In vitro antitumor mechanism of a new platinum complex, (-)-(R)-2-aminomethylpyrrolidine(1,1-cyclobutanedicarboxylato+ ++) platinum(II).
The antitumor mechanism of (-)-(R)-2- aminomethylpyrrolidine (1.1-cyclobutanedicarboxylato)platinum(II) (DWA2114R) was examined using cultured murine L1210 leukemia cells by estimating its effects on parameters such as proliferation, macromolecular synthesis, morphology and cell cycle progression. Each parameter was estimated in cells concomitantly exposed to the drug for 24-48 hr. More than 0.1 microM of DWA2114R markedly inhibited cell proliferation as well as DNA synthesis, and it decreased in mitotic index in a concentration-dependent manner. One microM of DWA2114R decreased DNA synthesis by 80% in the cells treated for 24 hr, while the inhibition of RNA synthesis was less than 40%. A significant inhibition of protein synthesis was caused only by treatment with a high concentration (100 microM) of the drug. Under complete cytostatic conditions (10 microM of DWA2114R), cell volume markedly increased and about 40% of the total cells were polynucleate. In addition, flow cytometrical analysis revealed that most of these cells were accumulated in the G2/M phase of the cell cycle, and a new peak located in the G2/M phase of tetraploid cells emerged. On the other hand, the cells treated with 100 microM of the drug did not increase in volume and their progress in the cell cycle was almost completely blocked.
Akamatsu
K
K
Exploratory Research Laboratories, Chugai Pharmaceutical Co., Ltd., Gotemba, Japan.
Endo
K
K
Matsumoto
T
T
Morikawa
K
K
Koizumi
M
M
Mitsui
H
H
Koizumi
K
K
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016190:Carboplatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004273:DNA, Neoplasm / Q000032:analysis / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005434:Flow Cytometry; D007700:Kinetics; D007939:Leukemia L1210 / Q000473:pathology; D051379:Mice
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; C058816:DWA 2114; D016190:Carboplatin