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Theophylline synergizes with chlorambucil in inducing apoptosis of B-
chronic lymphocytic leukemia cells
F Mentz, MD Mossalayi, F Ouaaz, S Baudet, F Issaly, S Ktorza, M Semichon, JL Binet and H Merle-Beral
Department of Hematology, Unite Claude-Bernard C20, Pitie-Salpetriere
Hospital, Paris, France.
We tested the effects of theophylline, a phosphodiesterase inhibitor
inducing intracellular accumulation of cyclic adenosine monophosphate
(cAMP), on malignant B cells from 15 patients with B-chronic lymphocytic
leukemia (B-CLL). We observed a large increase in apoptotic cell numbers
(mean, 90% v 20% in medium alone) in the presence of theophylline (100
micrograms/mL) or chlorambucil (10 mumol/L) after 72 hours of incubation.
Maximal apoptosis (90%) was reached after 36 hours when the two drugs were
used together at fourfold lower concentrations, indicating a synergistic
effect; no effect was observed with normal B cells, suggesting that the
combination might have therapeutic interest. Chlorambucil induced
intracellular Ca+2 influx, pointing to the involvement of two signaling
pathways that might explain its synergy with theophylline through their
effects on oncogenes. The expression of bcl-2 protein, a proto-oncogene
inhibiting apoptosis, decreased after incubation with the drugs, while
c-myc, recently described as having a potent role in apoptosis, was
overexpressed. For p53 we observed an overexpression in the presence of
chlorambucil or both theophylline- chlorambucil and a decrease after
theophylline incubation. Chlorambucil- and theophylline-induced apoptosis
was partially inhibited by interleukin-4 (IL-4), which also abrogated the
effects on oncogene expression. These results provide insight into the
mechanisms underlying B-CLL apoptosis and suggest that the theophylline-
chlorambucil combination may be of therapeutic value in this setting.
Volume 88,
Issue 6,
pp. 2172-2182,
09/15/1996
Copyright © 1996 by The American Society of Hematology
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