9-arabinofuranosylguanine and fludarabine

GW506U78 or nelarabine (Glaxo-SmithKline) is a nucleoside analog that is rapidly converted by cells of lymphoid lineage to its corresponding arabinosylguanine nucleotide triphosphate (araGTP). The triphosphate form of araG acts as a substrate for DNA polymerases and araG gets incorporated into the DNA, resulting in inhibition of DNA synthesis and subsequent cytotoxicity. It has been shown that nelarabine has activity as a single agent in patients with T-cell malignancies that have relapsed or are refractory to other therapy. The ongoing research on nelarabine has earned fast-track status from the U.S. Food and Drug Administration (FDA) for treatment of patients with T-cell acute lymphoblastic leukemia and lymphoblastic lymphoma who have not responded to or whose disease has progressed during treatment with at least two standard regimens. It is likely that nelarabine will be a useful drug in the treatment of leukemic diseases in the future and therefore nelarabine is an interesting drug to study further. Here we present an overview of what is known about the mechanism of action of nelarabine and its status in clinical trials.

Topics: Arabinonucleosides; Clinical Trials as Topic; DNA Repair; Dose-Response Relationship, Drug; Drug Resistance; Drug Therapy, Combination; Hematologic Neoplasms; Humans; Leukemia-Lymphoma, Adult T-Cell; Phosphorylation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Treatment Outcome; Vidarabine

Nucleoside analogues (NA) are essential components of AML induction therapy (cytosine arabinoside), effective treatments of lymphoproliferative disorders (fludarabine, cladribine) and are also used in the treatment of some solid tumors (gemcitabine). These important compounds share some general common characteristics, namely in terms of requiring transport by specific membrane transporters, metabolism and interaction with intracellular targets. However, these compounds differ in regard to the types of transporters that most efficiently transport a given compound, and their preferential interaction with certain targets which may explain why some compounds are more effective against rapidly proliferating tumors and others on neoplasia with a more protracted evolution. In this review, we analyze the available data concerning mechanisms of action of and resistance to NA, with particular emphasis on recent advances in the characterization of nucleoside transporters and on the potential role of activating or inactivating enzymes in the induction of clinical resistance to these compounds. We performed an extensive search of published in vitro and clinical data in which the levels of expression of nucleoside-activating or inactivating enzymes have been correlated with tumor response or patient outcome. Strategies aiming to increase the intracellular concentrations of active compounds are presented.

Topics: 2-Chloroadenosine; 5'-Nucleotidase; Acute Disease; Animals; Antimetabolites, Antineoplastic; Arabinonucleosides; Biological Transport; Carrier Proteins; Cytarabine; Cytidine Deaminase; Cytosine; Deoxyadenosines; Deoxycytidine; Deoxycytidine Kinase; Dioxolanes; DNA Repair; DNA Replication; DNA-Directed DNA Polymerase; Drug Resistance, Neoplasm; Gemcitabine; Hematopoietic Cell Growth Factors; Humans; Leukemia, Myeloid; Lymphoproliferative Disorders; Neoplastic Stem Cells; Nucleosides; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor); Remission Induction; Ribonucleotide Reductases; Vidarabine

The objective of this investigation was to evaluate the ability of arabinosyl nucleotides to modulate the cellular metabolism of different arabinosyl nucleosides in K562 cells. The maximum rate of accumulation of the respective 5'-triphosphate (TP) was observed in cells incubated with 10 microM arabinosylcytosine (ara-C), 10 microM arabinosylguanine (ara-G), 300 microM arabinosyl-2-fluoroadenine (F-ara-A), and greater than 1000 microM arabinosyladenine (ara-A). Cell extract fractionation studies demonstrated that ara-C and F-ara-A were phosphorylated by dCyd kinase, whereas ara-A was phosphorylated by dCyd kinase and Ado kinase; ara-G phosphorylation was attributed to dGuo kinase. When nucleoside kinase was rate limiting to arabinosyl nucleotide accumulation, cells preloaded with F-ara-ATP showed increased rates of ara-CTP and ara-GTP accumulation, whereas cells preloaded with ara-CTP had decreased rates of F-ara-ATP and ara-GTP accumulation. Preloading cells with ara-GTP had little effect on arabinosyl nucleoside triphosphate accumulation. F-ara-ATP accumulation was inhibited in cells containing all other arabinosyl nucleotides, whereas ara-ATP metabolism was not affected by preincubation with any other nucleoside. Cells incubated with ara-C and ara-G had a general rise in dNTP, whereas F-ara-A incubation was associated with a decrease in cellular dNTP. The differential effects of arabinosyl nucleotides and cellular metabolism of other arabinosyl nucleosides are due to phosphorylation by distinct nucleoside kinases that likely have characteristic sensitivities to cellular dNTP levels.

Topics: Arabinofuranosylcytosine Triphosphate; Arabinonucleosides; Arabinonucleotides; Cytarabine; Deoxyribonucleotides; Drug Interactions; Guanosine Triphosphate; Humans; Leukemia; Phosphorylation; Phosphotransferases; Tumor Cells, Cultured; Vidarabine; Vidarabine Phosphate