Methotrexate cytotoxicity as related to irreversible S phase arrest in mouse L1210 leukemia cells.
The association between cytotoxicity and cell cycle perturbation caused by methotrexate (MTX) was investigated in mouse L1210 leukemia cells by flow cytometric bromodeoxyuridine/DNA assay. In the range of concentrations of MTX from 10(-7) M to 10-6) M, in vitro exposure to the drug for 6 h caused a dose-dependent suppression of clonal growth of the tumor cells and S phase arrest in the cycle progression, resulting in an accumulation of cells in early S phase, in which they showed no definite increase of DNA content above G1 levels. The surviving fraction of the clonogenic cells corresponded with the fraction of cells which recovered from the S phase arrest in MTX-free medium. In mice bearing L1210 ascites tumors, a bolus injection of MTX caused the S phase arrest of the tumor cells as shown in suspension cultures, and cytokinetic recovery was observed in parallel with the regrowth of the tumor. These results showed that irreversible S phase arrest is a critical cytokinetic event associated with the cytotoxicity of MTX.
Tsurusawa
M
M
Department of Pediatrics, Aichi Medical University.
Niwa
M
M
Katano
N
N
Fujimoto
T
T
D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D005434:Flow Cytometry; D007399:Interphase / Q000187:drug effects*; D007939:Leukemia L1210 / Q000188:drug therapy*; D008727:Methotrexate / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D014407:Tumor Cells, Cultured
D004247:DNA; D001973:Bromodeoxyuridine; D008727:Methotrexate