The
purine nucleoside analogs (PNA) form an important group of cytotoxic drugs active in the treatment of neoplastic and
autoimmune diseases. Three of them,
fludarabine (FA),
cladribine (2-chlorodeoxyadenosine, 2-CdA) and
pentostatin (2'-deoxycoformycin, DCF) have established clinical activity in
hematological malignancies and have been approved by FDA. These drugs are also investigated in some autoimmune diosorders. Recently four novel PNA:
clofarabine (CAFdA),
nelarabine,
immucillin H (BCX-1777, forodesine) and
8-chloroadenosine (8-Cl-Ado) have been synthesized and introduced into clinical trials. All these drugs have chemical structure similar to
adenosine or
guanosine, however, the mechanism of their action is different. FA, 2-CdA and CAFdA mainly require phosphorylation by deoxynucleoside salvage pathways. The cytotoxic effect exerts the
triphosphate metabolites, which are incorporated into
DNA, and finally lead to programmed cell death. In contrast, DCF does not need to be phosphorylated and results in an increase of plasma
deoxyadenosine (dAdo) levels and intracellular
deoxyadenosine triphosphate (dATP).
Nelarabine is an arabinosylguanine (
ara-G)
prodrug, which after conversion to
ara-G is phosphorylated to
ara-G triphosphate (
ara-GTP). Accumulation of
ara-GTP finally leads to apoptosis.
Forodesine is a
purine nucleoside phosphatase (PNP) inhibitor which blocks intracellular deoxyguanine (dGuo) cleaving to
guanine (Guo), but instead converts it to
deoxyguanosine triphosphate (
dGTP), and similarly to other PNA resulting in apoptosis.
8-chloroadenosine (8-Cl-Ado) is a ribonucleoside analog. The mechanism of its action is quite different from other PNA and remains poorly understood. However, it is known that the
drug inhibits
RNA synthesis, but not
DNA. These agents have significant cytotoxic activity against lymphoid and myeloid malignant cells. Moreover, they have deleterious effects on the normal resting lymphocytes. They result in prolonged lymphocyte depletion especially in the CD4 subset of T-cells. Several clinical trials have demonstrated that PNA used alone or in combination with other cytotoxic drugs or
monoclonal antibodies shows good efficacy and acceptable toxicity profile in the treatment of lymphoid
malignancies. 2-CdA and DCF are drugs of choice in the treatment of
hairy cell leukemia. FA and 2-CdA have significant clinical activity in low-grade
non-Hodgkin's lymphoma and
chronic lymphocytic leukemia. 2-CdA exhibits some activity in progressive
multiple sclerosis and other autoimmune disorders. This review will summarize current knowledge concerning the mechanism of action, pharmacological properties, clinical activity and toxicity of PNA accepted for use in clinical practice as well as new agents available for clinical trials.