DNA interstrand crosslinks

Qu, Y. Scarsdale, N. J. Tran, M. C. Farrell, N. Cooperative effects in long-range 1,4 DNA-DNA interstrand crosslinks formed by polynuclear platinum complexes an unexpected syn-orientation of adenine bases outside the binding sites. J Biol Inorg Chem 2003, 8, 19-28. 

Kasparkova, J. Zehnulova, J. Farrell, N. Brabec, V. DNA interstrand crosslinks of novel antitumor trinuclear platinum complex BBR. Conformation, recognition by HMG-domain proteins and nucleotide excision repair. J Biol Chem 2002, 277, 48076-48086. 

Wojcik A, Bochenek A, Lankoff A, Risowska A, Padjas A, von Sonntag C, Obe G (2005) DNA interstrand crosslinks are induced in cells prelabelled with 5-bromo-2 -deoxyuridine and exposed to UVC radiation, in preparation... 

Bridgewater LC, Manning FCR, Patierno SR. 1994a. Base-specific arrest of in vitro DNA replication by carcinogenic chromium relationship to DNA interstrand crosslinking. Carcinogenesis 15(11) 2421-2427. 

Another alkylating drug in clinical use is mitomycin C. As a natural product isolated from Stremtomyces lavendulae, mytomycin C is an aziridine compound, which is closely related to nitrogen mustards. This compound is best known to the DNA repair field as a DNA interstrand crosslinking agent. Mytomycin C has been used to treat breast cancer and cancers of the gastrointestinal tract. 

Measurement of Drug-Induced DNA Interstrand Crosslinking Using the Single-Cell Gel Electrophoresis (Comet) Assay... 

Figure 2 illustrates DNA interstrand crosslinking in human lymphocytes. In... 

Fig. 2. DNA interstrand crosslinking in human lymphocytes as represented by percentage decrease in tail moment. (A) In vitro formation of DNA ISC with the nitrogen mustard Chlorambucil in normal lymphocytes taken from a healthy donor. Lympho-...

Sarkar, S., Davies, A.A., Ulrich, H.D., and McHugh, P.J. (2006) DNA interstrand crosslink repair during Gj involves nucleotide excision repair and DNA polymerase i. EMBO J., 25, 1285-1294. 

It has been shown that cells can be protected from the toxic effects of cis-PPP by preventing the formation of DNA crosslinks by incubating cells in the presence of thiourea immediately after treatment ( ), a finding which further supports a cytotoxic role for DNA interstrand crosslinks. Further investigation in mouse leukemia cells and human fibroblasts of varying sensitivity to cisplatin, have shown that cellular sensitivity often correlates with interstrand crosslink formation (55, 56, 57). However, studies of certain mouse leukemia L1210 lines resistant to cisplatin (5, ), as well as studies of Walker carcinoma cells (59)... 

Figure 5, Repair of ci DDP-iruiuced DNA-protein crosslinks and DNA inter-strand crosslinks in human fibroblasts during holding in the nondividing state. Stationary cultures were treated with 40 fjjnol cvs-DDP, and after various periods of holding in the nondividing state, crosslinking was measured by alkaline elution (U DNA-protein crosslinks and O, DNA interstrand crosslinks) or by estimation of renaturable DNA in cell lysates (%, DNA interstrand crosslinks).

Figure 4, The kinetics of formation and disappearance of DNA-protein cross-linking (DPC) and DNA interstrand crosslinking (ISC) in L1210 cells treated with cis- or trans-DDP. Key to conditions A, cis-DDP without proteinase (DPC and ISC) B, trans-DDP without proteinase (DPC and ISC) C, cis-DDP with proteinase (ISC only) and D, trans-DDP with proteinase (ISC only). (Reproduced with...

Figure 5. Relation between DNA interstrand crosslinking and DNA protein crosslinking and survival of L1210 cells as measured by soft-agar colony formation. Key to conditions top, without proteinase-K (DPC + ISC) and bottom, with proteinase-K (ISC only). (Reproduced with permission from Ref. 9.)...

Figure 9. Concentration dependence of cis-DDP DNA-protein crosslinking (top, 3000 R) and DNA interstrand crosslinking (bottom, 300 R) in sensitive (K25) and resistant (ZCR9) L1210 cells. (Reproduced with permission from Ref. 6.)...

L-phenylalanlne mustard l p , Intraperltoneal BUPMI 1630, Roswell Park Memorial Institute medium 1630 DPC, DNA-proteln crossllnk-Ing ISC, DNA Interstrand crosslinking SCE, sister-chromatid exchanges ... 

The equations describing both the cytotoxicities and the alkylating abilities of substituted aniline chloromustards have similar slopes, suggesting that these compounds express their cytotoxicity primarily by alkylation. It is evident that the critical biological alkylation site is DNA, and that cytotoxicity is due to formation of DNA interstrand crosslinks, since the UV4 mutant defective in repair of these lesions (J4) shows marked hypersensitivity to the aniline mustards. 

Dusre, L. et al., DNA interstrand crosslink and free radical formation in a human multidrug resistant cell line from mitomycin C and its analogues. Cancer Res., 50, 648, 1990. 

Deans AJ, West SC (2011) DNA interstrand crosslink repair and cancer. Nat Rev Cancer 11 467 80... 

A psoralen photoadduct to adenine was also isolated and characterized upon irradiation of a mixture of adenine and psoralen derivative, however, the latter photoadduct does not appear to be generated in cellular DNA. The psoralen adducts within nuclear DNA are formed primarily by a [2 -i- 2] photocycloaddition reaction between the 4, 5 -furan double bond of the psoralen molecule and the 5,6-double bond of thymine. Monoadducts involving the 3,4-pyrone double bond of the psoralen and the pyrimidine 5,6-double bond are also formed, but to a lesser extent (Figure 142.4). Photoisomerization can lead to 4, 5 -monoadducts being converted into 3,4-monoadducts, at least in isolated DNA. Interstrand crosslinks can be generated as the result of photoexcitation of the 4, 5 -monoadduct and its subsequent cycloaddition with the pyrone 3,4 double bond. The structures of the monoadducts and cross-links are shown in Figure 142.4. The cross-linking process depends on the structure of the psoralen derivative. Linear psoralens form cross-links efficiently with a yield, which may reach up to 50% of the overall adducts formed. 

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