Correlation of Bcl-2 with P-Glycoprotein Expression in Chronic Lymphocytic Leukaemia and Other Haematological Neoplasms but of Neither Marker with<i>Ex Vivo</i>Chemosensitivity or Patient Survival

Bosanquet, Andrew G.; Bell, Philip B.; Burlton, Alison R.; Amos, Tim

doi:10.3109/10428199609045722

Cited by 11 publications

(7 citation statements)

References 20 publications

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“…[48][49][50] The role of the Bcl-2 family of proteins in chemoresponse has been evaluated extensively using in vitro models and it is still a matter of dispute whether individual members of the Bcl-2 family influence drug sensitivity of B-CLL cells in vitro. 3,25 Previous studies support our finding that Bcl-2 is not an important determinant of response to purine nucleoside analogs in B-CLL 51,52 perhaps because cladribine and fludarabine may directly activate the downstream apoptosis cascade, 34,35 ie the caspases 37,53 or other proteases 54,55 which are related to apoptotic and other modes of cell death. 56 That fludarabine and cladribine do not make use of the Bcl-2/Bax pathway is consistent with their efficacy in patients resistant to the traditional therapies.…”

Section: Leukemiasupporting

confidence: 77%

Bax expression correlates with cellular drug sensitivity to doxorubicin, cyclophosphamide and chlorambucil but not fludarabine, cladribine or corticosteroids in B cell chronic lymphocytic leukemia

et al. 2002

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In B-CLL, non-proliferating B cells accumulate due to defective apoptosis. Cytotoxic therapies trigger apoptosis and deregulation of apoptotic pathways contributes to chemoresistance. Loss of the apoptosis-promoting Bax has been implicated in resistance to cytotoxic therapy. We therefore evaluated ex vivo drug sensitivity of CLL, producing chemoresponse data which are prognostic indicators for B-CLL, in particular in the case of purine nucleoside analogs. To analyze the underlying mechanisms of drug resistance, we compared endogenous Bax and Bcl-2 expression to ex vivo response to eight drugs, and to survival in 39 B-CLL patients. We found that reduced Bax levels correlated well with ex vivo resistance to traditional B-CLL therapies -anthracyclines, alkylating agents and vincristine (all P Ͻ 0.04). Surprisingly, no such relationship was observed for the purine nucleoside analogs or corticosteroids (all P Ͼ 0.5). Mutational analysis of p53 could not explain the loss of Bax protein expression. Levels of Bcl-2 were not associated with sensitivity to any drug. In contrast to the ex vivo data, neither Bax or Bcl-2 expression nor doxorubicin sensitivity were associated with increased survival whereas sensitivity to fludarabine correlated with better overall survival (P = 0.031). These findings suggest that the resistance to purine nucleoside analogs and corticosteroids in B-CLL is due to inactivation of pathways different from those activated by anthracyclines, vinca alkaloids and alkylating agents and may be the molecular rationale for the efficacy of purine analogs in this disease.

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Section: Leukemiasupporting

confidence: 77%

Bax expression correlates with cellular drug sensitivity to doxorubicin, cyclophosphamide and chlorambucil but not fludarabine, cladribine or corticosteroids in B cell chronic lymphocytic leukemia

et al. 2002

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“…This may be in some small part due to the use of¯udarabine in other chemotherapy later on and in part due to drug cross-resistance attributable to pleiotropic drug sensitivity in some untreated patients and pleiotropic drug resistance (but not multidrug resistance, MDR (Bosanquet et al, 1996)) in patients with advanced CLL. (Thus, patients test-resistant tō udarabine are more likely to be test-resistant to other CLL therapies.)…”

Section: Discussionmentioning

confidence: 99%

Prognosis for fludarabine therapy of chronic lymphocytic leukaemia based on ex vivo drug response by DiSC assay

Bosanquet

Johnson

Richards³

1999

Br J Haematol

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The cytotoxic antimetabolite fludarabine is a widely used active agent in chronic lymphocytic leukaemia (CLL). However, cost and occasional adverse side‐effects necessitate careful use. Identifying before treatment patients not likely to benefit from fludarabine could advance disease management both clinically and financially. We used the DiSC (differential staining cytotoxicity) assay, an ex vivo apoptotic drug response test, to identify the sensitivity or resistance to fludarabine of lymphocytes from B‐cell CLL patients and compared the results with subsequent patient treatment, response and survival. Patients were grouped thus: those receiving fludarabine within 1 year of assay (± other cytotoxic drugs), and those receiving other chemotherapy (excluding fludarabine) within 1 year of assay. Fludarabine‐test‐resistance was found in 12/100 (12%) of untreated patients and 45/143 (31%) of previously treated patients (17/32 (53%) of patients previously treated with fludarabine). Treating fludarabine‐test‐resistant patients with fludarabine resulted in poor response compared with fludarabine‐test‐sensitive patients (7% v 69%) and short survival (median 7.9 v 41.7 months; relative risk (RR) = 14.8; P < 0.0001). 81% of fludarabine‐test‐resistant patients were test sensitive to other regimens. If treated with chemotherapy other than fludarabine, test‐resistant patients responded better and survived substantially longer than those treated with fludarabine (RR = 2.9; P = 0.001). Not all CLL patients should receive fludarabine. Fludarabine‐test‐resistance by DiSC assay is a powerful independent prognostic factor. Pretreatment DiSC assay results could enable the toxic, clinical and financial costs of fludarabine treatment to be avoided in fludarabine‐test‐resistant patients. Disease management, response, survival and use of financial resources might be significantly improved if therapy choice in CLL patients was guided by DiSC assay.

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“…The phenomenon of MDR + phenotype seems to be more frequent in males than in females with CLL (66) and this may link with the proposed better survival likelihood in women. However, an MDR + phenotype in CLL does not appear to correlate with either staging and clinical parameters (66,72), and/or in vivo or in vitro sensitivity to drugs (73). Expression of p-glycoproteins has been documented in CD19 + CD5 + B cells from tonsils and blood in normal individuals (71,74), and it has been suggested that p-glycoprotein expression may be an inherent characteristic of CLL cells.…”

Section: Multidrug Resistance Phenotypementioning

confidence: 99%

Morphological and Immunophenotypic Features of Chronic Lymphocytic Leukemia

Matutes

Polliack²

2000

Rev Clin Exp Hematol

110

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In this review, we summarize the morphological features and immunophenotypic profile of chronic lymphocytic leukemia (CLL) cells, discuss the value of these investigations as front line diagnostic tests, and emphasize their correlation with the clinical features, disease progression, molecular genetics and pathogenesis of CLL. In CLL, the morphology of the circulating cells is characteristic and typical in the majority of cases. However, 15% of patients, either at diagnosis or during the course of the disease, show atypical morphology reflected by either (1) an increased (> 10%) number of circulating prolymphocytes, designated CLL/PL, or (2) an increased (> 15%) number of circulating lymphoplasmacytic and cleaved cells, designated 'atypical' CLL. There is strong evidence of a close association between atypical morphology (CLL/PL) and atypical (CLL) and clinical features, e.g. disease progression, advanced stage and survival, molecular genetics, particularly trisomy 12, but also the rare cases with t(11;14) or t(14;19), p53 abnormalities, unmutated immunoglobulin (Ig) VH genes and origin of the cell (naive, pregerminal center cell). CLL cells have a distinct immunological repertoire different from that of other lymphoproliferative disorders. The typical CLL phenotype is CD5+, CD23+, FMC7-, weak expression of surface Ig (sIg) and weak or absent expression of membrane CD22 and CD79b. The latter marker identifies an extracellular epitope of the B-cell receptor (BCR) beta chain and its weak or absent expression in CLL may derive from the expression of a truncated form. This, together with the low expression of CD22, might explain the abnormal signal transduction of CLL cells similar to that of anergic B lymphocytes. Because no single marker is specific for CLL, a composite phenotype considering this set of 5 or 6 markers compounded into a scoring system helps to distinguish CLL from the other B-cell malignancies. Immunophenotypic analysis has also been shown to be useful for minimal residual disease detection and adds valuable prognostic information because the expression of certain markers, such as FMC7 or CD38, seems to be associated with a poor outcome. In addition, CLL cells express a variety of Bcl-2 family proteins with a profile that favors inhibition of apoptosis which, together with the interaction with microenvironmental (e.g. stromal) cells and the release of cytokines, explains the long life span and subsequent accumulation of CLL cells in various organs. Despite controversies relating to the expression of adhesion molecules (selectins and integrins) in CLL cells, it appears that some of these molecules do play a role in the pathogenesis, biology and clinical patterns of the disease. In conclusion, morphology and immunophenotype are the two essential investigations, which must be carried out in all cases of CLL. Both provide relevant information in terms of diagnosis, course of the disease, prognosis and pathogenesis.

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Correlation of Bcl-2 with P-Glycoprotein Expression in Chronic Lymphocytic Leukaemia and Other Haematological Neoplasms but of Neither Marker withEx VivoChemosensitivity or Patient Survival

Cited by 11 publications

References 20 publications

Bax expression correlates with cellular drug sensitivity to doxorubicin, cyclophosphamide and chlorambucil but not fludarabine, cladribine or corticosteroids in B cell chronic lymphocytic leukemia

Bax expression correlates with cellular drug sensitivity to doxorubicin, cyclophosphamide and chlorambucil but not fludarabine, cladribine or corticosteroids in B cell chronic lymphocytic leukemia

Prognosis for fludarabine therapy of chronic lymphocytic leukaemia based on ex vivo drug response by DiSC assay

Morphological and Immunophenotypic Features of Chronic Lymphocytic Leukemia

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