Conformation, recognition by high mobility group domain proteins, and nucleotide excision repair of DNA intrastrand cross-links of novel antitumor trinuclear platinum complex BBR3464.
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.
Zehnulova
J
J
Institute of Biophysics, Academy of Sciences of the Czech Republic, Kralovopolska 135, CZ-61265 Brno, Czech Republic.
Kasparkova
J
J
Farrell
N
N
Brabec
V
V
D001483:Base Sequence; D001665:Binding Sites; D004247:DNA / Q000737:chemistry / Q000187:drug effects*; D018736:DNA Adducts / Q000378:metabolism*; D004260:DNA Repair; D006609:High Mobility Group Proteins / Q000378:metabolism*; D015335:Molecular Probes; D009690:Nucleic Acid Conformation; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000494:pharmacology*
D018736:DNA Adducts; D006609:High Mobility Group Proteins; D015335:Molecular Probes; D009944:Organoplatinum Compounds; D004247:DNA; C114062:BBR 3464