A comparison of in vitro platinum-DNA adduct formation between carboplatin and cisplatin.

DNA damage induced by carboplatin [cis-diammine-(1, 1-cyclobutanedicarboxylato)platinum(II)] was studied in vitro in comparison with cisplatin [cis-diammine-dichloroplatinum(II)]. The drug-induced DNA damage monitored by conformational change of pUC18 plasmid DNA showed that carboplatin required 10 times higher drug concentration and 7.5 times longer incubation time than those of cisplatin to induce the same degree of conformational change on plasmid DNA. The carboplatin-induced DNA damage was promoted by the increase of pH of the reaction mixture for platinum-DNA adduct formation. Sequence gel analysis of carboplatin-damaged DNA indicated that carboplatin attacked preferentially the sequence of GG >> AG > GA > GNG in the order, similarly to the case of cisplatin. DNA adducts formed by carboplatin were analyzed by HPLC after a sequential digestion of carboplatin-treated DNA with deoxyribonuclease I and S1 nuclease. A single peak having the same retention time as that of bifunctional adduct of (dGMP)2Pt(NH3)2 appeared by treating DNA with carboplatin. The adduct was assigned to be d(pGpG) > Pt(NH3)2. These results suggested that carboplatin induces the same platinum-DNA adducts as those induced by cisplatin, and that the difference in efficiency or kinetics of DNA damage between carboplatin and cisplatin is due to difference of aquation rate between them.