Potentiation of antitumor effects of cyclophosphamide derivatives in B-chronic lymphocytic leukemia cells by 2-chloro-2 '-deoxyadenosine

Because 2-chloro-2'-deoxyadenosine (CdA) is active in B-chronic lymphocytic leukemia (B-CLL), and may interfere with DNA repair, we investigated the p otentiating effect of CdA on the cytotoxicity induced in vitro in B-CLL lym phocytes by cyclophosphamide (CP) derivatives, which induce DNA damage by D NA cross-linking. Exposure to CdA at clinically achievable concentrations f or 2 h, followed by mafosfamide (MAF) or 4-hydroxycyclophosphamide (4HC) fo r 22 h, resulted in synergistic cytotoxicity in the majority of B-CLL sampl es tested. Synergy between CdA and MAF was observed in cell samples of sens itive/untreated patients, as well as in cells of resistant/pretreated patie nts, particularly at the highest concentrations of MAF. In the cells treate d with CdA and MAF, we observed loss in ATP and hallmarks of apoptosis, as evidenced by cellular morphology and high molecular weight DNA fragmentatio n. The synergy could be explained neither by an influence of MAF on the pho sphorylation of CdA, nor by an increase in the incorporation of CdA into DN A in the presence of MAF. The in vitro synergy between CdA and CP derivativ es provides a rationale for the use of this association in B-CLL patients.