Theophylline Synergizes With Chlorambucil in Inducing Apoptosis

We tested the effects of theophylline, a phosphodiesterase inhibitor inducing intracellular accumulation of cyclic adenosine monophosphate (CAMPI, 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% ~ 2 0 % in medium alone) in the presence of theophylline (100 pglmL) or chlorambucil (10 pmollL) 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 CB++ influx, pointing to the involvement of two signaling pathways that might explain its syn-