HUMAN MONOCYTOID LEUKEMIA-CELLS ARE HIGHLY SENSITIVE TO APOPTOSIS INDUCED BY 2'-DEOXYCOFORMYCIN AND 2'-DEOXYADENOSINE - ASSOCIATION WITH DATP-DEPENDENT ACTIVATION OF CASPASE-3

The adenosine deaminase (ADA) inhibitor 2'-deoxycoformycin (dCF) signi ficantly inhibits the proliferation of leukemia and lymphoma cell line s, When cells were incubated in the presence of both dCF and 2'-deoxya denosine (dAd), the concentration of dCF required to induce apoptosis of monocytoid leukemia cells was much lower than that required for mye loid, erythroid, or lymphoma cell lines. Among the cell lines tested, U937 cells were the most sensitive to this treatment. The concentratio n of dCF that effectively inhibited the proliferation of U937 cells wa s 1/1,000 of that required for lymphoma cell lines, on a molar basis. However, the uptake of dCF or dAd in U937 cells was comparable with th at in other leukemia and lymphoma cell lines, The intracellular accumu lation of dATP in U937 cells was only slightly higher than that in oth er leukemia cells in dCf-treated culture. Treatment with dCF plus dAd induced apoptosis in U937 cells at low concentrations, and this apopto sis was reduced by treatment with caspase inhibitors. Induction of cas pase-3 (CPP32) activity accompanied the apoptosis induced by dCF plus dAd, No activation of CPP32 was observed in cytosol prepared from expo nentially growing leukemia and lymphoma cells. However, dATP effective ly induced CPP32 activation in cytosol from monocytoid cells, but not in that from nonmonocytoid cells, suggesting that dATP-dependent CPP32 activation is at least partly involved in the preferential induction of apoptosis in monocytoid leukemia cells. The combination of dCF and dAd may be useful for the clinical treatment of acute monocytic leukem ia. (C) 1998 by The American Society of Hematology.