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Cancer Res. 1988 Aug 1;48(15):4288-93.

Flow cytometric analysis by bromodeoxyuridine/DNA assay of cell cycle perturbation of methotrexate-treated mouse L1210 leukemia cells.

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Department of Pediatrics, Aichi Medical University, Japan.


The in vitro effects of methotrexate (MTX) on cell cycle progression and DNA synthesis of L1210 leukemia cells were studied by the bromodeoxyuridine (BrdUrd)/DNA analysis technique. Low dose (10(-8) M) MTX, which slightly inhibits clonal replication of the cells, delays progress across the S phase, and treatment for 24 h results in a slight increase of the S-phase population. Much higher doses (10(-7) M and 10(-6) M) of MTX, which strongly reduce the clonogenicity, prevented the progression of cells at the G1-S boundary and across the S phase, but not in the other phases. The cells arrested at the G1-S boundary were able to incorporate BrdUrd in the medium for 6-12 h after the start of treatment and then lost the ability to incorporate BrdUrd. By determining the colony inhibitory activity of MTX, it could be shown that not only S-phase cells but non-S-phase cells are susceptible to cytotoxicity of MTX. MTX-induced S-phase arrest is closely associated with an alteration in the distribution of BrdUrd-labeled cells, and MTX apparently inhibits BrdUrd incorporation into L1210 cells as the dose and duration of treatment increase. These results suggest that MTX-induced cell cycle perturbation is related to inhibition of DNA synthesis.

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