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By J. Reedijk (auth.), Miles P. Hacker, Evan B. Douple, Irwin H. Krakoff (eds.)

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Additional info for Platinum Coordination Complexes in Cancer Chemotherapy: Proceedings of the Fourth International Symposium on Platinum Coordination Complexes in Cancer Chemotherapy convened in Burlington, Vermont by the Vermont Regional Cancer Center and the Norris Cotton

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Apparently, a nearby negative 5 ' -phosphate group may enhance the interaction, or promote the approach of the [cis-Pt(NH3)2(OH) (OH2)]+ ion. This may be attributed to a charge effect, or to a favourable hydrogen bonding. Finally, it is known that cis-PtCI 2 (NH 3 )2 reacts much slower with guanine residues than the aquated products. This is partly due to a slower ligand substitution process in case of CI (a poor leaving group), but repulsion between 06 and CI- may also playa role. In considering the first reaction step, one should also include the possible presence of dimeric and trimeric hydroxo-bridged species of the nature [(amine)2Pt(OH)2Pt(amine)2]2+ (12).

Been found that digestion of cis-Pt-treated DNA by exonuclease III stops at sites with sequences d(G)n with n=2 or larger (43,44). These data suggest the presence of intrastrand crosslinks at neighbouring guanines. Studies by Brouwer et al. coli bacteria, originate to a large extent from Ptadducts at GpCpG and GpApG base sequences. Fichtinger et al. (18) demonstrated in the enzymatic digest of Pt-treated salmon sperm DNA, among other products, cis-Pt(NH 3 )2(pGpG). Recently, she also found the adducts cis-Pt(NH3)2(pApG) and cis-Pt(NH3)2 (pTpGpG) (45), in which Pt is bound to N7 of the purines.

As our initial compound we chose the simple intercalating agent ethidium bromide (EtdBr, Fig. 34 We recently demonstrated that the binding kinetics of cis-DDP and its ability to unwind duplex DNA were unaltered when EtdBr was present during platination. 22 at (dG)n n = In the absence of the intercalator, the enzyme stopped 2,3,5, sites which had been platinated. 17 Curiously, a 5'-(dG)6-dC-(dG)2-3' sequence 29 bases from the 3' end of the labeled strand of the 165 bp DNA, expected to be a prime site for platination and therefore a major enzyme stopping point, was only faintly observed on the electrophoresis gel.

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