The formation of DNA interstrand cross-links by a novel bis-[Pt2Cl4(diminazene aceturate)2]Cl4.4H2O complex inhibits the B to Z transition.

Abstract

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.

• Authors: V M González, M A Fuertes, A Jiménez-Ruíz, C Alonso, J M Pérez
• Journal: Molecular pharmacology (Mol Pharmacol) Vol. 55 Issue 4 Pg. 770-7 (Apr 1999) ISSN: 0026-895X [Print] United States
• PMID: 10101036 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Cross-Linking Reagents
• Organoplatinum Compounds
• platinum-berenil
• Magnesium Chloride
• Poly G
• poly G-poly C
• Poly C
• DNA
• Cisplatin
• Diminazene

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Cattle
• Cisplatin (pharmacology)
• Cross-Linking Reagents (pharmacology)
• DNA (chemistry, drug effects)
• Diminazene (analogs & derivatives, pharmacology)
• Drug Resistance, Neoplasm
• Drug Screening Assays, Antitumor
• Humans
• Magnesium Chloride (pharmacology)
• Nucleic Acid Conformation (drug effects)
• Organoplatinum Compounds (pharmacology)
• Poly C (chemistry)
• Poly G (chemistry)
• Tumor Cells, Cultured