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Differential Induction of Apoptosis by Fludarabine Monophosphate in
Leukemic B and Normal T Cells in Chronic Lymphocytic Leukemia
Ugo Consoli,
Iman El-Tounsi,
Alex Sandoval,
Virginia Snell,
Hans-Dieter Kleine,
Wendy Brown,
Johnnie R. Robinson,
Francesco DiRaimondo,
William Plunkett, and
Michael Andreeff
From the Section of Molecular Hematology and Therapy, Department of
Hematology, and Department of Clinical Investigations, The University
of Texas M.D. Anderson Cancer Center, Houston; and the Institute of
Hematology, University of Catania, Italy.
Fludarabine (F-ara-A), an adenine nucleoside analog with efficacy in
B-cell chronic lymphocytic leukemia (B-CLL), has also been shown to
have a long-lasting suppressive effect on T lymphocytes. In
heterogeneous clinical samples, apoptosis cannot be detected by
standard methods in small cellular subsets. We developed, therefore, a
combined assay of in situ end-labeling of nicked DNA by terminal deoxynucleotide transferase, with measurements of cellular DNA content
and surface antigens (CD3, CD4, CD8, and CD19) by multiparametric flow
cytometry. This assay was used to determine F-ara-A-induced apoptosis
in different lymphocyte subsets from CLL patients and normal controls
treated with F-ara-A in vitro. Apoptosis was also correlated to bcl-2
protein levels. We observed a direct effect of F-ara-A on both B-CLL
and T lymphocytes. The response to F-ara-A in B-CLL lymphocytes in
vitro was Rai stage-dependent, the early-stages being more responsive
(P = .01). Higher levels of spontaneous apoptosis were
observed in B-CLL lymphocytes from early stage patients
(P = .02). No difference was observed in spontaneous apoptosis of normal T cells in B-CLL, although T lymphocytes in late-stage disease were more sensitive to F-ara-A-induced apoptosis. Incubation with cyclosporin A did not affect B-CLL and T-lymphocyte survival compared with control cultures. Results suggested a direct apoptotic effect of F-ara-A on B-CLL lymphocytes that decreases with
increasing clinical stage. No correlation was found between bcl-2 and
spontaneous or F-ara-A-induced apoptosis. Apoptosis occurred at all
cell-cycle stages and was not restricted to cells in S phase. The
mechanisms of this stage-dependent apoptosis in CLL remain to be
elucidated.
Blood, Vol. 91 No. 5 (March 1), 1998:
pp. 1742-1748
© 1998 by The American Society of Hematology.
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