Cisplatin intrastrand crosslink

Data taken from N. Poklar, D. S. Pilch, S. J. Lippard, E. A. Redding, S. U. Dunham, and K. J. Breslauer, Influence of Cisplatin Intrastrand Crosslinking on the Conformation, Thermal Stability and Energetics of a 20-mer DNA Duplex, Proc. Natl. Acad. Sci. USA, 93, 7606-76U (1996). 

Cyclopyrimidine dimer 6-4 Photoproduct cisplatin intrastrand crosslink... 

Binding of cisplatin to the neighbouring bases in the DNA disrupts the orderly stacking of the purine bases when it forms a 1,2-intrastrand crosslink, it bends the DNA helix by some 34° towards the major groove and unwinds the helix by 13°. These cross-links are believed to block DNA replication. 

Fig. 7. Schematic representation of cisplatin bonding to DNA. (1) monofunctional binding (X = Cr, OH", OH2) (2) interstrand crosslinking (3) protein-DNA crosslinking (4) intrastrand crosslinking between adjacent guanines (5) intrastrand crosslinking between two guanines separated by a third base (6) intrastrand crosslinking at a-AG-unit...

Recently, it could be established that in living cells the same types of Pt-adducts are formed as in DNA treated with cisplatin in vitro120,121. Also the strong preference of cisplatin to form intrastrand crosslinks on GG base sequences is found upon interaction with DNA in vivo120. ... 

The question which of the induced Pt-DNA adducts is (are) responsible for the antitumor activity is still unanswered. Many investigators have tried to correlate interstrand DNA and DNA-protein crosslink formation with the cytotoxic action of cisplatin. However, conflicting results were obtained18,50 Until now a biological role inside the cell has been indicated for only one type of Pt-DNA adduct. Brouwer et al.48 showed that cisplatin can induce base-pair substitutions in E. coli bacteria at GAG and GCG base sequences. This strongly suggests that the intrastrand crosslink of cisplatin on GBG is responsible for this effect. 

Fig. 22. Numbers of intrastrand crosslinks to GG-units in DNA isolated from white blood cells of two different patients at various time intervals after the onset of the cisplatin infusion (indicated by arrows).

The rate of formation of cisplatin-DNA adducts was found to be independent of superhelicity [59] and appears to be unaffected by the presence of histones in nucleosomes [29] and in chromatin [77], Therefore, isolated DNA in aqueous solution appears to be a relevant model for kinetic and mechanistic studies of cellular DNA-platination. It was early checked that the cisplatin-DNA adducts were stable for a least three days at 37 °C after their formation [78], There are now a few cases reported of unstable platinum adducts (vide supra) i) monoadducts with the diazapyrenium ligand [52], ii) a cisplatin intrastrand GG chelate rearranging into a GG interstrand crosslink [63], iii) cisplatin GG interstrand diadducts, slowly rearranging into intrastrand ones [65], tv) transplatin intrastrand GNG diadducts rearranging into interstrand crosslinks (J.-M. Malinge and M. Leng, Part 3). 

The major DNA lesions of cisplatin are intrastrand crosslinks, with cisplatin binding at the N7 position of purines. In vitro, reaction of ds-diamminedichloro-platinum (II) with DNA forms intrastrand crosslinks at the GG (65%), AG (25%),... 

Figure 16.4 DNA lesions used in TLS studies with gapped plasmids. BP-G, B[o]P-guanine adduct AP site, apurinic/apyrimidinic site 4-OHEN-C, 4-hydroxyequilenin-C adduct M12, dodecamethylene Cisplatin-GG, c/s-diamminedichloroplatinum(ll)-GG intrastrand crosslink ...

The alkylating agent Cisplatin forms intrastrand crosslink DNA adducts that trigger a series of intracellular events that ultimately results in ceU death. If the ceU can process and repair these lesions before the apoptotic pathway is initiated, the cell can survive the effects of cisplatin. One of the repair processes thought to have a major impact on resistance to alkylating cytotoxicty is nucleotide excision repair (NER). 

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