title: 1,2-GG intrastrand cross-link of antitumor dinuclear bifunctional platinum compound with spermidine linker inhibits DNA polymerization more effectively than the cross-link of conventional cisplatin.
abstract: In order to learn more about the molecular basis for the inhibition of DNA replication produced by antitumor platinum drugs, we investigated DNA polymerization using DNA templates site-specifically modified with the 1,2-GG intrastrand cross-link of dinuclear bifunctional [{trans-PtCl(NH(3))(2)}(2){l-spermidine-N1,N8}](3+)(BBR3571) or conventional mononuclear cisplatin. These cross-links which have the same nature, but differ in the size and character of the conformational alteration induced in double-helical DNA, were analyzed for bypass ability with reverse transcriptase of human immunodeficiency virus type 1 and Klenow fragment of DNA polymerase I deficient in exonuclease activity. We found that the 1,2-GG intrastrand CL of BBR3571 inhibited DNA translesion synthesis markedly more than the same adduct of cisplatin. This result was explained by a larger size of the cross-link of BBR3571 and by a flexibility induced in DNA by this cross-link which can make the productive binding of this adduct at the polymerase site more difficult.
authors.affiliation: Institute of Biophysics, Academy of Sciences of the Czech Republic, Brno, Czech Republic.
authors.forename: Branden
authors.initials: B
authors.lastname: Moriarity
authors.forename: Olga
authors.initials: O
authors.lastname: Nováková
authors.forename: Nicholas
authors.initials: N
authors.lastname: Farrell
authors.forename: Viktor
authors.initials: V
authors.lastname: Brabec
authors.forename: Jana
authors.initials: J
authors.lastname: Kaspárková
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D002945:Cisplatin / Q000737:chemistry*; D003432:Cross-Linking Reagents; D004247:DNA / Q000737:chemistry*; D004249:DNA Damage; D009690:Nucleic Acid Conformation; D009841:Oligonucleotides / Q000737:chemistry*; D009944:Organoplatinum Compounds / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; C403611:BBR 3571; D003432:Cross-Linking Reagents; D009841:Oligonucleotides; D009944:Organoplatinum Compounds; D004247:DNA; D002945:Cisplatin