Walking of antitumor bifunctional trinuclear PtII complex on double-helical DNA.
The trinuclear BBR3464 ([{trans-PtCl(NH(3))(2)}(2)µ-(trans-Pt(NH(3))(2)(H(2)N(CH(2))(6)NH(2))(2))](4+)) belongs to the polynuclear class of platinum-based anticancer agents. DNA adducts of this complex differ significantly in structure and type from those of clinically used mononuclear platinum complexes, especially, long-range (Pt, Pt) intrastrand and interstrand cross-links are formed in both 5'-5' and 3'-3' orientations. We show employing short oligonucleotide duplexes containing single, site-specific cross-links of BBR3464 and gel electrophoresis that in contrast to major DNA adducts of clinically used platinum complexes, under physiological conditions the coordination bonds between platinum and N7 of G residues involved in the cross-links of BBR3464 can be cleaved. This cleavage may lead to the linkage isomerization reactions between this metallodrug and double-helical DNA. Differential scanning calorimetry of duplexes containing single, site-specific cross-links of BBR3464 reveals that one of the driving forces that leads to the lability of DNA cross-links of this metallodrug is a difference between the thermodynamic destabilization induced by the cross-link and by the adduct into which it could isomerize. The rearrangements may proceed in the way that cross-links originally formed in one strand of DNA can spontaneously translocate from one DNA strand to its complementary counterpart, which may evoke walking of the platinum complex on DNA molecule.
Malina
Jaroslav
J
Institute of Biophysics, Academy of Sciences of the Czech Republic, Brno, Czech Republic.
Kasparkova
Jana
J
Farrell
Nicholas P
NP
Brabec
Viktor
V
D000970:Antineoplastic Agents / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning; D003432:Cross-Linking Reagents / Q000737:chemistry*; D004247:DNA / Q000737:chemistry; D018736:DNA Adducts / Q000737:chemistry*; D009944:Organoplatinum Compounds / Q000737:chemistry*; D013816:Thermodynamics
D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D018736:DNA Adducts; D009944:Organoplatinum Compounds; D004247:DNA; C114062:BBR 3464