Nucleoside Analogues in Leukaemia
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Group Leader Françoise Bontemps Eric Van Den Neste Contact Françoise Bontemps de Duve Institute and Université catholique de Louvain BCHM-GRM 75-39, 75 avenue Hippocrate B-1200 Brussels phone: 32 (0)2 764 75 68 fax: 32 (0)2 764 75 98 e-mail: Françoise Bontemps Eric Van Den Neste Group members > |
Research topics
The nucleoside analogues (NA) 2-chlorodeoxyadenosine and fludarabine are therapeutically active in chronic lymphoid malignancies, and especially in B-cell chronic lymphocytic leukaemia (B-CLL). Despite this activity, clinical resistance to these drugs is frequently observed. The main objectives of our group are to unravel the mechanism(s) leading to resistance to NA, and to find novel therapeutic strategies to counteract them. Our current investigations aim at (1) providing new insights into the mechanisms by which NA induce cell death and (2) studying the regulation of deoxycytidine kinase activity, a key enzyme for the activation of NA.
1. Mechanisms of action of nucleoside analogues: To exert their antileukaemic effect, NA have to be converted into triphosphate derivatives. The latter disturb DNA synthesis, leading to DNA lesions and to apoptosis by mechanisms that are not yet entirely understood. We currently analyse the effects on NA on various signalling pathways that could play a role in NA-induced cell death.
2. Deoxycytidine kinase: This enzyme catalyses the first and limiting step of the activation of numerous NA and plays thus a key role in their efficacy. We are interested in this enzyme because diminished activity of deoxycytidine kinase is a potential cause of resistance to NA. We are focusing on its activation by phosphorylation of Ser-74, a post-translational modification we have recently identified.
