Mitoxantrone, a topoisomerase II inhibitor, induces apoptosis of B-chronic lymphocytic leukaemia cells

B-chronic lymphocytic leukaemia (B-CLL) is characterized bg the accumulation of long-lived CD5(+) B lymphocytes. The effect of mitoxantrone, a topoisomerase II inhibitor, on B-CLL cells was studied. Treatment of B-CLL cells for 48 h with mitoxantrone (0.5 mu g/ml) induced a decrease in cell viability as determined by MTT assay. The IC50 calculated for the cells of three patients was 0.7 mu g/ml for two of them and 1.4 mu g/ml for the third. In all three patients the maximum effect was observed with 2 mu g/ml. An additive cytotoxic effect was observed when mitoxantrone (0.5 mu g/ml) was combined with fludarabine (5 mu g/ml). Mitoxantrone induced DNA fragmentation and the proteolytic cleavage of poly(ADP-ribose) polymerase (PARP), a marker of the activation of caspases, in all the patients studied, demonstrating that the cytotoxic effect of mitoxantrone was due to induction of apoptosis. These results suggest that mitoxantrone, and possibly other topoisomerase II inhibitors, mali be used in the chemotherapy of B-CLL, and that combination of mitoxantrone with fludarabine or other drugs could improve the effectiveness of the treatment.