pentostatin and Leukemia--Monocytic--Acute

Although 2'-deoxycoformycin (dCF) has been reported in clinical trials to be less effective against myeloid than lymphoid malignancies, it may be useful for treating monocytic leukemia with the aid of 2'-deoxyadenosine (dAd) analogs. In the presence of 10 microM dAd, the concentration of dCF required to inhibit the viability of monocytoid leukemia cells was much lower than that required on normal or non-monocytoid malignant cells in primary culture. Among the dAd analogs, 9-beta-D-arabinofuranosyladenine (AraA) was also effective in combination with dCF. Although dCF alone slightly but significantly prolonged the survival of mice inoculated with U937 monocytic leukemia cells, combined treatment with dCF and AraA markedly prolonged the survival. These results suggest that the combination of dCF and AraA may be useful for the clinical treatment of acute monocytic leukemia.

Topics: Animals; Antibiotics, Antineoplastic; Antimetabolites; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Dose-Response Relationship, Drug; Humans; Leukemia, Monocytic, Acute; Pentostatin; Vidarabine

2'-Deoxycoformycin (dCF) as a single agent has been reported to be less effective against myeloid than against lymphoid malignancies in clinical trials. However, previous studies have shown that in the presence of 2'-deoxyadenosine (dAd), human monocytoid leukemia cell lines are much more sensitive to dCF with regard to the inhibition of cell proliferation. Thus, dCF might be useful for treating monocytoid leukemia with the aid of dAd analogs. The antiproliferative effects of dCF in combination with dAd or its derivatives were examined on normal and malignant blood and bone marrow cells. In the presence of 10 micromol/L dAd, the concentration of dCF required to inhibit the viability of primary monocytoid leukemia cells was much lower than that required to inhibit normal or non-monocytoid leukemic cells. Among the dAd analogs, 9-beta-D-arabinofuranosyladenine (AraA) was also effective in combination with dCF. Athymic nude mice were inoculated with human monocytoid leukemia U937 cells and treated with dCF or a dAd analog or both. Although dCF alone slightly but significantly prolonged the survival of mice inoculated with U937 cells, combined treatment with dCF and AraA markedly prolonged their survival. These data suggest that the combination of dCF and AraA may be useful for the clinical treatment of acute monocytic leukemia. (Blood. 2000;96:1512-1516)

Topics: Animals; Antibiotics, Antineoplastic; Antimetabolites; Cell Survival; Humans; Leukemia, Monocytic, Acute; Mice; Mice, Nude; Pentostatin; U937 Cells; Vidarabine

The adenosine deaminase (ADA) inhibitor 2'-deoxycoformycin (dCF) significantly inhibits the proliferation of leukemia and lymphoma cell lines. When cells were incubated in the presence of both dCF and 2'-deoxyadenosine (dAd), the concentration of dCF required to induce apoptosis of monocytoid leukemia cells was much lower than that required for myeloid, erythroid, or lymphoma cell lines. Among the cell lines tested, U937 cells were the most sensitive to this treatment. The concentration of dCF that effectively inhibited the proliferation of U937 cells was 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 that in other leukemia and lymphoma cell lines. The intracellular accumulation of dATP in U937 cells was only slightly higher than that in other leukemia cells in dCF-treated culture. Treatment with dCF plus dAd induced apoptosis in U937 cells at low concentrations, and this apoptosis was reduced by treatment with caspase inhibitors. Induction of caspase-3 (CPP32) activity accompanied the apoptosis induced by dCF plus dAd. No activation of CPP32 was observed in cytosol prepared from exponentially growing leukemia and lymphoma cells. However, dATP effectively 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 leukemia.

Topics: Apoptosis; Caspase 3; Caspases; Cytosol; Deoxyadenine Nucleotides; Deoxyadenosines; Enzyme Activation; Growth Inhibitors; HL-60 Cells; Humans; Leukemia; Leukemia, Monocytic, Acute; Lymphoma; Neoplasm Proteins; Pentostatin; Tumor Cells, Cultured; U937 Cells