to-Z-DNA transition of poly(dG-m(5) dC).pol y(dG-m(5)dC) at salt concentrations (3 mM MgCl2) at which the native methyl ated polynucleotide readily adopts the Z-DNA conformation, which suggests t hat the induction of interstrand crosslinks by Pt-berenil inhibits the Z-DN A transition. On the basis of these results, we propose that bis(platinum) compounds with structure similar to Pt-berenil may act as blockers of DNA c onformational changes and may also display activity in cisplatin-resistant cells.