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Mechanism of action of purine analogues in chronic lymphocytic leukaemia

Fludarabine and chlorodeoxyadenosine are deaminationresistant analogues of deoxyadenosine (dAdo) that induce apoptosis in normal and malignant lymphocytes and have important therapeutic activity in chronic lymphocytic leukaemia (CLL). Both drugs are converted intracellularly to cytotoxic 5¢-phosphorylated derivatives through the action of deoxycytidine kinase. Phosphorylated purine analogues are substrates for several enzymes involved in DNA synthesis and repair. In proliferating cells, cytotoxicity seems to require incorporation of purine analogue into DNA. In resting lymphocytes, killing has been attributed to inhibition of DNA repair, accumulation of unrepaired DNA breaks and NAD ⁄ATP depletion due to sustained activation of poly(ADP-ribose) polymerase. Although this mechanism is demonstrable in occasional patients with CLL, p53-mediated apoptosis and direct induction of mitochondrial depolarization are probably more important. Caspase activation is not required for the induction of cell killing but determines whether death occurs by apoptosis or necrosis. Purine analogue resistance in CLL is associated with P53 mutation ⁄ deletion, relative over-expression of antiapoptotic Bcl-2 family proteins and a low capacity for nucleoside phosphorylation. To overcome drug resistance, strategies are required that target these points of blockade.