Current Status of Older and New Purine Nucleoside Analogues in the Treatment of Lymphoproliferative Diseases

Abstract

For the past few years more and more new cytotoxic agents active in the treatment of hematological malignancies have been synthesized and become available for either in vitro studies or clinical trials. Among them the class of antineoplastic drugs belonging to the purine nucleoside analogues group (PNAs) plays an important role. Three of them: pentostatin (DCF), cladribine (2-CdA) and fludarabine (FA) were approved by Food and Drug Administration (FDA) for the treatment of hematological malignancies. Recently three novel PNAs: clofarabine (CAFdA), nelarabine (ara-G) and forodesine (immucillin H, BCX-1777) have been synthesized and introduced into preclinical studies and clinical trials. These agents seem to be useful mainly for the treatment of human T-cell proliferative disorders and they are currently undergoing clinical trials in lymphoid malignancies. However, there are also several studies suggesting the role of these drugs in B-cell malignancies. This review will summarize current knowledge concerning the mechanism of action, pharmacologic properties, clinical activity and toxicity of PNAs accepted for use in clinical practice, as well as new agents available for clinical trials.

Nucleoside analogs induce proteasomal down-regulation of p21 in chronic lymphocytic leukemia cell lines

“…The purine nucleoside analogs (NAs) cladribine (2-chloro-2'-deoxyadenosine, CdA) and fludarabine (9--D-arabinofuranosyl-2-fluoroadenine-5'-monophosphate) are effective drugs in indolent B-cell malignancies, including chronic lymphocytic leukemia (CLL) [1][2][3]. To exert their antileukemic effects, purine NAs require intracellular conversion to triphosphate compounds.…”

Nucleoside Transporters (SLC28 and SLC29) Family

“…Both purine and pyrimidine nucleoside analogs are currently employed as anticancer drugs. The purine derivatives cladribine (2-CdA; 2-chlorodeoxyadenosine) and fludarabine (F-ara-A; 9-β-D-arabinosyl-2-fluoroadenine) are extensively used for chemotherapy of hematological malignancies (Robak et al, 2009). More recently, clofarabine (2-chloro-9-[2 -deoxy-2 -fluoro-β-D-arabinofuranosyl]adenine) has been employed to treat lymphoproliferative disorders, as has forodesine (Immucillin-H); the latter drug is currently in clinical trials (Robak et al, 2009).…”

“…The purine derivatives cladribine (2-CdA; 2-chlorodeoxyadenosine) and fludarabine (F-ara-A; 9-β-D-arabinosyl-2-fluoroadenine) are extensively used for chemotherapy of hematological malignancies (Robak et al, 2009). More recently, clofarabine (2-chloro-9-[2 -deoxy-2 -fluoro-β-D-arabinofuranosyl]adenine) has been employed to treat lymphoproliferative disorders, as has forodesine (Immucillin-H); the latter drug is currently in clinical trials (Robak et al, 2009). In contrast, the pyrimidine analogs gemcitabine (dFdC; 2 ,2 -difluorodeoxycytidine) and capecitabine are currently used for the treatment of solid tumors (Saiko et al, 2005;Wong et al, 2009).…”

Identification and characterization of small-molecule ligands that maintain pluripotency of human embryonic stem cells

“…Inhibition of ADA is anticipated to result in the accumulation of adenosine and deoxyadenosine, and these compounds are known to have wide-ranging effects on cells produced by a variety of mechanisms [16][17][18][19][20][21]. We also therefore explored whether other structurally unrelated ADA inhibitors, including the highly potent inhibitor pentostatin [22][23][24], could mimic the effect of EHNA. Pentostatin, however, had no EHNA-like effects.…”