Axial Ligands and Alicyclic Ring Size Modulate the Activity and Biochemical Pharmacology of Ammine/Cycloalkylamine-Platinum(IV) Complexes in Tumor Cells Resistant to cis-Diamminedichloroplatinum(II) or trans-1R,2R-1S,2S-Diaminocyclohexanetetrachloroplatinum(IV)

Abstract

A platinum(II) and 3 platinum(IV) ammine/cycloalkylamine homologous series were evaluated for cytotoxicity and biochemical pharmacology in murine leukemia L1210/0, cis-diamminedichloroplatinum(II)-resistant L1210/DDP, and diaminocyclohexaneplatinum-resistant L1210/1,2-diaminocyclohexane (DACH) cells. Within each series, which contained 4 homologues with differing alicyclic (cycloalkyl) ring size (cyclopropane, cyclobutane, cyclopentane, or cyclohexane), cytotoxicity increased with increasing ring size. This appeared to be due to an increase in partition coefficient, and the resulting increase in drug accumulation and intracellular DNA adducts in ascending each of the series. There were exceptions to this generalization, predominantly in L1210/DACH cells, where the biochemical pharmacology was not entirely consistent with the cytotoxic response and suggested that other factors may be at play. The relationship between structure and ability to circumvent cis-diamminedichloroplatinum(II) and/or trans-1R,2R-1S,2S-diaminocyclohexanetetrachloroplatinum(IV) resistance was complex. Ascending the platinum(II) series caused resistance factors to decrease in L1210/DDP cells but increase in L1210/DACH cells. An increase in resistance factors was also observed in ascending the axial chloroplatinum(IV) series in the L1210/DACH line. In contrast, ascending the axial chloroplatinum(IV) series in the L1210/DDP line and axial acetatoplatinum(IV) and axial hydroxoplatinum(IV) series in both cell lines resulted in increases in resistance factors for the first stepwise increase in the cycloalkylamine ring size, but resistance factors then decreased progressively with further increases in ring size. Reduction of the platinum(IV) analogues to the platinum(II) congener appears to be necessary for binding to DNA. The similarity in biological actions between the platinum(II) and axial chloroplatinum(IV) series is likely due to the rapid reduction of tetravalent members to platinum(II) forms. The axial acetatoplatinum(IV) and axial hydroxoplatinum(IV) complexes were reduced more slowly, which may explain their lower potency, but not the ability of the higher member to circumvent both cis-diamminedichloroplatinum(II) and trans-1R,2R-1S,2S-diaminocyclohexanetetrachloroplatinum(IV) resistances. Explanation for this will require additional studies. The results have demonstrated high dependencies on ring size of the carrier amine ligand, valence state of platinum, and the nature of the axial ligand for modulation of potency, cross-resistance property, and biochemical pharmacology of ammine/cycloalkylamine complexes.