Dasatinib sensitizes primary chronic lymphocytic leukaemia lymphocytes to chlorambucil and fludarabine in vitro.

[Guest guest]

Dasatinib sensitizes primary chronic lymphocytic leukaemia lymphocytes to

chlorambucil and fludarabine in vitro.

L Amrein, TA , C Ferrario, J ston, SB Gibson, L Panasci, and R

Aloyz

Br J Haematol, December 1, 2008; 143(5): 698-706.

Lady Institute for Medical Research-Cancer Segal Center, Sir MB

-Jewish General Hospital, Montreal, Canada

The dual c-abl/Src kinase inhibitor, dasatinib, utilized to treat chronic

myeloid leukaemia (CML) when used at clinically attainable sublethal

concentrations, synergistically sensitized primary chronic lymphocytic leukaemia

(CLL) lymphocytes to chlorambucil and fludarabine. In contrast, dasatinib alone

demonstrated toxicity to CLL lymphocytes at concentrations that are generally

not clinically attainable. Dasatinib resistance and poorer dasatinib-mediated

sensitization to chlorambucil and fludarabine was associated with higher

expression of c-abl protein levels. In contrast, chlorambucil and fludarabine

resistance correlated with basal p53 protein levels. Moreover, Western blot

analysis after in vitro treatment of primary CLL lymphocytes with dasatinib,

chlorambucil and/or fludarabine, showed that dasatinib: (i) inhibited c-abl

function (e.g. downregulation of c-abl protein levels and decreased the

phosphorylation of a c-abl downstream target, Dok2), (ii) decreased

chlorambucil/fludarabine induced accumulation of p53 protein levels, (iii)

altered the response to chlorambucil/fludarabine induced DNA-damage as evidenced

by an increase in chlorambucil/fludarabine-induced H2AX phosphorylation, and

(iv) accentuated the c-abl downregulation induced by chlorambucil/fludarabine.

Our results suggest that dasatinib in combination with chlorambucil or

fludarabine may improve the therapy of CLL.

PMID: 19062342