A CELL-CULTURE MODEL FOR THE TREATMENT OF ACUTE MYELOBLASTIC-LEUKEMIAWITH FLUDARABINE AND CYTOSINE-ARABINOSIDE

The purpose of this paper was to ascertain whether results obtained in cell cultures of AML clonogenic blast cells would provide a useful mo del for a clinical regimen that combines fludarabine (F-ara-AMP) and c ytosine arabinoside (ara-C). In the cultures the nucleoside F-ara-A wa s used. Blast cells from the continuous lines OCI/AML-2 and OCI/AML-3 were grown, either in methylcellulose to quantify clonogenic cells, or in suspension to measure self-renewal as reflected in changes in numb ers of clonogenic cells. F-ara-A, like ara-C, was found to be more tox ic to blast stem cells in suspension than in the clonogenic assay, ind icating that F-ara-A might, in addition to general cytotoxicity, have some specific inhibitory effects on self-renewing stem cells. F-ara-A was less cytotoxic than ara-C; but, when F-ara-A was given before ara- C, synergism was seen at some F-ara-A doses, as manifested by increase d ara-C cytoxicity. In contrast, when ara-C was given before F-ara-A, protection was observed. Control experiments make it unlikely that thi s effect is related to changes in the cell cycle following ara-C expos ure. We conclude that the cellular studies reported here confirm previ ous pharmacological data indicating that F-ara-A before ara-C increase s the effectiveness of ara-C by increasing the accumulation of ara-CTP . However the present experiments show that the synergism between F-ar a-A and ara-C is dependent on both dose and schedule.