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PubMed1975

Nucleoside 5'-phosphordiamidates, synthesis and some properties.

A simple way of preparing nucleoside 5'-phosphordiamidate is described. The procedure is based on the ammonolysis of nucleoside 5'-phosphordichloridates by dilute aqueous ammonium hydroxide. The behaviour of nucleoside phosphordiamidates under acidic and alkaline conditions is also reported. Alkaline hydrolysis results in the formation of the parent nucleoside, whereas one amide group can be removed selectively by mild acid hydrolysis. This property of nucleoside phosphordiamidates served as a basis for the elaboration of a simple synthesis of nucleoside phosphoramidates starting from nucleosides.

Chemical Phenomena↗
PubMed2001

Nucleoside analogues for chronic hepatitis B.

Hepatitis B virus replicates inside the hepatocyte through an intermediate step of reverse transcription mediated by the viral polymerase. We describe five nucleoside/nucleotide analogues that interfere with the replication mechanisms of the hepatitis B virus. The resemblance of nucleoside analogues to natural nucleosides may lead to direct cytotoxicity. Therefore, antiviral activity should always be interpreted in the light of cellular toxicity. In addition, prolonged therapy with a nucleoside analogue may induce mutations in the viral polymerase, causing structural and configurational changes of the polymerase resulting in a decreased affinity for the nucleoside analogue. Subsequently, the mutated virus is capable of renewed replication during continued antiviral pressure of the nucleoside analogue. The best antiviral strategy in the future is probably combination therapy, either with several nucleoside analogues or with a nucleoside analogue and interferon.

2-Aminopurine↗
PubMed2003

Detecting life-threatening lactic acidosis related to nucleoside-analog treatment of human immunodeficiency virus-infected patients, and treatment with L-carnitine.

OBJECTIVE: Our first objective was to determine a blood lactate threshold predictive of survival in human immunodeficiency virus patients experiencing lactic acidosis related to nucleoside analogs, and second, to test l-carnitine for the treatment of patients exceeding that threshold. DESIGN: a) Retrospective study using data from personal and published observations to determine the lactate threshold between survivors and nonsurvivors in human immunodeficiency virus patients being treated with nucleoside analogs. b) Prospective multicenter open trial to test l-carnitine treatment of human immunodeficiency virus patients receiving nucleoside analogs. SETTING: Medical intensive care units of four teaching hospitals and one general hospital. PATIENTS: Retrospective analysis of data from 39 human immunodeficiency virus patients (five personal cases and 34 patients from the literature) receiving nucleoside-analog treatment from which lactate values were available. An additional six patients with high lactate values were included as a pilot study testing the use of l-carnitine therapy. MEASUREMENTS AND MAIN RESULTS: An initial lactate level of 9 mmol/L, which gave good positive and negative predictive values, was determined as a threshold between survivors and nonsurvivors for the patients receiving nucleoside-analog treatment. Six patients with initial lactate levels >10 mmol/L were prospectively treated with l-carnitine; three survived beyond the end of the study. CONCLUSIONS: The blood lactate levels in human immunodeficiency virus patients receiving nucleoside-analog therapy can predict mortality in these patients. The preliminary data from this pilot study suggest that l-carnitine may be helpful for patients who have nucleoside-analog-related lactic acidosis with blood lactate levels >10 mmol/L. Further studies will be necessary to affirm the therapeutic efficacy of l-carnitine in this setting.

Acidosis, Lactic↗
PubMed1987

Purine Nucleoside Transport in Petunia Pollen Is an Active, Carrier-Mediated System Not Sensitive to Nitrobenzylthioinosine and Not Renewed during Pollen Tube Growth.

Adenosine and guanosine are transported into Petunia hybrida pollen by a saturable, carrier-mediated mechanism. The energy poisons carbonylcyanide-m-chlorophenylhydrazone, 2,4-dinitrophenol, 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole, and N,N'-dicyclohexylcarbodiimide all inhibit uptake, suggesting an energy coupled (active) transport process. Transport takes place against a concentration gradient, strongly favoring an active transport mechanism. The purine nucleoside transport in Petunia pollen differs from that already reported for pyrimidine nucleosides in that it exhibits a significantly higher K(m) for nucleoside and is not so severely inhibited by the polyamine, spermine. Like that for the pyrimidine nucleosides uridine and cytosine, however, the system exhibits a broad pH optimum, is inhibited by sulfydryl-binding reagents, while the potent inhibitors of nucleoside transport in animal cells, nitrobenzylthioinosine and dipyridamole, have no effect. Transport of both purine and pyrimidine nucleosides in germinating pollen decreases steadily with time, a finding consistent with reports that RNA synthesis and DNA repair are early events of pollen germination and tube elongation. However, since these precursors are often used to demonstrate nucleic acid synthesis, it cannot be ruled out that the lack of precursor transport itself leads to scoring nucleic acid synthesis as negative. The results indicate that the newly synthesized pollen tube membranes contain little or no nucleoside transporters.

Journal Article↗
PubMed2003

Interaction of the novel adenosine uptake inhibitor 3-[1-(6,7-diethoxy-2-morpholinoquinazolin-4-yl)piperidin-4-yl]-1,6-dimethyl-2,4(1H,3H)-quinazolinedione hydrochloride (KF24345) with the es and ei subtypes of equilibrative nucleoside transporters.

Nucleosides such as adenosine, as well as many nucleoside-based drugs, permeate cell membranes via a family of equilibrative nucleoside transporters (ENTs). We assessed the effects of (3-[1-(6,7-diethoxy-2-morpholino-quinazolin-4-yl)piperidin-4-yl]-1,6-dimethyl-2,4(1H,3H)-quinazolinedione hydrochloride (KF24345), a novel anti-inflammatory agent that potentiates the actions of adenosine, on the es (inhibitor-sensitive) and ei (inhibitor-resistant) subtypes of ENTs in human, mouse, and rat cells. KF24345 was similar to the prototypical high-affinity inhibitor nitrobenzylthioinosine (NBMPR) for blocking the human es transporter (K(I) of approximately 0.4 nM), but was 50-fold more effective than NBMPR at blocking the human ei transporter (K(I) of approximately 100 nM). KF24345 displayed significantly less species heterogeneity in its affinity for the es transporter than did dipyridamole, a widely used inhibitor of nucleoside transport; KF24345 may thus prove useful as an inhibitor for studies of nucleoside metabolism in a range of animal models. Furthermore, KF24345 seemed to act as a noncompetitive inhibitor of both [(3)H]NBMPR binding and [(3)H]nucleoside uptake by human es transporters, and these kinetics were consistent with an observed slow dissociation of KF24345 from the inhibitor binding site. KF24345 also exhibited unusual biphasic profiles for inhibition of [(3)H]NBMPR binding to membranes prepared from a recombinant human es transporter model (PK15-hENT1), suggesting the presence of multiple populations of NBMPR binding proteins in these membranes. The atypical tight binding interaction of KF24345 with the es transporter may prove useful for the molecular delineation of inhibitor binding domains and will facilitate its use as an in vivo inhibitor of nucleoside transport in studies focused on the biological effects of adenosine.

Adenosine↗
PubMed1999

Triple nucleoside analogue antiretroviral therapy: expanding the treatment approaches for management of HIV infection.

The expanding range of drug options for the management of persons with HIV infection and concerns about the long-term safety of some treatment approaches has precipitated the HIV treatment community to examine a wider range of treatment approaches. One new therapeutic approach is to consider using three nucleoside analogue reverse transcriptase inhibitors, particularly as initial therapy. Recent data comparing triple nucleoside analogue therapy with established 'standard of care' triple therapy regimens have demonstrated similar antiviral effects and tolerability for such regimens. Efficacy and tolerability of triple nucleoside therapy has been demonstrated up to 96 weeks of therapy. This approach has advantages over conventional two nucleoside plus either a protease inhibitor or non-nucleoside reverse transcriptase inhibitor in terms of drug interactions and maintenance of multiple class options. It creates regimens which are, for the most part, compact, twice daily and non-food dependent. Specifically, this approach has already become widely established for individuals for whom drug interactions exclude the use of protease or non-nucleoside antiretrovirals. Triple nucleoside analogue therapy is likely to represent an attractive option for both physicians and patients; its use in clinical practice is likely to further expand.

Journal Article↗
PubMed1991

Combined anti-herpes virus activity of nucleoside analogs and interferon.

Addition of interferon (IFN) to nucleoside analog therapy for herpetic keratitis has been shown to significantly increase the efficacy of therapy compared to nucleoside alone. We have analysed several nucleoside analogs and recombinant IFN-alpha 2 to determine which combinations have increased anti-herpes simplex virus type 1 (HSV) activity. Synergistic anti-HSV activity between IFN-alpha 2 and the acyclic guanosine analogs, acyclovir (ACV) and ganciclovir (DHPG), was demonstrated in cytopathic effect reduction assay in human corneal cell cultures as well as in Vero cells. In this assay system IFN-alpha 2 alone had little detectable antiviral activity at titers of greater than or equal to 2,000 IU/ml, however, treatment of cells with about 100 IU/ml of IFN-alpha 2 for 24 hrs prior to infection decreased the ED50 of ACV approximately 2- to 3-fold and of DHPG approximately 5- to 6-fold in Vero cells. Combinations of IFN-alpha 2 with bromovinyldeoxyuridine (BVdU) in Vero cells or human corneal stromal cells did not increase the antiviral activity of BVdU. Combinations of IFN-alpha 2 with trifluorothymidine (TFT) also did not increase the effective antiviral activity of this nucleoside and resulted in decreased uptake of TFT from the medium. These studies document that combinations of acyclic nucleoside analogs, ACV and DHPG, with IFN-alpha 2 resulted in synergistic anti-HSV activities in both Vero and human corneal stromal cells, while the pyrimidine analogs, TFT and BVdU, were not synergistic with IFN-alpha 2. IFN-alpha 2 treatment of cells induced modifications of nucleoside (e.g., thymidine and TFT), but not nucleobase (e.g., ACV) uptake. These studies suggest that selective inhibition of nucleoside versus nucleobase uptake may contribute to the mechanism of IFN/nucleobase synergy in the inhibition of HSV replication.

Animals↗
PubMed1984

Allosteric activation of rat liver cytosolic 3-hydroxy-3-methylglutaryl coenzyme A reductase kinase by nucleoside diphosphates.

Extensively purified rat liver cytosolic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase kinase was used to examine the role of ADP in inactivation of HMG-CoA reductase (EC 1.1.1.34). Solubilized HMG-CoA reductase was a suitable substrate for HMG-CoA reductase kinase. At sufficiently high concentrations of solubilized HMG-CoA reductase, reductase kinase activity approached that measured using microsomal HMG-CoA reductase as substrate. Inactivation of solubilized HMG-CoA reductase by HMG-CoA reductase kinase required both MgATP and ADP. Other nucleoside diphosphates, including alpha, beta-methylene-ADP, could replace ADP. HMG-CoA reductase kinase catalyzed phosphorylation of bovine serum albumin fraction V by [gamma-32P]ATP. This process also required a nucleoside diphosphate (e.g. alpha, beta-methylene-ADP). Nucleoside diphosphates thus act on HMG-CoA reductase kinase, not on HMG-CoA reductase. For inactivation of HMG-CoA reductase, the ability of nucleoside triphosphates to replace ATP decreased in the order ATP greater than dATP greater than GTP greater than ITP, UTP. TTP and CTP did not replace ATP. Both for inactivation of HMG-CoA reductase and for phosphorylation of bovine serum albumin protein, the ability of nucleoside diphosphates to replace ADP decreased in the order ADP greater than CDP, dADP greater than UDP. GDP did not replace ADP. Nucleoside di- and triphosphates thus appear to bind to different sites on HMG-CoA reductase kinase. Nucleoside diphosphates act as allosteric activators of HMG-CoA reductase kinase. For inactivation of HMG-CoA reductase by HMG-CoA reductase kinase, Km for ATP was 140 microM and the activation constant, Ka, for ADP was 1.4 mM. The concentration of ADP required to modulate reductase kinase activity in vitro falls within the physiological range. Modulation of HMG-CoA reductase kinase activity, and hence of HMG-CoA reductase activity, by changes in intracellular ADP concentrations thus may represent a control mechanism of potential physiological significance.

AMP-Activated Protein Kinases↗
PubMed1994

Nucleoside trapping during reperfusion prevents ventricular dysfunction, "stunning," in absence of adenosine. Possible separation between ischemic and reperfusion injury.

A previous study has shown that endogenous adenosine trapping during ischemia (by blocking adenine nucleoside transport and inhibiting adenosine breakdown) prevents myocardial stunning. In this study, we tested the hypothesis that delay of administration of inhibitors until reperfusion would similarly prevent myocardial stunning in the absence of entrapped adenosine. In both studies, a selective nucleoside transport blocker, p-nitrobenzyl-thioinosine, was used in combination with a potent adenosine deaminase inhibitor, erythro-9-(2-hydroxy-3-nonyl)adenine, to entrap adenosine (preischemic treatment) or inosine (postischemic treatment) in an in vivo canine model of reversible global ischemia. Twenty-five anesthetized adult dogs were instrumented (by sonomicrometry) to monitor left ventricular performance from the relationship between stroke work and end-diastolic length as a sensitive and load-independent index of contractility. Hearts of animals supported by cardiopulmonary bypass were subjected to 30 minutes of normothermic global ischemia and 60 minutes of reperfusion. Saline solution containing the pharmacologic agents were infused into the bypass circuit before ischemia (group 1) or during reperfusion (group 2). Control group (group 3) received saline before and after ischemia. Myocardial biopsy specimens were obtained before, during, and after ischemia, and levels of adenine nucleotides, nucleosides, oxypurines, and the oxidized form of nicotinamide-adenine dinucleotide were determined. Left ventricular contractility fully recovered within 30 minutes of reperfusion in the groups treated with erythro-9-(2-hydroxy-3-nonyl)adenine and p-nitrobenzyl-thioinosine (p < 0.05 versus control group). Myocardial adenosine triphosphate was depleted by 50% in all groups at the end of ischemia. Adenosine triphosphate recovered during reperfusion only in the group that was treated with inhibitors before ischemia (group 1). At the end of ischemia, adenosine levels were low (< 10% of total nucleosides) in the control group (group 3) and in the group treated only after ischemia (group 2). A high level of adenosine (> 90% of total nucleosides) was present in group 1. We infer that selective pharmacologic blockade of nucleoside transport, only after ischemic injury, accelerated functional recovery during reperfusion, even without trapping of endogenous adenosine during ischemia and without adenosine triphosphate recovery during reperfusion. Recovery of myocardial adenosine triphosphate required preischemic treatment and adenosine entrapment during ischemia and reperfusion. Therefore, nucleoside trapping may be used to prevent reperfusion-mediated injury after reversible ischemic injury.

Adenine↗
PubMed1993

Stimulation of astrocyte proliferation by purine and pyrimidine nucleotides and nucleosides.

Proliferation of brain astrocytes as a result of cell death has been well documented in vivo. Dying cells release purine and pyrimidine nucleosides and nucleotides and their deoxy derivatives both from soluble intracellular pools and from DNA and RNA. Previously, we have observed that purine nucleosides and nucleotides stimulate chick astrocyte proliferation in vitro. To further our analysis, we questioned whether pyrimidines or the deoxy derivatives of purine nucleosides and nucleotides might also be astrocyte mitogens. Pyrimidine nucleosides, nucleotides, and their deoxynucleotide derivatives were uniformly inactive. In contrast, deoxyguanosine, deoxyadenosine, and their mono-, di-, and triphosphates stimulated thymidine incorporation into astrocytes at concentrations similar to those at which their ribonucleoside and ribonucleotide analogues were active. Inosine, IMP, ITP, and hypoxanthine were active, whereas xanthine and xanthosine were not. However, XMP, XDP, and XTP stimulated thymidine incorporation. The effects of the nucleosides and deoxynucleosides were inhibited by antagonists of adenosine A2 receptors. These data indicate that most purine nucleosides, deoxynucleosides, and their 5' mono, di-, and triphosphate derivatives released from damaged cells are capable of stimulating astrocyte proliferation in vitro and may contribute to astrocyte proliferation in vivo following injury to the CNS.

Adenosine↗
PubMed1976

Nucleoside transport systems in Escherichia coli K12: specificity and regulation.

Two nucleoside transport systems have been verified and separated by mating and recombination experiments. The recipient strain was a mutant which is negative for transport of all nucleosides. The two systems differ in specificity and in regulation. One system transports pyrimidine and adenine nucleosides. It is regulated by the cytR gene. The other system transports all nucleosides and is regulated by the cytR as well as by the deoR genes. Enzyme assays performed on whole cells of strains, able or unable to transport nucleosides, indicate that the nucleoside catabolizing enzymes are located inside the permeability barrier of the cell.

Biological Transport, Active↗
PubMed2003

The equilibrative nucleoside transporter family, SLC29.

The human SLC29 family of proteins contains four members, designated equilibrative nucleoside transporters (ENTs) because of the properties of the first-characterised family member, hENT1. They belong to the widely-distributed eukaryotic ENT family of equilibrative and concentrative nucleoside/nucleobase transporters and are distantly related to a lysosomal membrane protein, CLN3, mutations in which cause neuronal ceroid lipofuscinosis. A predicted topology of 11 transmembrane helices with a cytoplasmic N-terminus and an extracellular C-terminus has been experimentally confirmed for hENT1. The best-characterised members of the family, hENT1 and hENT2, possess similar broad substrate specificities for purine and pyrimidine nucleosides, but hENT2 in addition efficiently transports nucleobases. The ENT3 and ENT4 isoforms have more recently also been shown to be genuine nucleoside transporters. All four isoforms are widely distributed in mammalian tissues, although their relative abundance varies: ENT2 is particularly abundant in skeletal muscle. In polarised cells ENT1 and ENT2 are found in the basolateral membrane and, in tandem with concentrative transporters of the SLC28 family, may play a role in transepithelial nucleoside transport. The transporters play key roles in nucleoside and nucleobase uptake for salvage pathways of nucleotide synthesis, and are also responsible for the cellular uptake of nucleoside analogues used in the treatment of cancers and viral diseases. In addition, by regulating the concentration of adenosine available to cell surface receptors, they influence many physiological processes ranging from cardiovascular activity to neurotransmission.

Animals↗
PubMed2001

Distinct regional distribution of human equilibrative nucleoside transporter proteins 1 and 2 (hENT1 and hENT2) in the central nervous system.

Nucleoside transport processes play an important role in human cells in salvage of nucleosides used in the biosynthesis of nucleic acids and in regulating endogenous adenosine concentrations in the human central nervous system (CNS). By altering the levels of adenosine available to interact with cell-surface receptors, nucleoside transporters have profound effects on the ability of adenosine to modulate neurotransmission, vascular tone and other physiological events. Although the human equilibrative nucleoside transporters 1 and 2 (hENT1 and hENT2) are believed to play a crucial role in modulating brain function, their distribution within the major divisions of the human CNS is not known. In this work, antibodies specific for hENT1 and hENT2 were produced against fragments of the transporter proteins and used for immunoblot analysis of enriched membrane fractions prepared from several regions of the human brain. While hENT1 was most prevalent in the frontal and parietal lobes of the cerebral cortex, thalamus, midbrain and basal ganglia, hENT2 was concentrated in the cerebellum and brainstem regions, particularly the pons. The apparent reciprocal distribution of hENT1 and hENT2 in human brain suggests that these nucleoside transporter proteins are produced in distinct regions of the CNS where they function in nucleoside salvage and/or regulation of exogenous adenosine. Within the brain regions that were investigated, the pattern of hENT1 distribution correlated well with adenosine A(1) receptor abundance. The regional co-localization of hENT1 and A(1) receptor protein suggests an important role of hENT1-mediated transport process in the control of neuromodulatory actions mediated by adenosine A(1) receptors in human brain.

Adenosine↗
PubMed2002

Nucleoside analogues and nucleobases in cancer treatment.

Cytotoxic nucleoside analogues and nucleobases were among the first chemotherapeutic agents to be introduced for the medical treatment of cancer. This family of compounds has grown to include a variety of purine and pyrimidine nucleoside derivatives with activity in both solid tumours and malignant disorders of the blood. These agents behave as antimetabolites, compete with physiological nucleosides, and interact with a large number of intracellular targets to induce cytotoxicity. Progress has recently been made in the identification and characterisation of nucleoside transporters and the enzymes of nucleoside metabolism. In addition, there is now greater understanding of the molecular mechanisms of anticancer nucleoside activity, which provides opportunities for potentiating their antitumour effects. Strategies to optimise intracellular analogue accumulation and to enhance cancer-cell selectivity are proving beneficial in clinical trials.

Animals↗
PubMed2000

Synthesis and cytotoxicity of 4-amino-5-oxopyrido[2,3-d]pyrimidine nucleosides.

A number of nucleoside analogues have been either used clinically as anticancer drugs or evaluated in clinical studies, while new nucleoside analogues continue to show promise. In this article, we report synthesis and cytotoxicity of a series of new pyrido[2, 3-d]pyrimidine nucleosides. 2-Amino-3-cyano-4-methoxypyridine was converted, in two steps, to 4-amino-5-oxopyrido[2,3-d]pyrimidine. A variety of 1-O-acetylated pentose sugar derivatives were condensed with silylated 4-amino-5-oxopyrido[2,3-d]pyrimidine, followed by protection, to afford a series of 4-amino-5-oxopyrido[2, 3-d]pyrimidine nucleosides. Further derivatizations provided an additional group of pyrido[2,3-d]pyrimidine nucleosides. These nucleosides were evaluated for in vitro cytotoxicity to human prostate cancer (HTB-81) and mouse melanoma (B16) cells as well as normal human fibroblasts (NHF). A number of compounds (1a,b, 2a-c,f, 3f+4d) showed significant cytotoxicity to cancer cells, with 4-amino-5-oxo-8-(beta-D-ribofuranosyl)pyrido[2,3-d]pyrimidine (1b) being the most potent proliferation inhibitor (EC(50): 0.06-0.08 microM) to all types of cells tested. However, a selective inhibition to the cancer cells was observed for 4-amino-5-oxo-8-(beta-D-xylofuranosyl)pyrido[2,3-d]pyrimidine (2b), which is a potent inhibitor of HTB-81 (EC(50): 0.73 microM) and has a favorable in vitro selectivity index (28).

Animals↗
PubMed1983

Synthesis of hypoxanthine, guanine, and 6-thiopurine nucleosides of 6-deoxy-D-allofuranose.

Hypoxanthine, guanine, and 6-thiopurine nucleosides of 6-deoxy-D-allofuranose have been prepared as potential antitumor agents. Thus, reaction of 6-deoxy-beta-D-allofuranosyl bromide (1) with the trimethylsilyl derivatives of hypoxanthine and guanine afforded mixtures of the 9- and the 7-substituted bases, which were separated and deblocked with ammonia to give 9-(6'-deoxy-beta-D-allofuranosyl)hypoxanthine (6), 7-(6'-deoxy-beta-D-allofuranosyl)hypoxanthine (7), 9-(6'-deoxy-beta-D-allofuranosyl)guanine (8), and 7-(6'-deoxy-beta-D-allofuranosyl)guanine (9). The two nucleosides with the purine joined at the N-9 position, namely, 6 and 8, are easily distinguished from the other two nucleosides (7 and 9), having N-7 junctions, by their NMR spectra. Reaction of 1 with the trimethylsilyl derivative of 6-chloropurine afforded 10, which upon treatment with thiourea and deblocking gave 9-(6'-deoxy-beta-D-allofuranosyl)-6-thiopurine (12). The hypoxanthine and guanine nucleosides showed no inhibition of mouse leukemia L1210 when tested in vivo, but the thiopurine nucleoside 12 showed strong inhibition of growth of L1210 both in vivo and in vitro. Compound 7 strongly inhibited purine nucleoside phosphorylase (KI = 8.8 X 10(-5) M), while compounds 8, 9, 6, and 12 were inactive.

Animals↗
PubMed2004

Nucleoside transporters in chronic lymphocytic leukaemia.

Nucleoside derivatives have important therapeutic activity in chronic lymphocytic leukaemia (CLL). Experimental evidence indicates that in CLL cells most of these drugs induce apoptosis ex vivo, suggesting that programmed cell death is the mechanism of their therapeutic action, relying upon previous uptake and metabolic activation. Although defective apoptosis and poor metabolism often cause resistance to treatment, differential uptake and/or export of nucleosides and nucleotides may significantly modulate intracellular drug bioavailability and, consequently, responsiveness to therapy. Two gene families, SLC28 and SLC29, encode transporter proteins responsible for concentrative and equilibrative nucleoside uptake (CNT and ENT, respectively). Furthermore, selected members of the expanding ATP-binding cassette (ABC) protein family have recently been identified as putative efflux pumps for the phosphorylated forms of these nucleoside-derived drugs, ABCC11 (MRP8) being a good candidate to modulate cell sensitivity to fluoropyrimidines. Sensitivity of CLL cells to fludarabine has also been recently correlated with ENT-type transport function, suggesting that, besides the integrity of apoptotic pathways and appropriate intracellular metabolism, transport across the plasma membrane is also a relevant event during CLL treatment. As long as nucleoside transporter expression in leukaemia cells is not constitutive, the possibility of regulating nucleoside transporter function by pharmacological means may also contribute to improve therapy.

Animals↗
PubMed2003

Functional characterization in yeast of genetic variants in the human equilibrative nucleoside transporter, ENT1.

The human equilibrative nucleoside transporter, ENT1, appears to play a critical role in the disposition of nucleosides and nucleoside analogs used clinically as anti-viral and anti-cancer drugs. Recently, we identified variants of ENT1 in an ethnically diverse DNA sample set from 247 individuals, focusing primarily on the coding region. The goal of the present study was to analyse the haplotype structure and functionally characterize the variants of ENT1. We observed that a single haplotype, ENT1*1, accounted for 91.3% of the 494 chromosomes. Functional analysis in Saccharomyces cerevisiae revealed no differences in the kinetics of uptake of nucleosides and nucleoside analogs by the two non-synonymous variant transporters, ENT1-I216T and ENT1-E391K, and the reference ENT1. These results, together with the observation that there are few haplotypes of ENT1, indicate that coding region variants of ENT1 do not contribute to inter-individual differences in response to nucleoside analog drugs.

Amino Acid Sequence↗