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Vol. 55, Issue 4, 770-777, April 1999

The Formation of DNA Interstrand Cross-Links by a Novel Bis-[Pt2Cl4(diminazene aceturate)2]Cl4·4H2O Complex Inhibits the B to Z Transition

Víctor M. González, Miguel A. Fuertes, Antonio Jiménez-Ruíz, Carlos Alonso, and José M. Pérez

Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Facultad de Ciencias, Universidad Autónoma de Madrid (V.M.G., M.A.F., C.A.); Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Alcalá, Alcalá de Henares (A.J.-R.); and Departamento de Química Inorgánica, Facultad de Ciencias, Universidad Autónoma de Madrid (J.M.P.), Madrid, Spain

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 by cis-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-m5 dC)·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.

Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics




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Copyright © 1999 by the American Society for Pharmacology and Experimental Therapeutics