IN-VITRO CYTOTOXICITY OF 2-CHLORODEOXYADENOSINE AND CHLORAMBUCIL IN CHRONIC LYMPHOCYTIC-LEUKEMIA

Chronic lymphocytic leukemia (CLL) is most commonly treated with the a lkylating agent chlorambucil (CLB), although the nucleoside analogs, f ludarabine (Flu) and 2-chlorodeoxyadenosine (CdA), are also effective in this disease. In this study, we investigated the in vitro cytotoxic ity of CdA and CLB in CLL cells from 12 patients in vitro. Treatment w ith CLB for 6 h, followed by CdA for 18 h, resulted in 2.3- to 7.5-fol d synergistic cytotoxicity in leukemic cells from 10 patients and an a dditive effect in cells from two patients. In general, synergy was gre atest in patients who were sensitive to CLB or CdA, and could be enhan ced by increasing the concentrations of CLB or CdA. Synergy was only o bserved if the cells were treated with CLB prior to CdA. Synergy could not be explained by an increase In the incorporation of CdA into DNA, or by the inhibition of repair of CLB-induced DNA crosslinks by CdA. In contrast to CLL cells, treatment of human marrow in vitro with CLB and CdA resulted in a low level of synergy for CFU-GM cells, and addit ive cell kill in erythroid progenitors. Thus, treatment with CdA and C LB can produce selective synergistic cell kill in CLL cells, and combi nation therapy may improve the therapeutic index of these agents in ch emosensitive patients.