Conformation, recognition by high mobility group domain proteins, and nucleotide excision repair of DNA intrastrand cross-links of novel antitumor trinuclear platinum complex BBR3464
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.
Grant support
R01-CA78754
NCI NIH HHS - United States
PubMed
11303029
DOI
10.1074/jbc.m103118200
PII: S0021-9258(20)78492-9
Knihovny.cz E-resources
- MeSH
- DNA Adducts metabolism MeSH
- DNA chemistry drug effects MeSH
- Nucleic Acid Conformation * MeSH
- Molecular Probes MeSH
- DNA Repair * MeSH
- Organoplatinum Compounds chemistry pharmacology MeSH
- High Mobility Group Proteins metabolism MeSH
- Base Sequence MeSH
- Binding Sites MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, U.S. Gov't, P.H.S. MeSH
- Names of Substances
- DNA Adducts MeSH
- BBR 3464 MeSH Browser
- DNA MeSH
- Molecular Probes MeSH
- Organoplatinum Compounds MeSH
- High Mobility Group Proteins MeSH
The new antitumor trinuclear platinum compound [(trans-PtCl(NH(3))(2))(2)mu-trans-Pt(NH(3))(2)(H(2)N(CH(2))(6)NH(2))(2)](4+) (designated as BBR3464) is currently in phase II clinical trials. DNA is generally considered the major pharmacological target of platinum drugs. As such it is of considerable interest to understand the patterns of DNA damage. The bifunctional DNA binding of BBR3464 is characterized by the rapid formation of long range intra- and interstrand cross-links. We examined how the structures of the various types of the intrastrand cross-links of BBR3464 affect conformational properties of DNA, and how these adducts are recognized by high mobility group 1 protein and removed from DNA during in vitro nucleotide excision repair reactions. The results have revealed that intrastrand cross-links of BBR3464 create a local conformational distortion, but none of these cross-links results in a stable curvature. In addition, we have observed no recognition of these cross-links by high mobility group 1 proteins, but we have observed effective removal of these adducts from DNA by nucleotide excision repair. These results suggest that the processing of the intrastrand cross-links of BBR3464 in tumor cells sensitive to this drug may not be relevant to its antitumor effects. Hence, polynuclear platinum compounds apparently represent a novel class of platinum anticancer drugs acting by a different mechanism than cisplatin and its analogues.
References provided by Crossref.org
Walking of antitumor bifunctional trinuclear PtII complex on double-helical DNA
Conformation of DNA GG intrastrand cross-link of antitumor oxaliplatin and its enantiomeric analog