MECHANISMS OF RESISTANCE TO CHLORAMBUCIL IN CHRONIC LYMPHOCYTIC-LEUKEMIA

The postulated biochemical mechanisms responsible for clinical resistance to chlorambucil (CLB) in chronic lymphocytic leukemia (CLL) have been examined. The total sulfhydryl, non-protein-bound sulfhydryl, protein-bound sulfhydryl (PSH) and glutathione (GSH) levels, in addition to glutathione S-transferase (GST) activities, were measured in the leukemic cells of 18 CLL patients. In addition, the formation and repair of DNA cross-links were measured following incubation of the cells with 100-mu-M chlorambucil in vitro. These parameters were then correlated with the subsequent clinical responses of the patients, as measured by the percent fall in lymphocyte count 3 weeks following 0.9 mg/kg chlorambucil. No correlations were observed between any of the individual parameters and clinical response, although a slight positive correlation was observed between the PSH:GSH ratio and clinical response. These findings suggest that multiple mechanisms may contribute to CLB-resistance in CLL.