Potentiation of chlorambucil toxicity in B-CLL lymphocytes using the DNA synthesis inhibitors aphidicolin and 1-beta-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.
Bramson
J
J
Lady Davis Institute for Medical Research of the Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, Canada.
Panasci
L
L
D016590:Aphidicolin / Q000494:pharmacology*; D002699:Chlorambucil / Q000494:pharmacology*; D003561:Cytarabine / Q000494:pharmacology*; D004261:DNA Replication / Q000187:drug effects; D004351:Drug Resistance; D004357:Drug Synergism; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000473:pathology*; D008214:Lymphocytes / Q000187:drug effects
D003561:Cytarabine; D002699:Chlorambucil; D016590:Aphidicolin