New and Existing Purine Analogs - How they Work

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Curr Med Chem. 2006;13(26):3165-89.

Purine nucleoside analogs as immunosuppressive and antineoplastic

agents: mechanism of action and clinical activity.

Robak T, Lech-Maranda E, Korycka A, Robak E.

Department of Hematology, Medical University of Lodz and Copernicus

Memorial Hospital, 93-513 Lodz, Pabianicka 62, Poland.

robaktad@....

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.

PMID: 17168705 [PubMed - in process]