DNA intrastrand

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. 

Reed FP, Yuspa SH, Zwelhng LA, Ozols RF, Poirier MC. Quantitation of cisplatin-DNA intrastrand adducts in testicular and ovarian cancer patients receiving cisplatin chemotherapy. J Clin Invest 1986 77 545-550. 

Despite knowing the structures of all of the DNA lesions, it remains to be determined if any one lesion is more or less toxic to the cells. As discussed above, it was originally thought that DNA interstrand cross-links were the critical lesion. Once it was realized that these lesions are very rare, opinions shifted to suggest that DNA intrastrand cross-links are more cytotoxic. Unfortunately, there is no specific data that implicates either type of lesion in cytotoxicity. For some drugs like nitrosoureas, DNA repair pathways that remove only selected lesions (i.e., 0(6)-methylguanine DNA methyltransferase) have helped to define the role of a particular lesion [24], No separate pathway has been found for repair of a specific cisplatin adduct, so this approach has not been informative. A number of experiments have been performed in which specific adducts on defined DNA sequence, have been transfected into cells. This approach has shown that an adduct inhibits replication or transcription, but this does not directly address the question of mechanism of cytotoxicity. 

Xerri, B., Morell, C., Grand, A., Cadet, J., Cimino, P., and Barone, V. (2006) Radiation-induced formation of DNA intrastrand crosslinks between thymine and adenine bases. A theoretical approach. Org. Biomol. Chem., 4, 3986-3992. 

M2011 Melphalan Forms DNA intrastrand cross-Unks by alkylation of 5 -(GGC) sequences. 

Trans-DPP has leaving groups stereochemlcally disposed to make the formation of crosslinks at adjoining base pairs within one strand of DNA (Intrastrand crosslinking) unlikely (see Figure... 

Iwamoto T, Hiraku Y, Oikawa S, et al. DNA intrastrand cross-link at the 5 -GA-3 sequence formed by busulfan and its role in the cytotoxic effect. Cancer Sci 2004 95 454-458. 

An ELISA, which measures dsplatin-DNA intrastrand adducts, and atomic absorbance spectrometry, which measures total platinum bound to DNA, have been used to quantify DNA modification in samples from patients receiving platinum drug-based therapy and rats in which the treatment of human cancer patients has been modeled. Adducts measured in blood cell DNA samples from cancer patients have correlated with dose and chemotherapeutic efficacy. Human tissue DNA adducts have a widespread distribution, and long-term adduct persistence (> 1 year) has been observed in many organs including tumor and target sites for drug toxicity. 

The different possible adducts formed between mitomycin C and DNA have been isolated by degradation of DNA after in vitro alkylation/crosslinking reactions and structurally characterized. Monoadduct 21 (Scheme 11.3), derived from alkylation at C-l only [53], and monoadducts 22 [54] and 23 [55, 56] (derived from C-10 alkylation by 16 at N-7 or N-2 of guanine, respectively) have been isolated, together with bisadducts 24 [57] and 25 [58], derived from interstrand and intrastrand crosslinks, respectively, and adduct 26 [59], formed by addition of a molecule of water to C-10 instead of the second guanine. All of these adducts have also been isolated from DNA after in vivo crosslinking [60, 61]. 

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. 

While the critical role of intrastrand 1,2-crosslinks in the mechanism of action of the anti-tumor drug cis- [PtCl2(NH3)2] is well established, much less is known about the few frans-analogs that exhibit similar efficacy. A series of 1,3-adducts has been characterized with 3-mers generally involving purine N7 coordination (32-34), and either monofunctional or interstrand adducts are formed with duplex DNA (35). However, one of the most active compounds, frans-[PtCl2 ( )-HN = C(OMe)Me 2], (2), has been shown to form a 1,2-adduct with 2-mer ribonucleotide sequence r(AG) (36). Though the formation of the... 

Similar incubations of the self-adduct in the presence of excess noncomple-mentary DNA had no effect after eight days on subsequent target alkylation. The self-adduct (1.1 pM) was even resistant to quenching by 0.5 mM 2-mercaptoethanol during a six day incubation under ambient conditions. Once again, intrastrand trapping of the transient QM seems to be extremely efficient, yet remains sufficiently dynamic for subsequently transfer of its QM to a complementary sequence (Scheme 9.22). These results are also consistent with those observed with QMP11 (Section 9.3.2). 

In DNA RNA hybrids, where intrastrand base stacking is comparable to B-DNA, we observed efficient long range guanine oxidation when using ethidium as an intercalating photooxidant [130]. Conversely, a Rh(III) com-... 

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) ... 

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. 

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