Site-specifically platinated DNA

It now appears153 that interindividual human variations in cisplatin response can be detected with an in vitro assay. Lippard et al.159 have reported that site-specifically platinated DNA is a new probe for the biological activity of cisplatin. 

This experiment provided compelling evidence that a solitary intrastrand d(GpG) adduct can be a lethal event in a single-stranded bacteriophage. The extent to which the other adducts, formed by cis- and Iraw-DDP on DNA, affect replication and survival is currently being addressed by studies of other site-specifically platinated genomes. 

The platinum-DNA adduct that is the major source of mutation induction by cis-DDP is a matter of controversy. One study (17) found platinated d(GpNpG) sequences to be the most mutagenic loci for base pair substitution. Another (18) reported that d(ApG) and d(GpG) cross-links accounted for 90% of single base pair mutations, and that d(ApG) crosslinks were five times more mutagenic. This conflict may be due to the different systems used for these studies, and the range of mutations they detect. Site-specifically modified M13 genomes were constructed in part to answer the question of the mutability of individual platinum-DNA adducts... 

Table 5.3 Cisplatin half-lives (/i for reaction with duplexes having specific binding sites and percentage of total platinated DNA adducts"...

In extending the PtR assignments using standard DNA sequential assignment methods Fig. 77), we found several structural changes and distinct chemical shifts around the platination site. We report these features in Table 3 and compare them to those of other duplexes with d(G pG ) crosslinks studied by NMR methods [51][71-74][77][105][107]. These duplexes are generically referred to here as PtD (see Table 1 for specific sequences and abbreviations). In addition, a duplex with a d(A pG ) crosslink has been studied by NMR spectroscopy, and these data are also included in the... 

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