The cytotoxicity of a novel
platinum(IV) complex, bis-acetato-amminedichloro-
cyclohexylamine platinum(IV) (
JM216), has been evaluated in vitro against a panel of human tumor cell lines (predominantly ovarian) representative of models of intrinsic and acquired to
cisplatin. In addition, the activity of
JM216 administered by the p.o. route has been determined in vivo using the murine ADJ/
PC6 plasmacytoma and four human ovarian
carcinoma xenograft lines. In vitro, against seven human ovarian
carcinoma cell lines,
JM216 showed similar cytotoxicity and pattern of cytotoxicity to
cisplatin (mean 50% inhibitory concentrations of 3.5 microM for
cisplatin and 1.7 microM for
JM216). The cytotoxicity of
JM216 was more dependent on the time of
drug exposure than that of
cisplatin, suggesting that extended split-dosing rather than a single bolus administration might be a more appropriate schedule in patients. Using six pairs of acquired
cisplatin-resistant and parent human tumor cell lines (four ovarian, one testicular, and one cervical)
JM216 exhibited non-cross-resistance (resistance factor of < 1.5) in three whereas
tetraplatin exhibited partial or full cross-resistance in all six pairs. Notably, in two of the acquired
cisplatin-resistant lines (41McisR and HX/155cisR) where
JM216 retained activity, resistance has previously shown to be due primarily to reduced
platinum uptake. In vivo, following p.o. administration using the
cisplatin-sensitive murine ADJ/
PC6 plasmacytoma,
JM216 showed antitumor selectivity far superior to that observed for either
cisplatin,
carboplatin, or
tetraplatin. Across four human ovarian
carcinoma xenografts of widely differing sensitivity to
cisplatin and
carboplatin,
JM216 exhibited p.o. activity, broadly comparable to that observed for i.v. administered
cisplatin and
carboplatin and markedly superior to i.p. administered
tetraplatin. These antitumor properties suggest that
JM216 provides a structural lead to
platinum complexes which may circumvent transport-determined acquired resistance to
cisplatin and is a suitable candidate as an p.o. administrable
platinum complex for phase I clinical trial.