Enhancement of the Cytotoxicity of Cytosine Arabinoside by Interleukin-3

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Abstract
We have evaluated the feasibility of enhancing the cytotoxic effect of cytosine arabinoside (ara‐C) on acute myeloid leukemia (AML) cells by increasing the proliferative activity with hematopoietic growth factors. Leukemic cells from 8 persons with AML were tested. Preincubation with interleukin (IL)‐3 (5 U/ml) for 3 days increased DNA synthesis as measured by tritiated thymidine incorporation and Ki67 expression in cells from 7 out of 8 persons with AML, Leukemic cells preincubated with IL‐1 (10 U/ml) or IL‐3 (5 U/ml) were subsequently exposed to ara‐C (3μg/ml) for the final 24 h and the activity of ara‐C against clonogenic acute myeloid leukemia cells was evaluated in terms of the inhibition of colony formation in semisolid media. The exposure to ara‐C inhibits the proliferation of a higher proportion of clonogenic cells in culture pretreated with IL‐3 than in control or cells pretreated with IL‐1. The enhanced cytotoxic effect of ara‐C in the cells pretreated with IL‐3 correlated with increased formation of intracellular ara‐CTP. IL‐3‐induced recruitment of quiescent blasts into the proliferative compartment will lead to increased formation of ara‐CTP in the cells, which would result in an enhanced leukemia cell kill.

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