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PubMedDate not supplied

The effects of oral RNA and intraperitoneal nucleoside-nucleotide administration on methicillin-resistant Staphylococcus aureus infection in mice.

The effects of oral RNA and intraperitoneal nucleoside-nucleotide mixture administration on methicillin-resistant Staphylococcus aureus (MRSA) strain 8985N infection were studied in mice. BALB/c mice were fed a nucleic acid-free diet or nucleic acid-free diet supplemented with 0.5% or 2.5% ribonucleic acid (RNA) for 30 days. Nucleoside-nucleotide mixture or saline (control) was intraperitoneally administered daily to these rats except for the 2.5% RNA group, which received saline only. On the 10th day of this treatment, the mice were inoculated intravenously with the viable MRSA organisms. Susceptibility to the MRSA was determined by animal survival and recovery of the MRSA from the organs. The survival rates in the three groups that were administered saline were 29%, 35%, and 40% for nucleic acid-free diet, 0.5% RNA, and 2.5% RNA groups, respectively, whereas in the two groups that received the nucleoside-nucleotide mixture the rates were 69% for the nucleic acid-free diet group and 55% for 0.5% RNA group. The susceptibility of the mice to the MRSA challenge was not affected by dietary RNA, which indicates the ineffectiveness of oral RNA. The combined survival rate in the two nucleoside-nucleotide groups (64%) was statistically different (p < .01) from that in the three saline groups (34%). There was a greater reduction in viable organism recovery in the kidney and spleen of the surviving mice that had been administered the nucleoside-nucleotide mixture than in those administered saline.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed2002

Synthesis and antiherpesvirus activities of 5-alkyl-2-thiopyrimidine nucleoside analogues.

Twenty 5-alkyl-2-thiopyrimidine nucleosides were newly synthesized and examined for antiviral activities against herpes simplex virus (HSV), varicella-zoster virus (VZV) and human cytomegalovirus (HCMV). In this study, 2'-deoxy-5-alkyl-2-thiocytidine analogues had lower 50% effective concentration (EC50) values against HSV-1, and 2'-deoxy-5-alkyl-2-thiouridine analogues showed lower EC50 against VZV than their congeners of arabinoside form. Among the compounds examined, 2'-deoxy-5-ethyl and 5-propyl-2-thiocytidine (TN-53 and TN-54) were most potent and selective anti-HSV compounds. Their EC50s were 0.04 and 0.15 microM, and selectivity indexes were more than 7,215 and 1,849, respectively. On the other hand, 2'-deoxy-5-propyl-2-thiouridine (TN-51), 5-bromovinyl-2-thiouracil arabinoside (TN-65) and 5-styryl-2-thiouracil arabinoside (TN-67) were most potent and selective anti-VZV compounds. Their EC50s were 3.1, 3.8 and 2.6 pM for CaQu strain of VZV, respectively, and 2.1 to 3.0 times lower than that of acyclovir. All 2-thiopyrimidine nucleoside analogues did not show antiviral activities against thymidine kinase (TK) negative strains of HSV-1 and VZV. Only three 2-thiocytosine arabinoside compounds showed marginal anti-CMV activities (EC50s were 57-159 pM). All of the five alkyl-2-thio-pyrimidine nucleoside analogues examined were not cytotoxic to human lymphoblastoid cells (RPM18226) and human embryonic fibroblast cells (MRC-5) at 240 microM (100 microg/ml) or more. Regarding the structure-activity relationship of 5-alkyl-2-thiopyrimidine nucleoside analogues, the following remarks will be noted. Elongation of 5-alkyl chain (methyl to ethyl) of 2-thiocytosine in both deoxyribosyl and arabinosyl nucleosides increased anti-HSV-1 activity but not anti-VZV activity. Furthermore, elongation of the same chain (ethyl to propyl) of 2-thiodeoxyuridine increased anti-VZV activity whereas it did not in the case of 2-thiouracil arabinosides.

Antiviral Agents↗

PubMed1993

[Synthetic studies on highly modified nucleosides directed towards creation of anti-HIV agents].

Recent studies on the synthesis of highly modified nucleosides, especially carbocyclic nucleosides, aiming at creating anti-HIV agents have been reviewed. The review includes new methods for the synthesis of carbocyclic C-nucleosides and carbocyclic N-nucleosides including carbocyclic oxetanocin and its analogues developed in our laboratory. Among the carbocyclic nucleosides synthesized, 9-(c-4,t-5-bishydroxymethylcyclopent-2-en-r-1-yl)-9H-adenine (BCA) showed significant anti-HIV activity.

Drug Design↗

PubMed2000

[Syntheses and properties of conformationally restrained nucleosides and oligonucleotides analogues].

This review summarizes our efficient syntheses of novel bicyclic nucleoside analogues, 3'-O,4'-C-methyleneribonucleosides (1) (4-BC type nucleoside analogue), 2'-O,4'-C-methyleneribonucleosides (2) (5-BC), 3'-amino-3'-deoxy-3'-N,4'-C-methyleneribonucleosides (3) (aza 4-BC), and 3'-azido- and 3'-amino-3'-deoxy-2'-O,4'-C-methyleneribonucleosides (4, 5) (aza 5-BC). From 1H-NMR and X-ray crystallographic analyses, the 4-BC and aza 4-BC type nucleoside analogues (1, 3) were found to have a S-conformation predominantly, while the conformations of 5-BC and aza 5-BC type nucleoside analogues (2, 4, 5) were exclusively locked in N-form. The 4-BC and 5-BC type nucleoside analogues (1, 2) were effectively introduced into oligonucleotides using a DNA synthesizer. Furthermore, unprecedented hybridizing ability towards complementary RNA and DNA, RNA selectivity, potent triplex forming ability, and sufficient enzymatic stability of these modified oligonucleotides were also confirmed. These results should reveal a promising route to the development of antisense/antigene methodology.

Carbohydrate Conformation↗

PubMed2006

Evaluation of Bacillus anthracis thymidine kinase as a potential target for the development of antibacterial nucleoside analogs.

Bacillus anthracis, which causes anthrax, has attracted attention because of its potential use as a biological weapon. The risk of multidrug resistance against B. anthracis increases the need for antibiotics with new molecular targets. Nucleoside analogs are well-known antiviral and anticancer prodrugs, and thymidine kinase catalyzes the rate-limiting step in the activation of pyrimidine nucleoside analogs used in chemotherapy. The thymidine kinase gene from B. anthracis Sterne strain (34F2) (Ba-TK) was cloned and expressed in E. coli, and the product was purified and characterized regarding its substrate specificity. Ba-TK phosphorylated pyrimidine nucleosides and all natural nucleoside triphosphates served as phosphate donors. Size exclusion chromatography indicated a dimeric form of Ba-TK, regardless of the presence of ATP. Thymidine was the most efficient substrate with a low K(m) value (0.6 microM) and a V(max) of 3.3 micromol dTMP mg(-1) min(-1), but deoxyuridine (K(m)=4.2 microM, V(max)=4.1 micromol dUMP mg(-1) min(-1)) was also a good substrate. Several pyrimidine analogs were also tested and analogs with 5-position modifications showed higher activities compared to analogs with 3'- and N3-position modifications. Deoxyuridine analogs were the most potent inhibitors of B. anthracis growth in vitro. These results may be used to guide future development of nucleoside analogs against B. anthracis.

Amino Acid Sequence↗

PubMed1993

Protection of BALB/c mice against methicillin-resistant Staphylococcus aureus infection by intraperitoneal administration of nucleoside-nucleotide mixture.

The effect of intraperitoneally administered nucleic acid components (nucleoside-nucleotide mixture) on the recovery from methicillin-resistant Staphylococcus aureus (MRSA) strain 8985N infection was studied in mice. Two experiments were conducted in which BALB/c mice were fed a nucleotide-free 20% casein diet for 30 days. On the 10th day, the mice were inoculated intravenously with viable MRSA organisms. The mice were intraperitoneally administered nucleoside-nucleotide mixture or saline (control) daily from the onset of the experiment (experiment 1) or from the day of inoculation (experiment 2). The survival rate in the nucleoside-nucleotide group in experiment 1 (70%) was significantly higher than that in the saline group (20%) (p < 0.05). In experiment 2, the survival rate in the nucleoside-nucleotide group (55%) tended to be higher than that in the saline group (36%) without statistically significant difference; furthermore, in the surviving mice, the viable MRSA organisms recovered from the spleen and the kidney were fewer in the former group than in the latter group (p < 0.05). The studies showed that the intraperitoneal administration either before or after the MRSA challenge of the nucleoside-nucleotide mixture was effective for the recovery of the mice from the infection.

Animals↗

PubMed1994

Nucleoside transport sites in a cultured human retinal cell line established by SV-40 T antigen gene.

Adenosine, an important neuromodulatory compound in the brain and retina, is a potent vasodilator in most vascular beds throughout the body. Its actions are potentiated by inhibitors of nucleoside transport into cells. Knowledge of the existence of specific adenosine uptake systems in mammalian retina and the inhibition of the uptake by nitrobenzylthioinosine (NBMPR), a potent inhibitor of nucleoside transport, raises the possibility that the associated nucleoside transport system may be of pharmacological importance in retinal function. We have characterized the binding of the nucleoside transporter probe, [3H]NBMPR, to a cultured human retinal cell line established by transfection of SV-40 T antigen plasmid-DNA. The binding was specific, saturable and reversible. Scatchard analysis of the saturation data revealed that NBMPR binds to a homogeneous population of high affinity binding sites (KD = 0.65 +/- 0.22 nM; Bmax = 466 +/- 157 fmol/mg protein) characteristically similar to the binding sites in human retinal tissue (KD = 0.32 +/- 0.01 nM; Bmax = 292 +/- 41 fmol/mg protein). Selected compounds inhibited the binding in the cell line and retinal tissue with the same rank order of potency, suggesting that the transporters in the cell line and retinal tissue are similar. The data showed that the cell line is a useful model for the study of nucleoside transporter function in human retina.

Adenosine↗

PubMed1986

Urinary nucleosides in leukemia: laboratory and clinical applications.

Urinary nucleosides offer a number of useful laboratory and clinical applications in the study and analysis of leukemia. There are significant differences in the excretion of modified nucleosides between normal individuals and individuals with various forms of leukemia, as well as between leukemia patients at opposite ends of the clinical spectrum, i.e., those with active disease and those in remission. The nucleoside excretion levels correlate to bone marrow tumor burden in certain forms of leukemia, and limited serial data indicate the potential value of the nucleosides for predicting relapse before the disease deterioration can be recognized clinically. In addition, it may be feasible to assess the effectiveness of chemotherapy used in the treatment of leukemia much more rapidly with the urinary nucleoside markers than with conventional invasive methods.

Acute Disease↗

PubMed2000

Nucleotide and nucleoside supplementation may morphologically promote the differentiation of human caco-2 cells.

The effects of nucleotide and nucleoside supplementation on the formation of tight junctions and the expression of microvilli, as indexes of morphological differentiation were studied by using a human colon adenocarcinoma cell line (Caco-2 cells). The formation of tight junctions and the expression of microvilli were evaluated by measuring the transepithelial electrical resistance (TEER) and observing the cell surface under electron microscopic analysis, respectively. To clarify the nutritional significance of human milk nucleotides. we used a nucleotide mixture (and a corresponding nucleoside mixture) with a composition similar to that found in human milk. Nucleotides had no effect on TEER, but nucleosides markedly promoted the increase of TEER. When alkaline phosphatase activity in the brush border membrane was enhanced by the addition of triiodothyronine (TIT), nucleotides also promoted the increase of TEER. Cytidine and CMP predominant in the mixture influenced the increase of TEER materially. Furthermore, an electron microphotograph of the cell surface showed that nucleosides contributed to the expression of microvilli. Thus the results presented in this study suggest that nucleotide and nucleoside supplementation may enhance the morphological differentiation of Caco-2 cells.

Alkaline Phosphatase↗

PubMed1994

5'-Azido and 5'-fluoro alpha-nucleosides as analogues of AZT and FLT.

5-Azido-2,5-dideoxy-beta-D-erythro-pentofuranosyl nucleosides 10 and their corresponding alpha-anomers 11 have been synthesized by condensation of methyl 3-O-acetyl-5-azido-2,5-dideoxy-beta-D-erythro-pentofuranoside (7) with silylated nucleobases followed by deprotection with methanolic ammonia. Reaction of silylated thymine (19) with methyl 2,3-di-O-benzoyl-5-deoxy-5-fluoro-D-arabino-pentofuranoside (15) and methyl 5-azido-2,3-di-O-benzoyl-5-deoxy-alpha-D-arabino-pentofuranoside (17 alpha) afforded a mixture of the alpha-nucleosides 20 and the acyclo nucleosides 5-fluoro- and 5-azido-2,3-O-dibenzoyl-5-deoxy-1-O-methyl-1-(thymin-1-yl)-D -arabinitol (22). Compounds 20 and 22 were deprotected with methanolic ammonia to give the acyclic nucleosides 21 and 23, respectively. The new nucleosides were inactive against HSV-1 and HIV-1.

Animals↗

PubMed2001

An introduction to nucleoside and nucleotide analogues.

The introduction of newer and more potent agents has diverted attention away from the importance of nucleoside analogue reverse transcriptase inhibitors (NRTIs) in modern antiretroviral drug regimens. As a class, these proviral chain terminators lack the virological potency of either non-nucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor (PI) drugs, due largely to their competitive mode of inhibition and requirement for metabolic activation. However, neither NNRTIs nor PIs alone can maintain the complete suppression of HIV replication required for extended therapy, and both suffer from serious class cross-resistance on therapeutic failure. Thus, the NRTIs will remain essential components of highly active antiretroviral therapy (HAART) for the foreseeable future, both for their contribution to a regimen's virological potency and the subsequent preservation of the more potent drug classes used with them. However, it has become apparent in recent years that the current NRTIs exhibit duration-dependent adverse events as a class, which may limit the length of time for which they can be safely used. An independent contribution to peripheral fat wasting in lipodystrophy syndrome has been established for the use of NRTI drugs. Of greater clinical concern is their established association with potentially fatal lactic acidaemia and hepatic steatosis. Both these class events, as well as several individual drug events, such as peripheral; neuropathy, can be linked to progressive mitochondrial destruction with a greater or lesser degree of confidence. Mitochondrial toxicity, due in large part to the high affinity of several NRTI agents for uptake by mitochondrial DNA polymerase gamma, has been demonstrated both in vitro and in vivo. New chain-terminating agents are urgently needed that address issues of improved virological potency, greater efficacy in NRTI-experienced individuals, and greater long-term safety. The nucleotide class of reverse transcriptase inhibitor (NtRTI), currently under clinical development, addresses improved potency by abbreviating the intracellular activation pathway to allow a more rapid and complete conversion to the active agent. These nucleoside monophosphate analogues are taken as masked prodrugs bearing labile lipophilic groups to facilitate penetration of target cell membranes. Subsequent unmasking by endogenous chemolytic enzymes releases a partially activated nucleoside analogue metabolite. The NtRTI furthest along the developmental process is tenofovir disoproxil fumarate (TDF), an orally available acyclic adenine phosphonate analogue, currently in Phase III clinical trials. This agent has shown high potency and an unusually durable response in trials of single-agent therapy intensification in highly treatment-experienced individuals, and its active metabolite, tenofovir diphosphate, exhibits a long intracellular half-life in both resting and activated peripheral blood mononuclear cells that permits once daily dosing. Tenofovir diphosphate also exhibits a very low affinity for DNA polymerase gamma in vitro, suggesting a low degree of in vivo mitochondrial toxicity may be observed on long-term follow-up, although clinical data to support this inference are not yet available. The introduction of TDF and other NtRTIs as 'second-generation' nucleoside analogues carefully evaluated for potential long-term toxicity, can be expected to significantly improve the therapeutic options for both those currently on HAART and those yet to begin.

Anti-HIV Agents↗

PubMed2001

Mutational patterns in the HIV genome and cross-resistance following nucleoside and nucleotide analogue drug exposure.

A variety of key mutations in HIV reverse transcriptase (RT) have been associated with nucleoside reverse transcriptase inhibitor (NRTI) exposure, which give rise to a diverse range of effects in terms of altered drug susceptibilities, viral replicative capacity and RT biochemistry. There are three basic mechanisms of resistance conferred by specific mutations in the coding region of RT. The first is drug discrimination, whereby a particular drug or drugs are either selectively excluded from uptake or from the RT-primer-template catalytic complex. Drug discrimination is, for the most part, relatively specific for individual drugs. Repositioning of the template-primer to prevent a catalytically competent complex in the presence of a bound drug molecule has also been observed in some instances, and forms a second mechanism. The third, and potentially most significant for long-term efficacy of the NRTIs, is pyrophosphorolysis, the primary mode of resistance to zidovudine. Mutations selected by this drug or stavudine serve to elevate the natural rate of the reverse reaction for RT. Pyrophosphorolysis uncouples the last nucleoside monophosphate added to the proviral transcript, and attaches it to either a free pyrophosphate (regenerating a deoxynucleoside triphosphate) or to a nucleoside di- or triphosphate (usually ATP). Uncoupling a chain-terminating NRTI residue therefore rescues reverse transcription and reduces drug susceptibility across the class, since the process is not specific for the selecting drug. Of all the nucleoside-associated mutations, the best known and most studied are the six associated with thymidine analogue exposure. These six mutations (M41L, D67N, K70R, L210W, T215Y/F, K219Q) enhance RT pyrophosphorolysis to confer high-level viral resistance to zidovudine, and clinically significant loss of response to stavudine and didanosine. They have also been found to confer reduced susceptibility to lamivudine and abacavir, particularly when present alongside other NRTI-induced changes. Other key mutations generally confer more limited resistance to specific agents, although the primary lamivudine- and abacavir-associated M184V substitution generates a broad spectrum of drug-dependent phenotypes, and uncommon mutational complexes conferring resistance across the entire class are well known. In addition to 'classical' multi-nucleoside-resistant genotypes, database-driven 'virtual phenotyping' for accumulations of NRTI-associated mutations around a core of thymidine analogue-induced changes predicts drug susceptibilities below wild-type across the entire NRTI class, even in the absence of key mutations associated with individual agents. When the natural range of drug susceptibilities for treatment-naive isolates is used as the basis for defining resistance, retrospective analysis of clinical isolates in the Virco database shows a significantly increased incidence of reduced susceptibility for the dideoxy NRTIs (didanosine, stavudine and zalcitabine) that was undetected in previous assays. These data imply a cumulative degradation of response to

Anti-HIV Agents↗

PubMed2002

[Investigation of urinary nucleosides excretion of intestinal cancer patients by reversed-phase high performance liquid chromatography].

A method for the determination of urinary nucleosides with reversed-phase high performance liquid chromatography is described. After nucleosides were extracted from urine on phenyl boronic acid affinity chromatography, the analysis was performed on a column (4.6 mm i.d. x 250 mm, 5 microns) at 22 degrees C using a linear gradient elution comprising 25 mmol/L KH2PO4 solution (pH 4.55) and 60% methanol in water with UV detection at 260 nm. This method was used for the determination of 15 urinary nucleosides of 41 intestinal cancer patients and 52 normal adults. The results showed that the average concentrations of 12 urinary nucleosides from intestinal cancer patients were much higher than those of normal adults with P < 0.001. Using the concentrations of 15 nucleosides as the data vectors, principal component analysis was applied to classify intestinal cancer patients and normal adults and 76% (31/41) of the cancer patients were correctly classified. It is concluded that the method is sensitive, reliable and suitable for basic research and clinical applications to malignant tumours.

Adult↗

PubMed1992

[Achievements and prospects of the directed search for antiviral agents in the nucleoside series and their derivatives].

Recent advances of antiviral drug design among nucleosides and their derivatives have been summarized. The first chapter deals with the history of nucleic acids components and further developments in this area. Next part discusses the mechanism of action of biologically active nucleosides: 2',3'-dideoxynucleosides, acyclic analogues, phosphonate derivatives and nucleoside antibiotics. The third chapter describes planning of complicated synthesis of nucleoside analogues from branched-chain sugars and stereo-specific formation of glycosidic bond upon synthesis of ribonucleoside and 2'-deoxyribonucleoside. The last part outlines further perspectives, i. e. preparation of antiviral compounds and use of nucleoside analogues in oligonucleotide synthesis.

Antiviral Agents↗

PubMed2003

[Nucleoside from Cordyceps kyushuensis and the distribution of two active components in its different parts].

AIM: To rapidly separate and determine the nucleosides from natural and cultured Cordyceps kyushuensis Kob., and to compare the content of cordycepin and adenosine in different parts of Cordyceps kyushuensis Kob., which are the main nucleoside active components in medicinal fungus belonging to Cordyceps (Fr.) Link. METHODS: The nucleosides were separated and determined by the high performance capillary zone electrophoresis (CZE). Beckman P/ACE system MDQ apparatus equipped with a PDA detector and a uncoated fused-silica capillary (41 cm x 45 microns ID, 30 cm effective length) were used. The experimental conditions were as follows: the running buffer was borax solution (adjust to pH 9.4 with sodium hydroxide), applied voltage was 20 kV, operated temperature was 20 degrees C and the detector wavelength was 258 nm. The content of cordycepin and adenosine in the fruiting body, stroma and host worm of natural and cultured C. kyushuensis were respectively investigated and quantitatively analyzed. RESULTS: There are at least 8 kinds of nucleoside or nitrogen base in Cordyceps kyushuensis Kob. The content of cordycepin which is a bio-active substance with anti-tumor activity in C. kyushuensis is significantly higher than that in C. sinensis and C. militaris, and furthermore the cordycepin in the cultured C. kyushuensis is notably higher than the natural one. Adenosine was mainly found from the stroma of C. kyushuensis, While the cordycepin content is high in the stroma of both natural and cultured C. kyushuensis as well as in the host worm of the cultured one. CONCLUSION: There are some differences about the nucleoside components between the natural and cultured C. kyushuensis and between the different parts of them. With a high cordycepin content, C. kyushuensis should have a considerable medicinal potential.

Adenosine↗

PubMed1992

5-hexyl-2'-deoxyuridine inhibition of nucleoside transport in L1210 cells.

Previous studies have shown that 5-hexyl-2'-deoxyuridine (HdUrd) blocked the cytotoxic effects of 5-fluorodeoxyuridine and deoxyadenosine in L1210 cells. HdUrd had no effect in preventing the inhibitory effects of 5-fluorouracil. These data suggested that HdUrd was an inhibitor of nucleoside transport in L1210 cells (Cory, J. G.; Halley, M. C.; Janey, A.; Lapis, K. Cancer Res. 50:4552-4556; 1990). Studies have now been carried out which show that HdUrd inhibits nucleoside transport as measured by [3H]uridine or [3H]formycin B transport into L1210 cells in culture. The IC50 for HdUrd inhibition of total [3H]uridine uptake was approximately 20 microM in wild-type L1210 cells. Since wild-type L1210 cells have three distinct nucleoside transporters, the effect of HdUrd on each transporter was examined using the non-metabolized nucleoside analog, formycin B. The nitrobenzylmercaptopurine riboside (NBMPR)-sensitive transporter, es, was most sensitive to HdUrd with an IC50 of 1.0 +/- 0.1 microM; the NBMPR-insensitive transporter, ei, was much less sensitive to HdUrd with an IC50 of 32 +/- 2 microM; the sodium ion-dependent transporter, cif, was the least sensitive transporter to HdUrd with an IC50 of 130 +/- 5 microM. These data support the concept that HdUrd, a relatively non-cytotoxic agent, could be useful in increasing the potency of antitumor inhibitors directed at the de novo pathways for nucleotide synthesis through the blockage of the salvage pathways for nucleosides.

Animals↗

PubMedDate not supplied

New nucleoside analogs in the treatment of solid tumors.

Physiologic deoxynucleotides are required for an error-proof DNA replication, repair and synthesis. Any inaccuracy in this process results in a block in DNA synthesis until the error is corrected. If the cell enzymes are unable to correct the error, a signal for apoptosis is generated. This mechanism is the main target for anticancer nucleoside analogs. They also interact with the metabolism of physiological nucleosides, and consequently, have a large number of intracellular targets to induce cytotoxicity. In addition, it is now reported that some analogs may interfere directly with RNA synthesis. A great deal of synthesized nucleoside analogs provide the opportunity to understand the structure-based differences in their metabolism and mechanisms of action as well as to identify the specific intracellular targets and diseases, in which each of these newer nucleoside analogs acts most efficiently. This paper summarizes developments in the area of new nucleoside analogs undergoing clinical evaluation for the treatment of solid tumors, namely tezacitabine, troxacitabine, DMDC, CNDAC, ECyD, clofarabine, and decitabine.

Adenine Nucleotides↗

PubMed1992

Reference intervals for eight modified nucleosides in serum in a healthy population from Italy and the United States.

We used a recently devised HPLC method to quantify eight modified nucleosides, an emerging group of tumor markers, in human serum and then calculated their reference intervals in a healthy population from Italy and the United States. We used the statistical procedure of element analysis, which reveals the effects of chosen variables (in this case, nationality, sex, and age) on an analyte (here, modified nucleosides). Using element analysis, we calculated the exact weight of each variable on the reference values. We found that nationality has the greatest effect on the serum concentrations of all the modified nucleosides apart from pseudouridine, whereas sex significantly influences only the concentrations of 4-pyridone-3-carboxamide-N1-ribofuranoside, 1-methylinosine and N2,N2-dimethylguanosine; age affects only N2,N2-dimethylguanosine. Thus, the reference intervals of all the nucleosides except pseudouridine were calculated separately for Italians and Americans, and the reference values for 4-pyridone-3-carboxamide-N1-ribofuranoside, 1-methylinosine, and N2,N2-dimethylguanosine were calculated separately for men and women. Our data form the baseline for study of variations in serum concentrations of modified nucleosides in various pathophysiological conditions.

Adult↗