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(NH3)(2)}(2)mu -trans Pt(NH3)(2){H2N(CH2)(2)NH2}(2)](4+) (designated as BBR3464) is curren tly in phase II clinical trials. DNA is generally considered the major phar macological target of platinum drugs. As such it is of considerable interes t to understand the patterns of DNA damage. The bifunctional DNA binding of BBR3464 is characterized by the rapid formation of long range intra-and in terstrand cross links. We examined how the structures of the various types of the intrastrand crosslinks of BBR3464 affect conformational properties o f DNA, and how these adducts are recognized by high mobility group 1 protei n and removed from DNA during in, vitro nucleotide excision repair reaction s. The results have revealed that intrastrand cross-links of BBR3484 create a local conformational distortion, but none of these cross-links results i n a stable curvature. In addition, we have observed no recognition of these crosslinks by high mobility group 1 proteins, but we have observed effecti ve removal of these adducts from DNA by nucleotide excision repair. These r esults suggest that the processing of the intrastrand cross-links of BBR346 4 in tumor cells sensitive to this drug may not be relevant to its antitumo r effects. Hence, polynuclear platinum compounds apparently represent a nov el class of platinum anticancer drugs acting by a different mechanism than cisplatin and its analogues.