TY - JOUR T1 - The Formation of DNA Interstrand Cross-Links by a Novel Bis-[Pt<sub>2</sub>Cl<sub>4</sub>(diminazene aceturate)<sub>2</sub>]Cl<sub>4</sub>·4H<sub>2</sub>O Complex Inhibits the B to Z Transition JF - Molecular Pharmacology JO - Mol Pharmacol SP - 770 LP - 777 VL - 55 IS - 4 AU - Víctor M. González AU - Miguel A. Fuertes AU - Antonio Jiménez-Ruíz AU - Carlos Alonso AU - José M. Pérez Y1 - 1999/04/01 UR - http://molpharm.aspetjournals.org/content/55/4/770.abstract N2 - We present data demonstrating that the cytotoxic compound [Pt2Cl4(diminazene aceturate)2]Cl4·4H2O (Pt-berenil) circumvents cisplatin resistance in ovarian carcinoma cells. The analysis of the interaction of Pt-berenil with linear and supercoiled DNA indicates that this compound induces the formation of a large number of covalent interstrand cross-links on DNA and that this number is significantly higher than that produced bycis-diamminedichloroplatinum(II) (cis-DDP). Renaturation experiments, interstrand cross-link assays, and electron microscopy indicate that the kinetics of DNA interstrand 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 influenced by supercoiling. Circular dichroism experiments show that Pt-berenil strongly inhibits the B-DNA-to-Z-DNA transition of poly(dG-m5dC)·poly(dG-m5dC) at salt concentrations (3 mM MgCl2) at which the native methylated polynucleotide readily adopts the Z-DNA conformation, which suggests that the induction of interstrand cross-links by Pt-berenil inhibits the Z-DNA 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 conformational changes and may also display activity in cisplatin-resistant cells. The American Society for Pharmacology and Experimental Therapeutics ER -