Abstract
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.
Highlights
The trinuclear compound [{trans-PtCl(NH3)2}2-transPt(NH3)2{H2N(CH2)6NH2}2]4ϩ (Fig. 1) is currently in phase II clinical trials
We examined how the structures of the various types of the intrastrand crosslinks 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
DNA is generally considered the major pharmacological target of platinum drugs [13]. As such it is of considerable interest to understand the patterns of DNA damage that may lead to differential cell signaling induced by polynuclear platinum complexes in comparison to those induced by mononuclear agents such as cisplatin and carboplatin
Summary
The trinuclear compound [{trans-PtCl(NH3)2}2-transPt(NH3)2{H2N(CH2)6NH2}2]4ϩ (Fig. 1) is currently in phase II clinical trials. Within the double-stranded oligonucleotides containing either intrastrand CL, other A residues in the bottom strand became reactive (shown for the TGGT[22] duplex in Fig. 2A (center, lane IAC)).
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