Conformation, recognition by high mobility group domain proteins, and nucleotide excision repair of DNA intrastrand cross-links of novel antitumor trinuclear platinum complex BBR3464
Jazyk angličtina Země Spojené státy americké Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem, Research Support, U.S. Gov't, P.H.S.
Grantová podpora
R01-CA78754
NCI NIH HHS - United States
PubMed
11303029
DOI
10.1074/jbc.m103118200
PII: S0021-9258(20)78492-9
Knihovny.cz E-zdroje
- MeSH
- adukty DNA metabolismus MeSH
- DNA chemie účinky léků MeSH
- konformace nukleové kyseliny * MeSH
- molekulární sondy MeSH
- oprava DNA * MeSH
- organoplatinové sloučeniny chemie farmakologie MeSH
- proteiny s vysokou pohyblivostí metabolismus MeSH
- sekvence nukleotidů MeSH
- vazebná místa MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, U.S. Gov't, P.H.S. MeSH
- Názvy látek
- adukty DNA MeSH
- BBR 3464 MeSH Prohlížeč
- DNA MeSH
- molekulární sondy MeSH
- organoplatinové sloučeniny MeSH
- proteiny s vysokou pohyblivostí 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.
Citace poskytuje Crossref.org
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