[Flow cytometric analysis of the effect of DWA2114R on the cell cycle traverse of RPMI 8402 cells--comparison with CDDP].
The (-) - (R) - 2-aminomethylpyrrolidine (1, 1-cyclobutanedicarboxylato) platinum(II) monohydrate, DW A2114R, is a new derivative of cis-dichlorodiammineplatinum(II), CDDP, which is reported to have a lower nephrotoxicity than CDDP. In this report, we investigated the effects of DW A2114R, in comparison with CDDP, on the cell growth, the cell cycle traverse and the colony-forming ability of human leukemia RPMI 8402 cells in vitro. The inhibitory effects of DW A2114R on the cell growth and the colony-forming ability were about 1/10 and 1/10-1/30, respectively, of the CDDP dose. And DW A2114R showed a higher time-dependency than CDDP in the experiment comparing exposure time to the drugs. Analysis of DNA histograms obtained by flow cytometry revealed that DW A2114R had a similar effect on the cell cycle traverse to that of CDDP. Both drugs exerted their growth-inhibitory effect by blocking cells at G2 phase. At higher concentrations, they prolonged the traverse of cells through S phase and completely inhibited them throughout the cell cycle. The comparative study on the colony-forming ability suggested that the G2 phase accumulation was irreversible and that these drugs are lethal, so the G2 phase accumulation could be considered a cytocidal effect of the drugs. In early clinical studies, however, the dose of DW A2114R was put at about 15-fold higher than the therapeutic dose of CDDP. This was comparable with our results in vitro and DW A2114R showed a much lower toxicities, with special regard to nephrotoxicity, than CD DP. These clinical data and our results suggest that DW A2114R could be clinically effective as an antitumor agent.
Takamoto
S
S
Dept. of Transfusion Medicine, Tokyo Metropolitan Komagome Hospital, Japan.
Souma
R
R
D000970:Antineoplastic Agents / Q000494:pharmacology*; D016190:Carboplatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D015458:Leukemia, T-Cell / Q000473:pathology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; C058816:DWA 2114; D016190:Carboplatin; D002945:Cisplatin