The formation of DNA interstrand cross-links by a novel bis-[Pt2Cl4(diminazene aceturate)2]Cl4.4H2O complex inhibits the B to Z transition.
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.
González
V M
VM
Facultad de Ciencias, Universidad Autónoma de Madrid, Madrid, Spain.
Fuertes
M A
MA
Jiménez-Ruíz
A
A
Alonso
C
C
Pérez
J M
JM
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002417:Cattle; D002945:Cisplatin / Q000494:pharmacology; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004247:DNA / Q000737:chemistry / Q000187:drug effects*; D004133:Diminazene / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015636:Magnesium Chloride / Q000494:pharmacology; D009690:Nucleic Acid Conformation / Q000187:drug effects*; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D011066:Poly C / Q000737:chemistry; D011068:Poly G / Q000737:chemistry; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D009944:Organoplatinum Compounds; C110112:platinum-berenil; D015636:Magnesium Chloride; D011068:Poly G; C008961:poly G-poly C; D011066:Poly C; D004247:DNA; D002945:Cisplatin; D004133:Diminazene