Antitumor activity and cellular accumulation of a new platinum complex, (-)-(R)-2-aminomethylpyrrolidine(1,1-cyclobutanedicarboxylato)platinum( II) monohydrate, in cisplatin-sensitive and -resistant murine P388 leukemia cells.
We have examined the cytotoxicity and accumulation of (-)-(R)-2-aminomethylpyrrolidine(1,1-cyclobutanedicarboxylato++ +)platinum(II) monohydrate (DWA2114R) in parent and cisplatin-resistant mouse P388 leukemia cells (P388 and P388/DDP), in comparison with those of cisplatin (CDDP) and carboplatin (CBDCA). The degrees of resistance to CDDP and CBDCA, expressed as the ratio of IC50 for P388/DDP cells to IC50 for P388 cells, were 75-33 and 100-27, respectively, under the conditions of 2-24 h exposure to each drug at a density of 10(6) cells/ml. The corresponding values (25-7) for DWA2114R were relatively low. Accumulations of CDDP and CBDCA were reduced in P388/DDP cells; however, no reduction in accumulation of DWA2114R was observed at various exposure periods and concentrations of the drugs. The accumulations of CDDP in P388 and P388/DDP cells at drug concentrations corresponding to the IC50 values for drug exposure periods of 2-24 h were 0.41-0.97 and 13.1-33.7 ng Pt/10(7) cells, respectively, suggesting that an intracellular mechanism of resistance against CDDP could be activated in P388/DDP cells. P388/DDP cells also showed relatively low resistance to DWA2114R via this mechanism in comparison with CDDP and CBDCA. From the relationship between structure and activity of several Pt-complexes, these different properties of DWA2114R compared with CDDP and CBDCA could be due not only to the differences in carrier ligand structure but also to the properties of the whole molecule associated with the carrier ligand and leaving group.
Kamisango
K
K
Exploratory Research Laboratories, Chugai Pharmaceutical Co. Ltd., Shizuoka.
Matsumoto
T
T
Akamatsu
K
K
Morikawa
K
K
Tashiro
T
T
Koizumi
K
K
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016190:Carboplatin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D002945:Cisplatin / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D007941:Leukemia P388 / Q000188:drug therapy* / Q000378:metabolism; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; C058816:DWA 2114; D016190:Carboplatin; D002945:Cisplatin