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 represents a major problem in the successful management of the condition. Experimental evidence points to the fact that most chemotherapeutic drugs ultimately exert their cell killing effect through the process of apoptosis. In this study we compared the apoptotic responses of B-CLL cells in vitro following exposure to several chemotherapeutic drugs. We found that there was a correlation between ID50 values for all the drugs under investigation; particularly between Chlorambucil and Fludarabine (P = 0.0002). In addition, we analysed the expression of Bcl-2 and Bax, two proteins pivotal to the regulation of apoptosis, both immediately ex vivo and in viable and apoptotic sub-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 and that modulation of these proteins is essential for the induction of cell death. Furthermore, it seems likely that the superior potency that has been ascribed to Fludarabine is due to it being administered in a more optimised dose. A recently reported clinical trial of Fludarabine against high-dose Chlorambucil supports this view since it showed that both treatment modalities were comparable in terms of response rate and survival times.
Pepper
C
C
Department of Haematology, Llandough Hospital, South Glamorgan, Wales, UK.
Thomas
A
A
Hidalgo de Quintana
J
J
Davies
S
S
Hoy
T
T
Bentley
P
P
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002699:Chlorambucil / Q000008:administration & dosage / Q000494:pharmacology; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005047:Etoposide / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology
D019253:Proto-Oncogene Proteins c-bcl-2; D002699:Chlorambucil; D005047:Etoposide; D004317:Doxorubicin; D014740:Vidarabine; C024352:fludarabine