1. Mechanisms of action of nucleoside analogues
Fludarabine and 2-chlorodeoxyadenosine (CdA) are two deoxyadenosine analogues. To exert their antileukaemic effects, these nucleoside analogues (NA), which mimic deoxyadenosine in term of uptake and metabolism, have to enter lymphocytes and to be phosphorylated by deoxycytidine kinase into NA monophosphates, followed by conversion into NA di- and triphosphates. The latter are considered as the active metabolites of NA. They inhibit various enzymes involved in DNA synthesis, including ribonucleotide reductase and DNA polymerase α, and can be incorporated in replicating or repairing DNA, causing DNA breaks. Moreover, the triphosphate derivatives of fludarabine and CdA disrupt mitochondrial membrane potential. All these effects result in apoptosis by mechanisms that are not yet entirely understood (Van Den Neste et al, Int J Oncol, 2005). To improve our understanding of the mechanisms by which CdA and fludarabine induce apoptosis, we are analysing their effects in cell lines derived from lymphocytes of patients with B-CLL. We are currently studying the effects of CdA and fludarabine on proteins involved in the regulation of cell cycle.
Structures of deoxyadenosine and analogues
Despite remarkable efficacy, a sizeable proportion of patients with B-CLL either does not respond to CdA or fludarabine, or relapses after treatment within a few years. Resistance to a chemotherapeutic agent may arise from (1) inefficient cellular uptake, (2) reduced intracellular activation, (3) repair of induced DNA damage, or finally (4) be the consequence of a defective induction of apoptosis. To identify mechanisms that could be involved in the chemoresistance of B-CLL lymphocytes to NA, we have initiated microarray analyses aimed at comparing genes induced or repressed by CdA or fludarabine in sensitive and refractory B-CLL patients. The working hypothesis would be that proapoptotic genes would fail to be induced in refractory patients, whereas anti-apoptotic genes, induced or not, would be expressed.
Possible causes of resistance to nucleoside analogues.
Reduced uptake (1) or intracellular activation (2), repair of lesions (3) or defects in apoptosis pathways (4).
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