DNA interstrand cross-links of trans-diamminedichloroplatinum(II) are preferentially formed between guanine and complementary cytosine residues.
Bases in the opposite strands of DNA cross-linked by clinically ineffective trans-diamminedichloroplatinum(II) (trans-[Pt(NH3)2Cl2]) have been identified by means of three experimental approaches. These include HPLC analysis of enzymatic digests of synthetic oligonucleotide duplexes containing the interstrand cross-link, footprinting experiments on the interstrand cross-linked oligonucleotide duplexes, and termination of the duplex transcription on trans-[Pt(NH3)2Cl2]-treated fragments of plasmid DNA. The results reveal that deoxyguanine and complementary deoxycytosine residues are preferential binding sites of trans-[Pt(NH3)2Cl2] in the interstrand adducts. The interstrand cross-linking reaction was studied by means of gel electrophoresis for the cis and trans isomers. The rate of formation of interstrand cross-links was lower for the trans isomer; however, trans-[Pt(NH3)2Cl2] formed about twice the amount of interstrand cross-links as compared with the cis isomer after 48 hr. The present results are suggested to be relevant to differences in clinical activity of the two platinum(II) isomers.
Centre de Biophysique Moléculaire, Centre National de la Recherche Scientifique, Orléans, France.
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D001483:Base Sequence; D002945:Cisplatin / Q000737:chemistry* / Q000494:pharmacology; D003432:Cross-Linking Reagents; D003596:Cytosine; D004247:DNA / Q000737:chemistry*; D006147:Guanine; D007700:Kinetics; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000138:chemical synthesis / Q000737:chemistry*; D010880:Piperidines; D015183:Restriction Mapping; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects
D003432:Cross-Linking Reagents; D009838:Oligodeoxyribonucleotides; D010880:Piperidines; C034697:transplatin; D006147:Guanine; D003596:Cytosine; D004247:DNA; D002945:Cisplatin