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Nucleic Acids Research 2005 33(18):5819-5828; doi:10.1093/nar/gki884
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Published online 19 October 2005

© The Author 2005. Published by Oxford University Press. All rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions{at}oxfordjournals.org

Article

Conformation, protein recognition and repair of DNA interstrand and intrastrand cross-links of Antitumor trans-[PtCl2(NH3)(thiazole)]

Victoria Marini, Petros Christofis, Olga Novakova, Jana Kasparkova, Nicholas Farrell1 and Viktor Brabec*

Institute of Biophysics, Academy of Sciences of the Czech Republic CZ-61265 Brno, Czech Republic 1Department of Chemistry, Virginia Commonwealth University Richmond, VA 23284-2006, USA

*To whom correspondence should be addressed. Tel: +42 5 41517148; Fax: +42 5 41240499; Email: brabec{at}ibp.cz

Received July 26, 2005. Revised September 2, 2005. Accepted September 20, 2005.

Replacement of one ammine in clinically ineffective trans-[PtCl2(NH3)2] (transplatin) by a planar N-heterocycle, thiazole, results in significantly enhanced cytotoxicity. Unlike ‘classical’ cisplatin {cis-[PtCl2(NH3)2]} or transplatin, modification of DNA by this prototypical cytotoxic transplatinum complex trans-[PtCl2(NH3)(thiazole)] (trans-PtTz) leads to monofunctional and bifunctional intra or interstrand adducts in roughly equal proportions. DNA fragments containing site-specific bifunctional DNA adducts of trans-PtTz were prepared. The structural distortions induced in DNA by these adducts and their consequences for high-mobility group protein recognition, DNA polymerization and nucleotide excision repair were assessed in cell-free media by biochemical methods. Whereas monofunctional adducts of trans-PtTz behave similar to the major intrastrand adduct of cisplatin [J. Kasparkova, O. Novakova, N. Farrell and V. Brabec (2003) Biochemistry, 42, 792–800], bifunctional cross-links behave distinctly differently. The results suggest that the multiple DNA lesions available to trans-planaramine complexes may all contribute substantially to their cytotoxicity so that the overall drug cytotoxicity could be the sum of the contributions of each of these adducts. However, acquisition of drug resistance could be a relatively rare event, since it would have to entail resistance to or tolerance of multiple, structurally dissimilar DNA lesions.

Correspondence may also be addressed to Nicholas Farrell. Tel: +1 804 828 6320; Fax: +1 804 828 8599; Email: nfarrell{at}mail1.vcu.edu


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