Characterization of adducts produced in DNA by isomeric 1,2-diaminocyclohexaneplatinum(II) complexes.
The cancer chemotherapeutic drug cis-diamminedichloroplatinum(II) (cis-DDP) is active as a result of its bifunctional reactions with DNA. Many other platinum complexes also have therapeutic activity. Of current interest are complexes containing 1,2-diaminocyclohexane (DACH). The DACH ligand exists in three isomeric forms with reported differences in therapeutic activity in the order R,R greater than S,S greater than R,S-DACH-Pt. The reaction of the sulphate form of each of these three isomers with DNA has been characterized as a possible explanation for the apparent differences in antitumor activity. These reactions have been characterized by platinating pure DNA followed by enzyme digestion, HPLC separation and analysis by atomic absorption and nuclear magnetic resonance. The spectrum of adducts produced was similar for each isomer and similar to that reported for cis-DDP with adduction at d(GpG), d(ApG) and (dG)2. The R,S-isomer additionally demonstrated isomeric adducts at d(GpG) and d(ApG). The kinetics of formation of the various adducts was the same for each isomer; total platination of DNA was complete in 15 min as were bifunctional adducts at d(GpG) and (dG)2. However, rearrangement to bifunctional adducts took several hours in the case of adducts at d(ApG) sequences. These results did not provide a reason for the different activities of the isomers. It is suggested that the interaction of these adducts with metabolic processes such as DNA repair might explain these differences.
Jennerwein
M M
MM
Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha 68105.
Eastman
A
A
Khokhar
A
A
D002945:Cisplatin / Q000031:analogs & derivatives* / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D013237:Stereoisomerism
D004247:DNA; D002945:Cisplatin