Effect of geometric isomerism in dinuclear platinum antitumor complexes on DNA interstrand cross-linking
Language English Country United States Media print
Document type Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.
Grant support
R01-CA78754
NCI NIH HHS - United States
PubMed
10460154
DOI
10.1021/bi990245s
PII: bi990245s
Knihovny.cz E-resources
- MeSH
- DNA Adducts chemistry metabolism MeSH
- Circular Dichroism MeSH
- Cisplatin chemistry metabolism MeSH
- Transcription, Genetic MeSH
- Nucleic Acid Heteroduplexes chemical synthesis metabolism MeSH
- Nucleic Acid Conformation MeSH
- Molecular Sequence Data MeSH
- Oligodeoxyribonucleotides chemical synthesis metabolism MeSH
- Antineoplastic Agents chemistry metabolism MeSH
- Cross-Linking Reagents chemistry metabolism MeSH
- Base Sequence MeSH
- Stereoisomerism MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
- Research Support, U.S. Gov't, P.H.S. MeSH
- Names of Substances
- DNA Adducts MeSH
- Cisplatin MeSH
- Nucleic Acid Heteroduplexes MeSH
- Oligodeoxyribonucleotides MeSH
- Antineoplastic Agents MeSH
- Cross-Linking Reagents MeSH
- transplatin MeSH Browser
The requirement for novel platinum antitumor drugs led to the synthesis of dinuclear bisplatinum complexes. To understand the molecular mechanisms underlying the biological activity of this new class of platinum cytostatics, modifications of natural DNA and synthetic oligodeoxyribonucleotide duplexes by dinuclear bisplatinum complexes with equivalent monofunctional coordination spheres, represented by the general formula [{cis-PtCl(NH(3))(2)}(2)(H(2)N-R-NH(2)](2+) (1,1/c,c), in which R is a linear alkane chain, butane or hexane, were studied by various biochemical and molecular biology methods. The results indicated that the major adducts of 1,1/c,c complexes in DNA ( approximately 90%) were interstrand cross-links preferentially formed between guanine residues. Besides 1,2 interstrand cross-links (between guanine residues in neighboring base pairs), 1,3 or 1,4 interstrand cross-links were also possible. In the latter two long-range adducts, the sites involved in the cross-links were separated by one or two base pairs. 1,2, 1,3, and 1,4 interstrand cross-links were formed with a similar rate and were preferentially oriented in the 5' --> 5' direction. In addition, the DNA adducts of these complexes inhibited DNA transcription in vitro. Thus, the binding of the 1,1/c, c complexes modifies DNA in a way that is distinctly different from the modification by the antitumor drug cisplatin. In addition, there are significant differences between the dinuclear 1,1/c,c and 1,1/t, t isomers. The results of this work are consistent with the hypothesis and support the view that platinum drugs that bind to DNA in a fundamentally different manner can exhibit different biological properties including the spectrum and intensity of antitumor activity. The intracellular DNA binding of the dinuclear compounds is compared to the results presented here. It has been suggested that differences in cross-link structure may be an important factor underlying their different biological efficiencies.
References provided by Crossref.org
Formation of platinated GG cross-links on DNA by photoactivation of a platinum(IV) azide complex