Purine nucleoside analogs (PNAs) compose a class of cytotoxic drugs that have played an important role in the treatment of
hematological neoplasms, especially lymphoid and myeloid
malignancies. All PNA drugs have a chemical structure similar to
adenosine or
guanosine, and they have similar mechanisms of action. They have many intracellular targets: they act as
antimetabolites, competing with natural
nucleosides during
DNA or
RNA synthesis, and as inhibitors of key cell
enzymes. In contrast to other
antineoplastic drugs, PNAs act cytotoxically, both in the mitotic and quiescent cell cycle phases. In the last few years, three PNAs have been approved for the treatment of lymphoid
malignancies and other hematological disorders:
2-chlorodeoxyadenosine (2-CdA),
fludarabine and
pentostatin. 2-CdA and
fludarabine are also active in the treatment of
acute myeloid leukemia (AML). These drugs, in combination with
cytarabine and other agents, are commonly used as salvage regimens in relapsed or refractory AML. Moreover, the addition of 2-CdA to the standard induction regimen is associated with an increased rate of complete remission and improved survival of adult patients with AML. More recently three novel PNAs have been synthesized and introduced into clinical trials:
clofarabine,
nelarabine and
forodesine.
Clofarabine is the most promising PNA in current clinical trials in pediatric and adult patients with acute
leukemias.
Nelarabine is more cytotoxic in T-lineage than in B-lineage
leukemias.
Clofarabine and
nelarabine have been approved for the treatment of refractory patients with
acute lymphoblastic leukemia (ALL) and
lymphoblastic lymphoma.
Clofarabine is also an active
drug in AML treatment when administered either alone or in combination regimens as front-line treatment and in relapsed or refractory patients. Unlike other PNA,
forodesine is not incorporated into
DNA but displays a highly selective
purine nucleoside phosphorylase inhibitory action.
Forodesine is undergoing clinical trials for the treatment of T-cell
malignancies, including T-cell ALL. This article summarizes recent achievements in the mechanism of action, pharmacological properties and clinical activity and toxicity of PNAs, as well as their emerging role in lymphoid and myeloid acute
leukemias.