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PubMed2000

Cloning, genomic organization and chromosomal localization of the gene encoding the murine sodium-dependent, purine-selective, concentrative nucleoside transporter (CNT2).

A PCR-based strategy was used to isolate a 2653 bp cDNA encoding the mouse sodium-dependent, purine nucleoside selective, concentrative nucleoside transporter (designated mCNT2). The deduced protein sequence exhibits 93 and 80% identity to the previously cloned rat and human sodium-dependent, purine nucleoside selective, nucleoside transporters, respectively. Characterization of 3H-nucleoside uptake by COS-1 cells transiently transfected with the cDNA demonstrated that it encoded a functional nucleoside transport activity with selectivity for purine nucleosides. The cDNA was used to screen a murine (strain 129SvJ/6) genomic library in pBeloBAC11 to identify a clone containing the mCNT2 gene. A PCR strategy was used to identify and sequence the intron-exon boundaries and to determine the approximate sizes of the introns. The mCNT2 gene spans approximately 13.7 kb and is encoded by 15 exons. The gene was mapped to mouse chromosome 2e3 by fluorescence in situ hybridization.

Amino Acid Sequence↗
PubMed1998

Nucleoside-nucleotide mixture increases bone marrow cell number and small intestinal RNA content in protein-deficient mice after an acute bacterial infection.

The aim of this study was to determine if intraperitoneal administration of a nucleoside-nucleotide mixture would affect small intestinal morphology, bone marrow cell number, and DNA content in protein-deficient mice subjected to acute bacterial infection. Mice were randomized into two groups and orally fed protein-free diet or nucleotide-free 20% casein diet for 10 d. The mice in each group were divided into two subgroups and intraperitoneally administered 0.35 mL saline or nucleoside-nucleotide mixture (17.5 mL/kg body weight) for 10 d. On day 10, one subgroup from each major dietary group was either inoculated intravenously with methicillin-resistant Staphylococcus aureus or saline. Three days later, small intestinal morphology, bone marrow cell number, and DNA content were evaluated in infected and noninfected mice. Protein-deficiency in association with infection significantly (P < 0.05) reduced body weight, small intestinal weight, crypt depth, villous height, and wall thickness. All dietary groups exhibited similar small intestinal DNA and protein contents (protein:DNA ratio, RNA:DNA ratio) at 3 d postinfection. However, small intestinal RNA content in the infected protein-free dietary group administered nucleoside-nucleotide mixture was higher (P < 0.05) and tended to be higher relative to the infected nucleotide-free 20% casein group administered nucleoside-nucleotide mixture compared with the rest of the groups. In the infected protein-free dietary group administered nucleoside-nucleotide mixture, bone marrow cell number and bone marrow DNA content were higher (P < 0.05) relative to the infected protein-free dietary group, nucleotide-free 20% casein diet administered saline, or nucleoside-nucleotide mixture, respectively. We conclude that intraperitoneal administration of nucleoside-nucleotide mixture may stimulate bone marrow cell proliferation, DNA content, and small intestinal RNA content during periods of relative deficiency such as protein-deficiency in combination with infection.

Animals↗
PubMed1984

Antibody-nucleic acid complexes. Antigenic domains within nucleosides as defined by solid-phase immunoassay.

The usefulness of solid-phase immunoassays for the characterization of anti-nucleoside antibodies was investigated. Antibodies specific for guanosine (G), 7-methyl-guanosine (m7G), and cytidine (C) were obtained from the serum of rabbits immunized with nucleoside-KLH (keyhole limpet hemocyanin) conjugates. Solid-phase assays consisted of measuring the ability of these antibodies to be retained by microtiter wells containing immobilized nucleoside-BSA (bovine serum albumin) conjugates. Nucleosides employed as haptens included adenosine (A), N6-methyl-A (m6A), guanosine (G), N2,N2-dimethyl-G (m22G), 1-methyl-G (m1G), O6-methyl-G (m6G), 7-methyl-G (m7G), cytidine (C), 5-methyl-C (m5C), uridine (U), and ribothymidine (T). Spectral analysis of these conjugates revealed that 15-20 nucleosides were coupled to each BSA molecule. Quantitative information regarding the various reactions associated with these assays was obtained by employing antigen and antibody (IgG) preparations radiochemically labeled via reductive methylation using NaB3H4 and formaldehyde (specific activities 0.6-2.1 X 10(6) cpm/micrograms). Data obtained with 3H-labeled antigens indicated that the adsorption of all nucleoside-BSA conjugates was uniform and irreversible with respect to the assay conditions used. Assays designed to measure antibody binding in the presence of excess antigen revealed that (i) nonspecific binding to immobilized BSA was negligible, (ii) as little as 0.5 ng of bound antibody could be detected, (iii) antibody retention was directly proportional to antibody concentration, and (iv) each anti-nucleoside antibody cross-reacted to a considerable extent with nonhomologous haptens.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies↗
PubMed2002

Enzymatic phosphorylation of unnatural nucleosides.

In an effort to expand the genetic alphabet, a number of unnatural, predominantly hydrophobic, nucleoside analogues have been developed which pair selectively in duplex DNA and during enzymatic synthesis. Significant progress has been made toward the efficient in vitro replication of DNA containing these base pairs. However, the in vivo expansion of the genetic alphabet will require that the unnatural nucleoside triphosphates be available within the cell at sufficient concentrations for DNA replication. We report our initial efforts toward the development of an unnatural in vivo nucleoside phosphorylation pathway that is based on nucleoside salvage enzymes. The first step of this pathway is catalyzed by the D. melanogaster nucleoside kinase, which catalyzes the phosphorylation of nucleosides to the corresponding monophosphates. We demonstrate that each unnatural nucleoside is phosphorylated with a rate that should be sufficient for the in vivo replication of DNA.

Animals↗
PubMed1988

Nucleosides. 150. Synthesis and some biological properties of 5-monofluoromethyl, 5-difluoromethyl, and 5-trifluoromethyl derivatives of 2'-deoxyuridine and 2'-deoxy-2'-fluoro-beta-D-arabinofuranosyluracil.

A new synthesis of 5-(monofluoromethyl)- and 5-(difluoromethyl)-2'-deoxy-2'-fluoro-beta-D-arabinofuranosyluracil (F-FMAU and F2-FMAU) is reported. 3',5'-Di-O-(tert-butyldiphenyl)silylated thymidine or FMAU was photochemically brominated with NBS to the corresponding alpha-monobromide, which was hydrolyzed to the 5-hydroxymethyl derivative. Further oxidation of the latter with MnO2 afforded the 5-formyluracil nucleoside. Treatment of these nucleosides with DAST in CH2Cl2 gave the protected alpha-fluorinated nucleosides. Desiylation with TBAF afforded the desired free nucleosides. Also, 5-(trifluoromethyl)-2'-deoxy-2'-fluoro-beta-D-arabinofuranosyluracil (F3-FMAU) was synthesized by copper-catalyzed trifluoromethylation of 5-iodo-2'-fluoro-ara-U (FIAU). These new nucleosides were studied in comparison with the corresponding 2'-deoxy-erythro-pentofuranosyl derivatives, for their inhibitory activity against cellular thymidylate synthase (TS) and [3H]TdR incorporation into DNA, cytotoxicity against HL-60 cells, and antiviral activity against herpes simplex types 1 and 2 (HSV-1 and -2). F2-TDR and F3-TDR strongly inhibited TS and were also quite cytotoxic and antiherpetic, whereas FTDR was only active in the antiviral assay. In the 2'-fluoroarabino series, fluorine substitution at the alpha-methyl function did not alter significantly the antiherpetic activity. Although FMAU and F-FMAU did not inhibit TS to any significant extent, F2-FMAU and F3-FMAU were weakly inhibitory. The latter nucleosides did not inhibit [3H]TDR incorporation into DNA, while all the other alpha-fluorinated thymine nucleosides inhibited the incorporation of radioactivity of [3H]TDR into DNA to various extents. F2-FMAU and F3-FMAU were about 2 orders of magnitude less cytotoxic against HL-60 cells than were F2-TDR and F3-TDR. The results strongly suggest that in both the 2'-deoxy-2'-fluoroarabino and the 2'-deoxy-erythro-pentofurano series the cytotoxic action of the alpha,alpha-difluoro and alpha,alpha,alpha-trifluoro derivatives may involve the inhibition of TS. The synthesis of [2-14C]F2-FMAU, as an experimental imaging agent, is also described. Unfortunately, the highly selective uptake of the labeled compound within infected brain regions previously noted with [2-14C]FMAU was not detected with the derivative [2-14C]F2-FMAU.

Animals↗
PubMed2001

Analysis of peroxynitrite reactions with guanine, xanthine, and adenine nucleosides by high-pressure liquid chromatography with electrochemical detection: C8-nitration and -oxidation.

Peroxynitrite, the reaction product of nitric oxide and superoxide anion, and a powerful oxidant, was found to nitrate as well as oxidize adenine, guanine, and xanthine nucleosides. A highly sensitive reverse-phase HPLC method with a dual-mode electrochemical detector, which reduces the nitro product at the first electrode and detects the reduced product by oxidation at the second electrode, was applied to detect femtomole levels of 8-nitroguanine and 8-nitroxanthine. This method was used to separate and identify the products of nitration and oxidation from the reactions of nucleosides with peroxynitrite. Peroxynitrite nitrates deoxyguanosine at neutral pH to give the very unstable 8-nitrodeoxyguanosine, in addition to 8-nitroguanine. 8-Nitrodeoxyguanosine, with a half-life of approximately 10 min at room temperature and </=3 min at 37 degrees C, hydrolyzes at pH 7 to 8-nitroguanine. A decrease in the reaction pH resulted in a decrease in the level of C8-nitration. Peroxynitrite also oxidizes deoxyguanosine in a pH-dependent manner, to give 8-oxodeoxyguanosine with a maximum yield (0.5-0.7%) at pH 5. Guanosine and xanthosine exhibit reactivity similar to that of deoxyguanosine toward peroxynitrite at neutral pH, producing only the corresponding 8-nitronucleosides as well as 8-nitroguanine and 8-nitroxanthine, respectively. 8-Nitroguanosine at pH 7, with a half-life of several weeks at 5 degrees C and 5 h at 37 degrees C, was much more stable than 8-nitrodeoxyguanosine. C8-nitration was confirmed by dithionite reduction to the corresponding amino nucleosides, which cochromatographed with synthesized 8-amino nucleoside standards. In contrast to guanine nucleosides, adenine nucleosides undergo peroxynitrite-mediated C8 oxidation even at neutral pH to give the corresponding 8-oxoadenine nucleosides in approximately 0.3% yield. Adenine nitration, though minor compared to C8-oxidation, appears to occur at both C2 and C8 positions of the adenine ring. Lowering the reaction pH from 7 to 5 results in 2.4- and 2.2-fold increases in the yields of 8-oxo-dA and 8-oxo-Ado, respectively, but the level of nitration is not altered.

Adenine↗
PubMed2005

A "gain of function" mutation in a protein mediates production of novel modified nucleosides.

The mutation sufY204 mediates suppression of a +1 frameshift mutation in the histidine operon of Salmonella enterica serovar Typhimurium and synthesis of two novel modified nucleosides in tRNA. The sufY204 mutation, which results in an amino-acid substitution in a protein, is, surprisingly, dominant over its wild-type allele and thus it is a "gain of function" mutation. One of the new nucleosides is 5-methylaminomethyl-2-thiouridine (mnm(5)s(2)U34) modified by addition of a C(10)H(17) side chain of unknown structure. Increased amounts of both nucleosides in tRNA are correlated to gene dosage of the sufY204 allele, to an increased efficiency of frameshift suppression, and to a decreased amount of the wobble nucleoside mnm(5)s(2)U34 in tRNA. Purified tRNA(Gln)(cmnm(5)s(2)UUG) in the mutant strain contains a modified nucleoside similar to the novel nucleosides and the level of aminoacylation of tRNA(Gln)(cmnm(5)s(2)UUG) was reduced to 26% compared to that found in the wild type (86%). The results are discussed in relation to the mechanism of reading frame maintenance and the evolution of modified nucleosides in tRNA.

Amino Acid Substitution↗
PubMed1998

Na+-dependent nucleoside transport in liver: two different isoforms from the same gene family are expressed in liver cells.

Hepatocytes show a Na+-dependent nucleoside transport activity that is kinetically heterogeneous and consistent with the expression of at least two independent concentrative Na+-coupled nucleoside transport systems (Mercader et al. Biochem. J. 317, 835-842, 1996). So far, only a single nucleoside carrier-related cDNA (SPNT) has been isolated from liver cells (Che et al. J. Biol. Chem. 270, 13596-13599, 1995). This cDNA presumably encodes a plasma membrane protein responsible for Na+-dependent purine nucleoside transport activity. Thus, the liver must express, at least, a second nucleoside transporter which should be pyrimidine-preferring. Homology cloning using RT-PCR revealed that a second isoform is indeed present in liver. This second isoform turned out to be identical to the 'epithelial-specific isoform' called cNT1, which shows in fact high specificity for pyrimidine nucleosides. Although cNT1 mRNA is present at lower amounts than SPNT mRNA, the amounts of cNT1 protein, when measured using isoform-specific polyclonal antibodies, were even higher than the SPNT protein levels. Moreover, partially purified basolateral plasma membrane vesicles from liver were enriched in the SPNT but not in the cNT1 protein, which suggests that the subcellular localization of these carrier proteins is different. SPNT and cNT1 protein amounts in crude membrane extracts from 6 h-regenerating rat livers are higher than in the preparations from sham-operated controls (3.5- and 2-fold, respectively). These results suggest that liver parenchymal cells express at least two different isoforms of concentrative nucleoside carriers, the cNT1 and SPNT proteins, which show differential regulation and subcellular localization.

Animals↗
PubMed2002

Cytotoxicity of 2-chlorodeoxyadenosine and arabinosylcytosine in leukaemic lymphoblasts from paediatric patients: significance of cellular nucleoside transporter content.

2-chlorodeoxyadenosine (2-CdA) and arabinosylcytosine (araC) are nucleoside drugs that are used to treat various leukaemias, although 2-CdA has not been tested extensively in children with acute lymphoblastic leukaemia (ALL). Nucleoside cytotoxicity depends on the conversion of these agents to 5'-phosphate derivatives, following drug entry into cells via nucleoside transport (NT) processes. This study compared es nucleoside transporter content, determined using a flow cytometric assay with SAENTA [5'-S-(2-aminoethyl)-N6-(4-nitrobenzyl)-5'-thioadenosine] fluorescein, and cytotoxicities of 2-CdA and araC in fresh lymphoblasts from previously untreated paediatric ALL patients and the human T-lymphoblast cell line, CCRF-CEM. Lymphoblast samples from individual patients ranged widely in sensitivity to both 2-CdA (IC50, 6 nmol/l to > 5 micromol/l; mean = 418 nmol/l; n = 8) and araC (IC50, 59 nmol/l to > 5 micromol/l; mean = 1050 nmol/l; n = 7), although IC50 values for the two drugs were correlated (r = 0.78, P = 0.032, n = 7). Cellular es nucleoside transporter content varied more than 35-fold among samples from 10 patients. The correlation between es nucleoside transporter content and drug sensitivity was statistically significant for araC (r = -0.93, P = 0.023, n = 5), but not for 2-CdA (r = -0.57, P = 0.23, n = 6). Exposure of CCRF-CEM cells to araC resulted in a substantial araC concentration-dependent increase in the relative survival of es transporter-deficient cells, whereas the increase was slight following exposure to 2-CdA. We conclude that, in ALL lymphoblasts, es nucleoside transporter content is a determinant of araC sensitivity and that a deficiency in NT may impart resistance to araC.

Antimetabolites, Antineoplastic↗
PubMed2000

Nutritional regulation of nucleoside transporter expression in rat small intestine.

BACKGROUND & AIMS: Concentrative nucleoside transporters CNT1 (pyrimidine preferring) and CNT2 (purine preferring) may be involved in the uptake of nucleoside-derived drugs used in antiviral and chemical therapies. The possibility that nucleoside carrier isoform expression is modulated by nutrient availability has been studied. METHODS: CNT1 and CNT2 tissue distribution was determined by Western blot analysis. The effect of 48-hour starvation on CNT expression was then studied. Nucleoside transporter expression and uptake activity were measured in jejunal brush border plasma membrane vesicles from fed and starved rats. The expression of nucleoside transporters was later determined in a second model of nutrient deficiency: rats fed a purified diet with or without nucleotides for 10 days. RESULTS: CNT1 and CNT2 nucleoside transporters were expressed in a wider variety of tissues than expected from messenger RNA distribution analysis. CNT1 was sensitive to nutrient availability in small intestine and, accordingly, jejunal brush border membrane vesicles from 48-hour-fasted rats showed increased expression of CNT1 and enhanced Na(+)-dependent thymidine and gemcitabine uptake. This effect was mimicked by feeding semipurified diets lacking nucleotides. CONCLUSIONS: Substrate availability modulates nucleoside transporter expression (CNT1) in rat jejunum in vivo.

Animal Nutritional Physiological Phenomena↗
PubMed2004

Triple-nucleoside regimens versus efavirenz-containing regimens for the initial treatment of HIV-1 infection.

BACKGROUND: Regimens containing three nucleoside reverse-transcriptase inhibitors offer an alternative to regimens containing nonnucleoside reverse-transcriptase inhibitors or protease inhibitors for the initial treatment of human immunodeficiency virus type 1 (HIV-1) infection, but data from direct comparisons are limited. METHODS: This randomized, double-blind study involved three antiretroviral regimens for the initial treatment of subjects infected with HIV-1: zidovudine-lamivudine-abacavir, zidovudine-lamivudine plus efavirenz, and zidovudine-lamivudine-abacavir plus efavirenz. RESULTS: We enrolled a total of 1147 subjects with a mean baseline HIV-1 RNA level of 4.85 log10 (71,434) copies per milliliter and a mean CD4 cell count of 238 per cubic millimeter were enrolled. A scheduled review by the data and safety monitoring board with the use of prespecified stopping boundaries led to a recommendation to stop the triple-nucleoside group and to present the results in the triple-nucleoside group in comparison with pooled data from the efavirenz groups. After a median follow-up of 32 weeks, 82 of 382 subjects in the triple-nucleoside group (21 percent) and 85 of 765 of those in the combined efavirenz groups (11 percent) had virologic failure; the time to virologic failure was significantly shorter in the triple-nucleoside group (P<0.001). This difference was observed regardless of the pretreatment HIV-1 RNA stratum (at least 100,000 copies per milliliter or below this level; P< or =0.001 for both comparisons). Changes in the CD4 cell count and the incidence of grade 3 or grade 4 adverse events did not differ significantly between the groups. CONCLUSIONS: In this trial of the initial treatment of HIV-1 infection, the triple-nucleoside combination of abacavir, zidovudine, and lamivudine was virologically inferior to a regimen containing efavirenz and two or three nucleosides.

Adult↗
PubMed2001

Chlorination of guanosine and other nucleosides by hypochlorous acid and myeloperoxidase of activated human neutrophils. Catalysis by nicotine and trimethylamine.

Activated human neutrophils secrete myeloperoxidase, which generates HOCl from H2O2 and Cl(-). We have found that various (2'-deoxy)nucleosides react with HOCl to form chlorinated (2'-deoxy)nucleosides, including novel 8-chloro(2'-deoxy)guanosine, 5-chloro(2'-deoxy)cytidine, and 8-chloro(2'-deoxy)adenosine formed in yields of 1.6, 1.6, and 0.2%, respectively, when 0.5 mM nucleoside reacted with 0.5 mM HOCl at pH 7.4. The relative chlorination, oxidation, and nitration activities of HOCl, myeloperoxidase, and activated human neutrophils in the presence and absence of nitrite were studied by analyzing 8-chloro-, 8-oxo-7,8-dihydro-, and 8-nitro-guanosine, respectively, using guanosine as a probe. 8-Chloroguanosine was always more easily formed than 8-oxo-7,8-dihydro- or 8-nitro-guanosine. Using electrospray ionization tandem mass spectrometry, we show that several chlorinated nucleosides including 8-chloro(2'-deoxy)guanosine are formed following exposure of isolated DNA or RNA to HOCl. Micromolar concentrations of tertiary amines such as nicotine and trimethylamine dramatically enhanced chlorination of free (2'-deoxy)nucleosides and nucleosides in RNA by HOCl. As the G-463A polymorphism of the MPO gene, which strongly reduces myeloperoxidase mRNA expression, is associated with a reduced risk of lung cancer, chlorination damage of DNA /RNA and nucleosides by myeloperoxidase and its enhancement by nicotine may be important in the pathophysiology of human diseases associated with tobacco habits.

Animals↗
PubMed1999

Contribution of the nucleoside transport system to doxorubicin transport in HL60 cells but not in mononuclear cells.

Previously, we reported that pirarubicin (THP), an anthracycline, was transported, at least in part, via a nucleoside transport system in human leukemic HL60 cells, but not in mononuclear cells (MNCs). In this study, the contribution of the nucleoside transport system to the transport of other anthracyclines, doxorubicin (DOX), daunorubicin (DNR) and idarubicin (IDA), in HL60 cells and MNCs was investigated. The experiments were performed after both types of cells had been pretreated with a metabolic inhibitor, 2,4-dinitrophenol, to deplete cellular ATP. The DOX uptake by HL60 cells was partially inhibited by inhibitors of equilibrative nucleoside transporters. In HL60 cells, moreover, the uptake of DOX depended on an inwardly directed Na(+)-gradient, and was inhibited by concentrative nucleoside transporters, but there was no change in the DNR or IDA uptake under any of these conditions. On the other hand, the uptake of the three drugs by MNCs was not affected by any inhibitors of the nucleoside transporters, and there was no dependence of the uptake on an Na(+)-gradient. These results suggested that DOX, but not DNR or IDA, was partially transported in HL60 cells via the nucleoside transport system, whereas in MNCs the system did not contribute to the uptake of any of these three drugs. Thus, nucleoside transport systems contributing to the transport of anthracyclines may be different among different derivatives and cell types.

Antibiotics, Antineoplastic↗
PubMed1977

Thymidine uptake in bacteria: the effect of purine nucleosides.

The kinetics of thymidine uptake by Escherichia coli and Bacillus subtilis cells in the presence of adenine and guanine nucleosides was investigated. The initial concentration of thymidine in the growth medium was 0.35 microng/ml while the initial concentration of purine nucleosides ranged from 25 to 250 microng/ml. Adenine nucleosides when present at a concentration more than 50 microng/ml strongly inhibit thymidine uptake by the bacteria. The duration of the inhibition depends on the initial concentration of adenine nucleoside in the growth medium. At an initial concentration of deoxyadenosine (or adenosine) of 250 microng/ml the time of inhibition of thymidine uptake was about 60 min. During this period thymidine is almost completely preserved from the action of bacterial thymidine phosphorylase. Guanine nucleosides (guanosine or deoxyguanosine) do not markedly inhibit thymidine uptake by bacteria even at a concentration of 250 microng/ml. It is shown that they do protect thymidine from the phosphorolytic action of the thymidine phosphorylase although much less effectively than adenine nucleosides. It is suggested that some areas in the bacterial membrane where thymidine phosphorylase is located are not available to guanine nucleosides.

Bacillus subtilis↗
PubMed2005

Normal and modified urinary nucleosides represent novel biomarkers for colorectal cancer diagnosis and surgery monitoring.

BACKGROUND: Up to now, there is still no ideal tumor marker in early diagnosis and effective monitoring, especially for surgical resection of colorectal cancer (CRC). The aim of the present study was to evaluate the application of urinary normal and modified nucleosides in diagnosis and surgery monitoring of CRC. METHODS: Between October 2002 and July 2003, 52 consecutive patients with pathological confirmed CRC were enrolled. Spontaneous urine samples were collected 1 day before surgery and on day 8 postoperatively, and 14 urinary nucleosides were determined by reverse-phase high-performance liquid chromatography (RP-HPLC). Another 62 healthy people were also studied as control. The clinical routine tumor markers, serum carcinoembryonic antigen (CEA), carbohydrate antigen (CA)199, CA125, and alpha-fetoprotein (AFP) of CRC patients, were correspondingly evaluated by electrochemiluminescent immunoassay. RESULTS: The levels of 11 out of 14 of the determined urinary nucleosides in the CRC group were much higher than those of normal controls. Through the principal component analysis of these 14 nucleosides, 76.9% of CRC patients were correctly classified. The sensitivity of this analysis was much higher than that of CEA (38.5%), CA199 (40.4%), CA125 (15.4%), and AFP (17.3%; P < 0.01). Receiver operating characteristic (ROC) curve analysis of 1-methylguanosine (m1G) and pseudouridine (Pseu) showed good sensitivity-specificity profiles of the diagnosis of CRC. The elevated levels of the nine nucleosides significantly decreased after curative resection of 40 CRC cases. The data also showed that the preoperative levels of some nucleosides were positively related with tumor size and Dukes staging of CRC. CONCLUSION: The evaluation of normal and modified urinary nucleosides might become novel tumor markers, which will be facilitated in the clinical setting and helpful in the diagnosis, management and follow up of CRC. Pseu and m1G may be more promising for clinical use and be worthy of further studies in the near future.

Adult↗
PubMed2006

Antiviral activities of novel 5-phosphono-pent-2-en-1-yl nucleosides and their alkoxyalkyl phosphonoesters.

Three acyclic nucleoside phosphonates are currently approved for clinical use against infections caused by cytomegalovirus (Vistide), hepatitis B virus (Hepsera), and human immunodeficiency virus type 1 (Viread). This important antiviral class inhibits viral polymerases after cellular uptake and conversion to their diphosphates, bypassing the first phosphorylation, which is required for conventional nucleoside antivirals. Small chemical alterations in the acyclic side chain lead to marked differences in antiviral activity and the spectrum of activity of acyclic nucleoside phosphonates against various classes of viral agents. We synthesized a new class of acyclic nucleoside phosphonates based on a 5-phosphono-pent-2-en-1-yl base motif in which the oxygen heteroatom usually present in acyclic nucleoside phosphonates has been replaced with a double bond. Since the intrinsic phosphonate moiety leads to low oral bioavailability and impaired cellular penetration, we also prepared the hexadecyloxypropyl esters of the 5-phosphono-pent-2-en-1-yl nucleosides. Our earlier work showed that this markedly increases antiviral activity and oral bioavailability. Although the 5-phosphono-pent-2-en-1-yl nucleosides themselves were not active, the hexadecyloxypropyl esters were active against DNA viruses and hepatitis B virus, in vitro. Notably, the hexadecyloxypropyl ester of 9-(5-phosphono-pent-2-en-1-yl)-adenine was active against hepatitis B virus mutants resistant to lamivudine, emtricitabine, and adefovir.

Antiviral Agents↗
PubMed1982

Interconversion and uptake of nucleotides, nucleosides, and purine bases by the marine bacterium MB22.

Whole cells and isolated membranes of the marine bacterium MB22 converted nucleotides present in the external medium rapidly into nucleosides and then into bases. Nucleosides and purine bases formed were taken up by distinct transport systems. We found a high-affinity common transport system for adenine, guanine, and hypoxanthine, with a Km of 40 nM. This system was inhibited noncompetitively by purine nucleosides. In addition, two transport systems for nucleosides were present: one for guanosine with a Km of 0.8 microM and another one for inosine and adenosine with a Km of 1.4 microM. The nucleoside transport systems exhibited both mixed and noncompetitive inhibition by different nucleosides other than those translocated; purine and pyrimidine bases had no effect. The transport of nucleosides and purine bases was inhibited by dinitrophenol or azide, thus suggesting that transport is energy dependent. Inside the cell all of the substrates were converted mainly into guanosine, xanthine, and uric acid, but also anabolic products, such as nucleotides and nucleic acids, could be found.

Adenine↗
PubMed1996

Comparative effects of dietary nucleoside-nucleotide mixture and its components on endotoxin induced bacterial translocation and small intestinal injury in protein deficient mice.

BACKGROUND: Nucleoside-nucleotide mixture has been shown to improve gut morphology and reduce the incidence of bacterial translocation in protein deficient mice. AIMS: To compare the reparative effect of nucleoside-nucleotide mixture and their individual components on maintenance of gut integrity and bacterial translocation based on their differential metabolism and utilisation. METHODS: ICR (CD-1) mice were randomised into eight groups of 10 animals each and fed 20% casein diet (control), protein free diet, or protein free diet supplemented with 3 M cytidine, uridine, thymidine, inosine, guanosine monophosphate, or nucleoside-nucleotide mixture for four weeks. On the fourth week, each mouse was injected lipopolysaccharide intraperitoneally (50 micrograms/500 microliters) and the incidence of bacterial translocation, caecal bacterial populations, and the ileal histology, noted 48 hours later. RESULTS: The death rate in the control group was 40% compared with 10% in the nucleoside-nucleotide mixture and 20% each in the individual components groups, respectively. Bacterial translocation to the mesenteric lymph node did occur in 100% of the surviving mice fed the control diet in comparison with 44% (nucleoside-nucleotide), 50% (cytidine), 75% (thymidine), 75% (uridine), 63% (inosine), and 63% (guanosine monophosphate). Histologically, the damage to the gut was more distinct in the protein free diet group. Villous height, crypt depth, and wall thickness in the nucleoside-nucleotide mixture group mean (SEM) (5.01 (0.34); 0.87 (0.14); 0.33 (0.10)), were respectively, higher compared with the protein free diet (3.34 (0.34); 0.61 (0.03); 0.18 (0.04)) group. In the cytidine group, crypt depth (0.86) (0.08)), and wall thickness (0.30 (0.002)) were higher. The same measurements in the components groups tended to be higher than the protein free diet group. Caecal bacterial populations were, however, similar in all groups. CONCLUSIONS: These results suggest that dietary nucleosides and nucleotides are essential nutrients for intestinal repair; nucleotides or cytidine provide a better response.

Animals↗