Three homologous alicyclic mixed
amine cis-(NH3)(R-NH2)Cl2Pt(II) complexes, in which R = C3H5, C6H11, and C8H15 (complexes abbreviated C3, C6, and C8, respectively), were evaluated with reference compounds
cisplatin and
tetraplatin for antitumor activities and biochemical pharmacology in wild-type (murine
leukemia L1210/0 and human ovarian A2780) and corresponding variant cell lines resistant to
cisplatin (L1210/DDP and 2780CP) and
tetraplatin (L1210/
DACH and 2780TP). Cytotoxicities, measured by either a
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide or a clonogenic assay, were maximal for the C6 complex, which was up to 12-, 40-, and 6-fold more potent than C3 against wild-type,
cisplatin-resistant, and
tetraplatin-resistant models, respectively, and up to 2-fold more potent than C8 against these cell lines. In general, cross-resistance to mixed
amine analogues was partial in
cisplatin- and
tetraplatin-resistant cells and decreased (in L1210/DDP and 2780CP) or increased (in L1210/
DACH and 2780TP) with increase in the alicyclic ring size. The increase in ring size resulted in a corresponding increase in partition coefficient, which correlated directly with intracellular accumulations of mixed
amine analogues in all cell lines. However, the intracellular
DNA-
platinum adducts, and not cellular
platinum content, was the pharmacological entity that corresponded closely to potencies of the molecules.
DNA adduct formation was disproportionate to the level of cellular
drug accumulation. For instance, complex C8, which accumulated to the greatest extent in any given cell line, produced adduct levels that were similar to or lower than those produced by C6. A partial explanation for this observation was the demonstrated reduced rate of binding of C8 to
DNA. This study has highlighted the significance of alicyclic ring size in modulating the potency, cross-resistance profile, and biochemical pharmacology of mixed
amine platinum(II) complexes in sensitive and
cisplatin- or
tetraplatin-resistant
tumor cells.