Ammine/amine platinum (II) complexes effective in vivo against murine tumors sensitive or resistant to cisplatin and tetraplatin

Abstract

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%). Longterm 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.