Skip Navigation

This Article
Right arrow Full Text Freely available
Right arrow Print PDF (225K) Freely available
Right arrow Supplementary Material
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (32)
Right arrowRequest Permissions
Right arrow Commercial Re-use Guidelines
for Open Access NAR Content
Google Scholar
Right arrow Articles by Novakova, O.
Right arrow Articles by Brabec, V.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Novakova, O.
Right arrow Articles by Brabec, V.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Nucleic Acids Research, 2003, Vol. 31, No. 22 6450-6460
© 2003 Oxford University Press

Article

DNA–protein cross-linking by trans-[PtCl2(E-iminoether)2]. A concept for activation of the trans geometry in platinum antitumor complexes

Olga Novakova, Jana Kasparkova, Jaroslav Malina, Giovanni Natile1 and Viktor Brabec*

Institute of Biophysics, Academy of Sciences of the Czech Republic, CZ-61265 Brno, Czech Republic and 1 Department of Pharmaceutical Chemistry, University of Bari, I-70125 Bari, Italy

*To whom correspondence should be addressed. Tel: +420 54 151 7148; Fax: +420 54 124 0499; Email: brabec{at}ibp.cz

The structure–pharmacological activity relationships generally accepted for antitumor platinum compounds stressed the necessity for the cis-[PtX2(amine)2] structure while the trans-[PtX2(amine)2] structure was considered inactive. However, more recently, several trans-platinum complexes have been identified which are potently toxic, antitumor-active and demonstrate activity distinct from that of conventional cisplatin (cis-[PtCl2(NH3)2]). We have shown in the previous report that the replacement of ammine ligands by iminoether in transplatin (trans-[PtCl2(NH3)2]) results in a marked enhancement of its cytotoxicity so that it is more cytotoxic than its cis congener and exhibits significant antitumor activity, including activity in cisplatin-resistant tumor cells. In addition, we have also shown previously that this new trans compound (trans-[PtCl2(E-iminoether)2]) forms mainly monofunctional adducts at guanine residues on DNA, which is generally accepted to be the cellular target of platinum drugs. In order to shed light on the mechanism underlying the antitumor activity of trans-[PtCl2(E-iminoether)2] we examined oligodeoxyribonucleotide duplexes containing a single, site-specific, monofunctional adduct of this transplatin analog by the methods of molecular biophysics. The results indicate that major monofunctional adducts of trans-[PtCl2(E-iminoether)2] locally distort DNA, bend the DNA axis by 21° toward the minor groove, are not recognized by HMGB1 proteins and are readily removed from DNA by nucleotide excision repair (NER). In addition, the monofunctional adducts of trans-[PtCl2(E-iminoether)2] readily cross-link proteins, which markedly enhances the efficiency of this adduct to terminate DNA polymerization by DNA polymerases in vitro and to inhibit removal of this adduct from DNA by NER. It is suggested that DNA–protein ternary cross-links produced by trans-[PtCl2(E-iminoether)2] could persist considerably longer than the non-cross-linked monofunctional adducts, which would potentiate toxicity of this antitumor platinum compound toward tumor cells sensitive to this drug. Thus, trans-[PtCl2(E-iminoether)2] represents a quite new class of platinum antitumor drugs in which activation of trans geometry is associated with an increased efficiency to form DNA–protein ternary cross-links thereby acting by a different mechanism from ‘classical’ cisplatin and its analogs.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Nucleic Acids ResHome page
K. Chvalova, V. Brabec, and J. Kasparkova
Mechanism of the formation of DNA-protein cross-links by antitumor cisplatin
Nucleic Acids Res., March 19, 2007; 35(6): 1812 - 1821.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
S. Zorbas-Seifried, M. A. Jakupec, N. V. Kukushkin, M. Groessl, C. G. Hartinger, O. Semenova, H. Zorbas, V. Yu. Kukushkin, and B. K. Keppler
Reversion of Structure-Activity Relationships of Antitumor Platinum Complexes by Acetoxime but Not Hydroxylamine Ligands
Mol. Pharmacol., January 1, 2007; 71(1): 357 - 365.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
J. Kasparkova, O. Novakova, O. Vrana, F. Intini, G. Natile, and V. Brabec
Molecular Aspects of Antitumor Effects of a New Platinum(IV) Drug
Mol. Pharmacol., November 1, 2006; 70(5): 1708 - 1719.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
J. T. Reardon and A. Sancar
Repair of DNA-polypeptide crosslinks by human excision nuclease.
PNAS, March 14, 2006; 103(11): 4056 - 4061.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
V. Marini, P. Christofis, O. Novakova, J. Kasparkova, N. Farrell, and V. Brabec
Conformation, protein recognition and repair of DNA interstrand and intrastrand cross-links of Antitumor trans-[PtCl2(NH3)(thiazole)]
Nucleic Acids Res., October 19, 2005; 33(18): 5819 - 5828.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.