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

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-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.

In vitro Response of Human Pathological Hematopoietic Cells to Cladribine

“…The mechanisms of cladribine activity are based on inhibition of enzymes involved in DNA, RNA, and protein synthesis. Cytotoxicity of CdA is associated with events critical to cell entry into S phase (BEUTLER 1992;ROBAK et al 2006aROBAK et al , 2006b). …”

“…Cladribine has established clinical activity in hematological malignancies (DELANNOY 1996;ROBAK 2003;PARKER et al 2004;GREYZ & SAVEN 2004;ROBAK et al 2005ROBAK et al , 2006aROBAK et al , 2006bROBAK et al , 2006c. Nevertheless, some aspects of the action of cladribine are as yet unclear.…”

Synthesis of Some Substituted 6-Phenyl Purine Analogues and Their Biological Evaluation as Cytotoxic Agents

“…3) were approved in FDA for the therapy of hematologic disorders between 1991 and 1992. 18,19 2. Experimental…”

Four generations of transition-state analogues for human purine nucleoside phosphorylase

“…PNP deficiency causes the presence of elevated concentrations of d-guanosine in the blood resulting in apoptosis of dividing T-cells due to the metabolic accumulation of dGTP, an inhibitor of ribonucleotide reductase (1,2). Inhibitors of PNP have been used for the treatment of T-cell cancers and autoimmune disorders where T-cell clones are misdirected against self-antigens causing disorders, including psoriasis, rheumatoid arthritis, and multiple sclerosis (2,3). PNP inhibitors are also in clinical trials for gout because formation of purine base precursors for uric acid formation requires PNP in humans.…”