Perturbation of Generation Cycle of Human Leukemic Myeloblasts In Vivo by Methotrexate

Abstract

Abstract The cytokinetic effects of Methotrexate (MTX) on leukemic myeloblasts in vivo in man have been studied, utilizing in vitro and in vivo labeling with 3H-TDR, mitotic index, stathmokinetic index after VCR, measurements of single-cell DNA content, and in vitro labeling with 3H-UDR. It is demonstrated that MTX arrests cells in S for a period (about 20 hr) that corresponds to their DNA synthesis time. This S-phase arresting effect of MTX seems restricted to those cells that are in S at the time of MTX exposure. Cells in G1, G2, and M are not directly influenced by MTX. Some implications of these observations for combination drug therapy and for exploiting differences in the duration of cell cycle phases between leukemic blast cells and differentiating hemopoietic cells to obtain preferential killing of leukemic cells are briefly discussed. In one case, erythroblasts hardly incorporated exogenous TDR and UDR, although their mitotic activity was high. After MTX there was a transient but very pronounced increase in TDR and UDR ultilization. It is suggested that these cells may have had a large intracellular pool of thymidine triphosphate that was temporarily reduced by the action of MTX. Whether these erythroblasts were of leukemic origin remains undecided.