Abstract
For the past few years more and more new cytotoxic agents active in the treatment of hematological malignancies have been synthesized and become available for either in vitro studies or clinical trials. Among them the class of antineoplastic drugs belonging to the purine nucleoside analogues group (PNAs) plays an important role. Three of them: pentostatin (DCF), cladribine (2-CdA) and fludarabine (FA) were approved by Food and Drug Administration (FDA) for the treatment of hematological malignancies. Recently three novel PNAs: clofarabine (CAFdA), nelarabine (ara-G) and forodesine (immucillin H, BCX-1777) have been synthesized and introduced into preclinical studies and clinical trials. These agents seem to be useful mainly for the treatment of human T-cell proliferative disorders and they are currently undergoing clinical trials in lymphoid malignancies. However, there are also several studies suggesting the role of these drugs in B-cell malignancies. This review will summarize current knowledge concerning the mechanism of action, pharmacologic properties, clinical activity and toxicity of PNAs accepted for use in clinical practice, as well as new agents available for clinical trials.
Highlights
For the past few years more and more new cytotoxic agents active in the treatment of hematological malignancies have been synthesized and become available for either in vitro studies or clinical trials
Several in vitro and in vivo studies have shown a synergy between purine nucleoside analogues group (PNAs) and other chemotherapeutic agents and monoclonal antibodies active in hematological malignancies
PNAs alone or in combinations with other agents are the drugs of choice in hairy cell leukemia (HCL), chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphomas (NHL)
Summary
As it was mention above, the PNAs share several similar characteristics including transportation into the cells, phosphorylation to monophosphates by cytosolic dCK or mitochondrial deoxyguanosine kinase (dGK) and dephosphorylation by 5’-NT. The main role in the mechanism of PNA activity plays induction of apoptosis which is the end-point of their action This proces takes place mainly through the intristic pathway, via modulation of P53 expression or directly via binding to proteins located in mitochondrial membrane, leading to changes in mitochondrial membrane permeability. ABCG2 (breast cancer resistance protein), like a first transporter directly linked to the efflux of nucleoside monophosphate analogues from mammalian cells-MRP4 (multidrug resistance protein), transport and confer resistance to PNA. These two transporeters work in parallel to affect drug cytotoxicity and tissue distribution [26]. MRP4 dramatically reduces MRP4 function by impairing its cell membrane localization [27]
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