Mode of DNA binding of cis-platinum(II) antitumor drugs: a base sequence-dependent mechanism is proposed

Abstract

Chloroammine and similar complexes of platinum(II) having the ammine ligands in the cis configuration are effective antitumor agents but the corresponding trans isomers are not. This is possibly due to the different manner in which these drugs attack DNA. There is considerable controversy in the literature over the type of DNA lesion caused by cis-platinum(II) complexes. Some have proposed an attack on a single guanine base via chelation to N(7) and O(6) as being the biologically important interaction. However, much indirect evidence suggests that binding to adjacent guanine bases in the same strand of DNA is important to the mechanism of action. Following initial binding to guanine bases, DNA is then locally denatured, exposing additional crosslinking sites. Thus, the selectivity of cis-platinum(II) complexes in inhibiting tumor growth may be due to a combination of intrastrand and interstrand crosslinking to DNA at areas of specific base sequences.