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.
Brabec
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V
Centre de Biophysique Moléculaire, Centre National de la Recherche Scientifique, Orléans, France.
Leng
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M
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