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Blood, Vol. 92 No. 9 (November 1), 1998:
pp. 3368-3375
Human Monocytoid Leukemia Cells Are Highly Sensitive to Apoptosis
Induced by 2 -Deoxycoformycin and 2-Deoxyadenosine:
Association With dATP-Dependent Activation of Caspase-3
Nozomi Niitsu,
Yuri Yamaguchi,
Masanori Umeda, and
Yoshio Honma
From the Department of Chemotherapy, Saitama Cancer Center Research
Institute, Saitama; and the First Department of Internal Medicine, Toho
University School of Medicine, Tokyo, Japan.
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.
© 1998 by The American Society of Hematology.
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