title: The stability of DNA intrastrand cross-links of antitumor transplatin derivative containing non-bulky methylamine ligands.
abstract: Oligonucleotides modified by clinically ineffective trans-diamminedichloridoplatinum(II) (transplatin) have been shown to be effective modulators of gene expression. This is so because in some nucleotide sequences the 1,3-GNG intrastrand adducts formed by transplatin in double-helical DNA readily rearrange into interstrand cross-links so that they can cross-link the oligonucleotides to their targets. On the other hand, in a number of other sequences these intrastrand adducts are relatively stable, which represents the major difficulty in the clinical use of the antisense transplatin-modified oligonucleotides. Therefore, we examined in this study, the stability of 1,3-GNG intrastrand adducts in double-helical DNA formed by a new antitumor derivative of transplatin, trans-[Pt(CH3NH2)2Cl2], in the sequence contexts in which transplatin formed relatively stable intrastrand cross-links which did not readily rearranged into interstrand cross-links. We have found that 1,3-GNG intrastrand adducts in double-helical DNA formed by trans-[Pt(CH3NH2)2Cl2] even in such sequences readily rearrange into interstrand cross-links. This work also suggests that an enhanced frequency of intrastrand cross-links yielded by trans-[Pt(CH3NH2)2Cl2] is a consequence of the fact that these DNA lesions considerably distort double-helical DNA in far more sequence contexts than parent transplatin. Our results suggest that trans-[Pt(CH3NH2)2Cl2]-modified oligonucleotides represent promising candidates for new agents in antisense or antigene approach.
authors.affiliation: Department of Biophysics, Faculty of Science, Palacky University, 17. listopadu 12, 77146, Olomouc, Czech Republic.
authors.forename: Michaela
authors.initials: M
authors.lastname: Frybortova
authors.forename: Olga
authors.initials: O
authors.lastname: Novakova
authors.forename: Viktor
authors.initials: V
authors.lastname: Brabec
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001483:Base Sequence; D002945:Cisplatin / Q000737:chemistry / Q000494:pharmacology*; D003432:Cross-Linking Reagents / Q000737:chemistry / Q000494:pharmacology*; D004247:DNA / Q000737:chemistry*; D018736:DNA Adducts / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D008744:Methylamines / Q000737:chemistry / Q000494:pharmacology*; D009841:Oligonucleotides / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D018736:DNA Adducts; D008024:Ligands; D008744:Methylamines; D009841:Oligonucleotides; C034697:transplatin; D004247:DNA; C027451:methylamine; D002945:Cisplatin