Old and new insights into the mechanisms of action of two nucleoside analogs active in lymphoid malignancies: fludarabine and cladribine (Review)

This review focuses on two chemotherapeutic agents belonging to the family of purine analogs, 9-β-D-arabinosyl-2-fluoroadenine-5'-monophosphate (F-ara-AMP, fludarabine), which is the soluble form of F-ara-A, and 2-chloro-2'-deoxyadenosine (CdA, cladribine). Both compounds display remarkable activity in malignancies arising from the clonal expansion of lymphocytes, and particularly in B-cell chronic lymphocytic leukemia (B-CLL). These analogs are prodrugs that must be converted into their respective nucleotides as an essential requirement for cytotoxicity. Triphosphate analogs inhibit various processes involved in DNA and RNA synthesis. Moreover, the effect of nucleoside analogs in leukemic cells may involve modulation of apoptosis pathways, cell-cycle control, or signal transduction pathways. These findings are of crucial importance because alterations in these pathways may be involved in leukemic cell resistance toward nucleoside analogs and, hence, constitute new molecular targets to sensitize leukemic cells to these drugs.