Enhancement of cytosine arabinoside cytotoxicity by granulocyte/macrophage colony-stimulating factor and granulocyte colony-stimulating factor in a human myeloblastic leukemia cell line.

Abstract

Enhancement of the cytotoxicity of cytosine arabinoside (ara‐C) by granulocyte/macrophage colony‐stimulating factor (GM‐CSF) and granulocyte colony‐stimulating factor (G‐CSF), and the mechanisms involved, were studied in the AML‐193 human leukemia cell line. AML‐193 cells require GM‐CSF and G‐CSF(CSFs) for optimum growth, and 24 h deprivation of CSFs decreased DNA synthesis measured in terms of 3H‐thymidine incorporation. The DNA synthesis gradually recovered upon addition of CSFs. To examine the sensitivity to ara‐C under different growth conditions, two groups of cell suspensions, one pretreated with CSFs after 24 h deprivation (CSFs(+) cells), and the other held continuously under CSFs‐free conditions (CSFs(‐) cells), were exposed to 1.0 μg/ml of ara‐C for 16 h. In clonogenic assays, CSFs(+) cells showed higher sensitivity to ara‐C than CSFs(‐) cells. These cell groups showed no significant difference in ara‐C triphosphate accumulation or retention, though the amount of ara‐C incorporated into the acid‐insoluble fraction was two times greater in CSFs(+) cells than CSFs(‐) cells, and that difference became even clearer in the retention pools. These data suggest that the enhancement of cytotoxicity by CSFs was due to the promotion of ara‐C incorporation into DNA as a result of an increase of the cell fraction in the S phase.