Three homologous series, each differing from the other in the coordinated
amine ligand class, namely alicyclic, heterocyclic or isoaliphatic, were highly effective against wild-type murine
leukemia L1210/0 cells in vivo (T/C = 171%-426% at optimal doses). Of the 13 complexes comprising the three series, 3 were inactive in the
cisplatin-resistant L1210/DDP model, but the other 10 maintained good efficacy (T/C = 131%-167%). Long-term survivors, frequently observed with these complexes in the L1210/0 model, were also seen in the L1210/DDP model but to a lesser extent. In the homologous alicyclic series, which contained six analogs, as the alicyclic ring size increased, potency against L1210/0 and L1210/DDP cells also increased up to
cyclohexylamine, and then declined. Four ammine/alicyclic
amine analogs were evaluated against L1210/
DACH cells, which are cross-resistant to
tetraplatin, and the clinically predictive M5076
reticulosarcoma. Although the congeners were ineffective or minimally effective in prolonging the survival time of L1210/
DACH-bearing mice (T/C = 111%-134%), 20%-40% cure rate was consistently observed and suggested that the compounds possessed a low inherent ability to circumvent resistance in these
tumor cells also. In the solid M5076 model, activity was greatest (
tumor growth delays of about 25 days) for the alicyclic homologs containing the ammine/cyclobutylamine or ammine/
cyclopentylamine carrier
ligand combination. In summary, ammine/
amine platinum (II) analogs have demonstrated promise at the preclinical level in their ability to circumvent acquired resistance, which is a major drawback of
cisplatin use in treating
cancer.