Purine Nucleoside Analogs as Immunosuppressive and Antineoplastic Agents: Mechanism of Action and Clinical Activity

Tadeusz      Robak; Ewa      Lech-Maranda; Anna      Korycka; Ewa      Robak

Abstract

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-Hodgkins 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.

Keywords: Fludarabine, cladribine, clofarabine, pentostatin, nelarabine, immucillinH, leukemia, lymphoma