Potentiation of chlorambucil toxicity in B-CLL lymphocytes using the DNA synthesis inhibitors aphidicolin and 1-β-d-arabinofuranosylcytosine

Previous studies in our laboratory have identified enhanced cross-link repair as a primary mechanism of resistance to nitrogen mustards in B-cell chronic lymphocytic leukemia (B-CLL). To evaluate the therapeutic potential for modulation of DNA repair by aphidicolin and 1-beta-D-arabinofuranosylcytosine (ara-C), we examined the interaction between these two agents and chlorambucil in lymphocytes from untreated and treated-resistant B-CLL patients. We found that both aphidicolin and ara-C displayed synergy with chlorambucil over a range of inhibitor concentrations. This synergy was not restricted to the resistant samples. Our results indicate that these combinations can enhance the potency of chlorambucil in a clinically relevant model and should be considered for further preclinical and, eventually, clinical trials.