DNA INTERSTRAND CROSS-LINKS OF TRANS-DIAMMINEDICHLOROPLATINUM(II) AREPREFERENTIALLY FORMED BETWEEN GUANINE AND COMPLEMENTARY CYTOSINE RESIDUES

Bases in the opposite strands of DNA cross-linked by clinically ineffe ctive trans-diamminedichloroplatinum(II) {trans-[Pt(NH3)2Cl2]} have be en identified by means of three experimental approaches. These include HPLC analysis of enzymatic digests of synthetic oligonucleotide duple xes containing the interstrand cross-link, footprinting experiments on the interstrand cross-linked oligonucleotide duplexes, and terminatio n of the duplex transcription on trans-[Pt(NH3)2Cl2]-treated fragments of plasmid DNA. The results reveal that deoxyguanine and complementar y deoxycytosine residues are preferential binding sites of trans-[Pt(N H3)2Cl2] in the inter-strand adducts. The interstrand cross-linking re action was studied by means of gel electrophoresis for the cis and tra ns 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 diff erences in clinical activity of the two platinum(II) isomers.