Fludarabine and Gemcitabine interaction with Cytosine-arabinoside on human acute myeloid leukemia cells

We compared the effects of Fludarabine (F-Ara-A) and Gemcitabine (dFdC) on Cytosine Arabinoside (Ara-C) uptake and retention on human acute myeloid leukemia cells, employing HL-60 cell line as a model. Cells were exposed to either drugs (10 mu M) for 3 hrs and further incubated with [H-3]-Ara-C (5 mu M), immediately (day 0) or after 24 hrs culture in drug free medium (day 1). At day 0 F-Ara-A caused a significant (p < 0.01) increase in Ara-C uptake with respect to control and cytoplasmic Ara-C peaked after 180 min of exposure, as well as nuclear bound Ara-C. At the same time, a significant decrease in the number of S-phase leukemic cells was observed. At day 0 dFdC did not have potentiating effects on Ara-C uptake, but it showed a high degree of intrinsic cytotoxicity as demonstrated by cell cycle distribution, plating efficiency (PE) and percentage of apoptotic cells. At day 1 cells exposed to dFdC showed a significant increase of Ara-C uptake and a reduced number of S-phase cells, a decrease of PE, as well as an increase of apoptotic cell death. Ara-C uptake by leukemic cells call be modulated with dFdC, similarly to F-Ara-A, but the kinetic and time of efficacy are different for the two drugs. dFdC could be considered a suitable candidate for Ara-C association therapy in acute leukemia.