Preclinical antitumor evaluation of bis-acetato-ammine-dichloro-cyclohexylamine platinum(IV): an orally active platinum drug.
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.
Drug Development Section, Institute of Cancer Research, Belmont, Sutton, Surrey, United Kingdom.
L R
LR
Kelland
G
G
Abel
M J
MJ
McKeage
M
M
Jones
P M
PM
Goddard
M
M
Valenti
B A
BA
Murrer
K R
KR
Harrap
D000818:Animals; D016190:Carboplatin / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007939:Leukemia L1210 / Q000188:drug therapy; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy*; D009373:Neoplasms, Germ Cell and Embryonal / Q000188:drug therapy; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy; D010954:Plasmacytoma / Q000188:drug therapy; D013736:Testicular Neoplasms / Q000188:drug therapy; D013997:Time Factors; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy
D009944:Organoplatinum Compounds; C081294:satraplatin; D016190:Carboplatin; D002945:Cisplatin; C049777:ormaplatin