cis-Amminedichlorido(
cyclohexylamine)
platinum(II) (
JM118) is an antitumor Pt(II) analogue of
cisplatin exhibiting considerably higher activity than
cisplatin in human
tumor cells.
JM118 is also the major metabolite of the first orally administered Pt(IV)
drug satraplatin. In an effort to design improved
platinum antitumor agents, it is important to elucidate the biochemical factors that affect the cytotoxic properties of existing
platinum drugs. Since
DNA is considered the major pharmacological target of
platinum drugs, the objective in the present work was to understand more fully the
DNA binding mode of antitumor
JM118. We examined the rate of aquation of the first
chloride of bifunctional
JM118 and found that it was considerably lower than that of
cisplatin; consequently, the rate of the reaction of
JM118 with
DNA was lower compared to
cisplatin. The influence of global modification by
JM118 and its major site-specific adducts on DNA conformation by biochemical methods was investigated as well. While examination of the global modification revealed in several cases no substantial differences in the lesions induced by
JM118 and
cisplatin,
DNA bending due to the 1,2-GG intrastrand adduct of
JM118 was lower than that of
cisplatin. The bending angles afforded by the adducts of
JM118 were only slightly affected by the orientation of the
cyclohexylamine ligand toward the 3' or 5' direction of the duplex. We also used in vitro assays that make it possible to monitor DNA repair synthesis by cell-free extracts and
DNA-
protein cross-linking to probe properties of
DNA adducts of
JM118. These results showed a higher
DNA-
protein cross-linking efficiency of
JM118 and a less efficient removal from
DNA of the adducts of
JM118 in comparison with
cisplatin. Thus, the results of the present work provide additional evidence that
DNA binding of
JM118 is in several aspects different from that of conventional
cisplatin.