Bax Expression and Responsiveness to Chemo

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: Leukemia 2002 Jun;16(6):1035-44

Bax expression correlates with cellular drug

sensitivity to doxorubicin, cyclophosphamide and

chlorambucil but not fludarabine, cladribine or

corticosteroids in B cell chronic lymphocytic

leukemia.

Bosanquet AG, Sturm I, Wieder T, Essmann F, Bosanquet

MI, Head DJ, Dorken B, PT.

Bath Cancer Research, Royal United Hospital, Bath,

Department of Medical Sciences, University of Bath,

Bath, UK.

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 < 0.04).

Surprisingly, no such relationship was observed for

the purine nucleoside analogs or corticosteroids (all

P > 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.

PMID: 12040435 [PubMed - in process]

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