Intrastrand DNA cross-link

Platinum agent forms inter-and intrastrand DNA cross-links inhibition of DNA synthesis aquated species is cytotoxic... 

Organometallic antineoplastics (platinum coordination complexes) also cross-link DNA, and many do so by binding to adjacent guanine nucleotides, called diguanosine dinucleotides, on a single strand of DNA. This leads to intrastrand DNA cross-linking. The anionic phosphate group on a second strand of DNA stabilizes... 

Hambley and co-workers have reported the synthesis, DNA cross-linking, and in vitro anticancer properties of a platinum(II) complex that was designed to bind the macromolecule in an interstrand rather than intrastrand manner,162 the latter being the dominant mode of DNA-binding by platinum anticancer drugs such as cisplatin. The complex [PtCl2(hpip)] ((46) ... 

Cisplatin Forms intrastrand and interstrand DNA cross-links binding to nuclear and cytoplasmic proteins Non-small cell and small cell lung cancer, breast cancer, bladder cancer, gastroesophageal cancer, head and neck cancer, ovarian cancer, germ cell cancer Nausea and vomiting Nephrotoxicity, peripheral sensory neuropathy, ototoxicity, nerve dysfunction... 

The chemotherapeutic agent d.v-diammincdichloroplatinum(II), cis-DDP, or cisplatin, can form covalent adducts with many cellular macromolecules, but there is convincing evidence that its cytotoxic properties are a consequence of bifunctional-DNA adduct formation [ 1 ] [2]. Platinum binds to the N(7) position of purine nucleotides, resulting predominantly in 1,2-d(GpG) and l,2-d(ApG) intrastrand cross-links, but also in l,3-d(GpNpG) intrastrand, interstrand and protein-DNA cross-links [3][4], The 1,2-intrastrand cross-links, which comprise 90% of the DNA adducts, are not formed by the clinically inactive trans-DDP because of geometric constraints, and attention has therefore focused on these adducts as the active lesions in the anticancer activity of the drug. 

Figure 6.6 Main DNA-cA-platin adducts (a) interstrand cross-link (b) 1,2-intrastrand cross-link (c) 1,3-intrastrand cross-link (d) protein-DNA cross-link. Adapted from Ho et al.12...

Sanchez, A.M., Kozekov, I.D., Harris, T.M., and Uoyd, R.S. (2005) Formation of inter- and intrastrand imine type DNA-DNA cross-links through secondary reactions of aldehydic adducts. Chem. Res. Toxicol, 18, 1683-1690. 

UV radiation and some chemical agents damage DNA by creating intrastrand or interstrand DNA cross-links (Figure 17.3). Intrastrand cross-links, which occur when covalent bonds form between two bases on the same strand of DNA, tend to distort the double helix. Interstrand cross-links, which occur when covalent bonds form between two bases on opposite strands of the double helix, are particularly problematic since they prevent the melting at the point of the cross-link and pose absolute blocks to replication and transcription. 

Intrastrand and interstrand DNA cross-links are also formed in DNA by another important class of chemotherapeutic drugs-the cisplatins. The majority of the adducts formed in vivo and in vitro are 1,2-intrastrand d(GpG) and d(ApG) crosslinks that represent 80-90% of the bound platinum. In addition 1,3-intrastrand d(GpTpG) cross-links and a small percentage of interstrand cross-links and monofunctional adducts are formed [127]. 

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. 

The interstrand cross-link also induces DNA bending.72 X-ray and NMR studies on this adduct show that platinum is located in the minor groove and the cytosines of the d(GC) base pair involved in interstrand cross-link formation are flipped out of the helix stack and a localized Z-form DNA is observed.83-85 This is a highly unusual structure and very distorting—implications for differential repair of the two adducts have been addressed. Alternatively, the interstrand cross-link of the antitumor inactive trans-DDP is formed between a guanine (G) and its complementary cytosine (C) on the same base p a i r.86,87/ nms- D D P is sterically incapable of producing 1,2-intrastrand adducts and this feature has been cited as a dominant structural reason for its lack of antitumor efficacy. It is clear that the structural distortions induced on the DNA are very different and likely to induce distinctly different biological consequences. 

B-DNA 1,2-Intrastrand cross-link 1,2-Interstrand cross-link... 

The polynuclear platinum compounds stand in vivid contrast to mononuclear platinum complexes because the predominant DNA lesions are long-range inter- and intrastrand cross-links where the sites of platination may be separated by up to four base pairs. The consequent structural and conformational changes in DNA are also distinct. 

Aliosman, F., Caughlan, J., and Gray, G.S. (1989) Diseased DNA intrastrand cross-linking and cytotoxicity induced in human brain tumor cells by 1,3-fcis(2-chlorocthyl)-1 -nitrosourea after in vitro reaction with glutathione. Cancer Res. 49, 5954. 

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