Platination of DNA

The high affinity of many platinum compounds for sulfur and the availability of many sulfur-containing biomolecules have raised the question whether Pt-sulfur biomolecule interactions could serve as a drug reservoir for platination at DNA, necessary for the antitumor activity of cis-Pt. Two reaction paths are possible, i.e., spontaneous release of plantinum from the sulfur, or nucleophilic displacement of platinum from sulfur by guanine (N7), for example. At the moment, there is no real evidence for the existence of such reactivation mechanisms. In fact, it has been reported that Pt-protein interactions in the plasma (albumin) are not reversible under normal conditions (161, 165). Further, a mixture of cis-Pt-methionine products does not show antitumor properties (166), indicating no induced platination of DNA. More research is required to investigate the existence of a reactivation mechanism. However, it is predicted that if such a reactivation phenomenon is operational, the most likely candidate is the labile Pt-methionine bond, as has been shown by its rapid reaction with Naddtc, STS, and thiourea (vide supra) (131). 

DNA interstrand cross-links were also purified and found to be formed between two deoxyguanosines, but this requires a major contortion of the DNA structure and may only occur when an alternate purine is not in close proximity on the same strand [12]. This presumably explains why interstrand cross-links occur at less than 1% of the total platination of DNA. One other adduct that was shown to form in vitro was a cross-link between deoxyguanosine and glutathione [18]. This adduct could be produced when... 

General considerations. The competition experiments described above have illustrated the possibility of N(7) platination of DNA via Pt-S intermediates. These studies also showed the great stability of S,N chelates of bifunctional platinum complexes. All of the above-discussed intramolecular competition studies were performed on models containing both the thi-oether function and the N(7) in the same molecule, thus in relatively close proximity. 

Can rescue agents and sulfur-containing peptides cause in vivo de-platination of DNA and proteins Do such interaction products still have antitumor activity on their own, and may this knowledge be used to the development of new drugs ... 

Platination of DNA usually takes place on a G - C base pair it breaks the hydrogen bond between the two bases, thus causing shrinkage of the DNA. This selective action of, for example, m-dichlorodiamminoplatinum... 

Radiation-induced thymine release from DNA is also inhibited by cisplatin [78]. The possibility exists that platination of DNA (presumably via the purine bases at biologically relevant concentrations) may affect the inherent radiosensitivity of the bases, which for aerated solutions, follows the order Thy > Cyt > Ade > Gua. An analysis of this type of damage should take into consideration profiles of base release and decomposition with and without platination, as well as the effects the conformational and electronic changes in platinated DNA will have on the radiation interaction. In this respect the studies on radiosensitivity of Ag and Hg DNA complexes [85], as well as the effects on the radiation chemistry of simple bases of Cu(II) [86] and Fe(III) [87], are relevant. 

Fig. 3. Reaction scheme for the preparation of platinated parallel DNA (psPtDNA). Adapted from Ref. (28).

The X-ray crystal structure of platinated duplex DNA dodecamer d(CCTCTG G TCTCC) d(GGAGACCAGAGG), where G G represents the binding sites (G-N7) of m-[Pt(NH3)2]2+, is depicted in Figure 12 [67]. The coordination of Pt(II) to adjacent guanine bases distorts the... 

Cisplatin (Platinol) is an inorganic coordination complex with a broad range of antitumor activity. It is especially useful in the treatment of testicular and ovarian cancer. It binds to DNA at nucleophilic sites, such as the N7 and 06 of guanine, producing alterations in DNA structure and inhibition of DNA synthesis. Adjacent guanine residues on the same DNA strand are preferentially cross-linked. This platinating activity is analogous... 

Acting as a drug reservoir for platination at DNA. Although there is no evidence for the existence of such a phenomenon, in principle Pt-methionine interactions are labile and therefore are likely candidates to serve as a drug reservoir for platination at DNA, i.e., spontaneous release and binding to DNA or nucleophilic displacement of platinum by guanine, for example. 

Extensive exchange reactions of platinated sulfurs of the methionine type with mononucleotides and longer DNA fragments. This is with the aim to investigate the possibility that such Pt—S methionine bonds could act as drug reservoirs for platination at DNA. 

Very recently, Lippard has introduced a new model which reinterprets the NMR results of Reedijk and Chotard and which is esthetically more satisfactory. Lippard and his colleagues measured the uptake of both trans- and cis-platin in CV-1 monkey cells infected with SV-40 virus particles. Initially tra/w-platin was taken up more rapidly than cis-platin but DNA concentrations of tawis-platin reached a maximum after eight hours and then dropped rapidly. cis-Platin continued to rise throughout the whole 24 hour period of the experiments and DNA concentrations of cis-platin were very much higher than trans concentrations after 24 hours. The results were interpreted as removal of the bound frans-platin by the repair proteins whereas the bound cis-platin was not removed by the repair mechanism. 

What is the influence of DNA-platination on transcription of DNA and on translation to produce proteins ... 

Legendre, F. and Chottard, J.-C. (1999) Kinetics and Selectivity of DNA-Platination in Cisplatin Chemistry and Biochemistry of a Leading Anticancer Drug, pp. 223-245 (Lippert, B., Ed.) Verlag Helvitica Chimica Acta, Zurich. 

Interestingly, the emission of [Pt(tpy)(OH)]+ is quenched in water, but is restored upon intercalation with double-stranded nucleic acids [poly(dA-dT)]2 and [poly(dI-dC)]2 [73]. Although intercalation can also occur at G-C-rich sequences - and indeed it does so more strongly than for A-T - emission is then quenched by electron-transfer from guanine, the most readily oxidized of the nucleobases. The initial intercalative interactions are probably followed by covalent platination of the DNA, most likely by purine-N7 displacing the OH ligand, reminiscent of cisplatin. The absorption... 

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