Pleiotropic drug resistance in B-cell chronic lymphocytic leukaemia - the role of Bcl-2 family dysregulation

B-cell chronic lymphocytic leukaemia (B-CLL) is an incurable clonal disease which shows initial responsiveness to a number of chemotherapeutic drugs. However, most treated patients become resistant to treatment and this repre sents a major problem in the successful management of the condition. Experi mental evidence points to the fact that most chemotherapeutic drugs ultimat ely exert their cell killing effect through the process of apoptosis. In th is study we compared the apoptotic responses of B-CLL cells in vitro follow ing exposure to several chemotherapeutic drugs. We found that there was a c orrelation between ID50 values for all the drugs under investigation; parti cularly between Chlorambucil and Fludarabine (P = 0.0002), In addition, we analysed the expression of Bcl-2 and Bax, two proteins pivotal to the regul ation of apoptosis, both immediately ex vivo and in viable and apoptotic su b-populations following exposure to drug. Our data suggest that high Bcl-2/ Bax ratios may be predictive of a drug resistant phenotype in B-CLL cells a nd that modulation of these proteins is essential for the induction of cell death. Furthermore, it seems likely that the superior potency that has bee n ascribed to Fludarabine is due to it being: administered in a more optimi sed dose. A recently reported clinical trial of Fludarabine against high-do se Chlorambucil supports this view since it showed that both treatment moda lities were comparable in terms of response rate and survival times. (C) 19 99 Elsevier Science Ltd. All rights reserved.