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PubMed1986

Effects of acivicin and dichloroallyl lawsone upon pyrimidine biosynthesis in mouse L1210 leukemia cells.

Acivicin (NSC 163501) and dichloroallyl lawsone (NSC 126771) are potent inhibitors of nucleotide biosynthesis with consequent anti-cancer activity against certain experimental tumors. To determine in detail the metabolic events induced by each inhibitor, we have devised a new two-dimensional chromatographic procedure for measurement of the concentrations of all pyrimidine intermediates and some purine nucleotides from 100 microliter of an extract of cells grown in the presence of [14C]bicarbonate. Addition of acivicin (25 microM) to mouse L1210 leukemia cells causes severe depletion in the cellular levels of CTP and GTP, accumulation of uridine nucleotides, and abrupt but transient increases in the concentrations of the early intermediates of both the pyrimidine and purine pathways. Addition of dichloroallyl lawsone (25 microM) results in a rapid depletion of uridine and cytidine nucleotides; carbamyl aspartate and dihydroorotate accumulate to high levels in an equilibrium ratio of 20.5:1, and orotate, orotidine, and UMP increase transiently before decreasing to levels approaching their original steady states. The predominant inhibitory effects of acivicin are upon the reactions UTP----CTP and XMP----GMP, but there is also an initial transient activation of both the pyrimidine and purine pathways by acivicin. The data obtained with dichloroallyl lawsone are consistent with inhibition of the conversion of UMP----UDP initially followed by potent inhibition of dihydroorotate----orotate.

Animals↗

PubMed1979

[Effect of prodigiozan and pyrimidine derivatives on the effectiveness of the antibiotic therapy of experimental infections].

The effect of prodigiozan and pyrimidine derivatives, such as methyluracyl, oxymetacyl and 2-methyl-4-amino-6-hydroxypyrimidine on the efficiency of antibiotic therapy of experimental infections caused by Staph. aures and E. Coli under conditions of immune depression due to levomycetin, prednisolone, 6-mercaptopurine and ionizing radiation was studied. The effect of prodigiozan on the efficiency of the antibiotic treatment of staphylococcal infection in the presence of the immune depression due to 6-mercatopurine, levomycetin and prednisolone was higher than that of pyrimidines. The combined use of prodigiozan and pyrimidines usually was not more effective than the use of every drug alone. The efficiency of the drugs in radiation disease was the same. After prednisolone administration prodigiozan increased the host resistance to the infection without the antibiotic use.

Animals↗

PubMed1979

Nude mouse models as predictors of chemotherapy in man: thymidine and pyrimidines.

The National Cancer Institute cancer treatment screening program has been reorganized incorporating, as an important feature, a panel of human tumors growing as xenografts in congenitally athymic mice. The new screening program is a prospective experiment in the search for new and more effective agents for the treatment of clinical neoplasia. The new program is described and questions that are being asked prospectively are presented. Data are summarized on the activity against human tumor xenografts for a number of clinically established antitumor drugs and examples are presented in which there is interest in compounds for the clinic on the basis of activity in the new screen. Studies are outlined in which high dose thymidine inhibited the growth of human melanoma and teratocarcinoma transplanted in athymic mice. Studies are discussed employing murine tumors in which marked augmentation of the in vivo antitumor activity of 5-fluorouracil was obtained by combination therapy with the pyrimidine nucleosides thymidine, uridine and cytidine. The desirability of investigating combination chemotherapy with pyrimidine nucleosides and 5-fluorouracil and other pyrimidine antagonists in the treatment of human tumor xenografts is stressed. There is a broad range of investigations that can be conducted in nude mouse models and it is important to conduct such programs in relation to the clinic.

Animals↗

PubMedDate not supplied

[Two pathways of pyrimidine nucleotide biosynthesis in birds].

Dillerent chicken tissues are shown to display a clearly pronounced specificity relative to [2-14C] orotic acid and [5-3H]uridine as precursors of synthesis of the pool and RNA pyrimidine nucleotides. The fraction of pyrimidine nucleotides synthetized relative to the reserve pathway (uridine utilization) decreases in the series: kidneys greater than duodenum mucosa greater than lungs greater than liver greater than pancreas greater than bone marrow greater than brain greater than spleen. The results of [2-14C]orotic acid and [53H]uridine incorporation into UMP and CMP of the liver and spleen tissues RNA are interpreted in terms of the concept on existence of separate pools of pyrimidine phosphates--RNA precursors.

Animals↗

PubMedDate not supplied

[Effect of adenosine on synthesis of pyrimidine nucleotides and RNA in normal lymphocytes and under conditions of chronic lymphoid leukosis].

Effect of exogenous adenosine on synthesis of pyrimidine nucleotides and RNA was studied in lymphocytes of the patients with leukemic form of chronic lymphoid leukosis. In presence of adenosine lymphocytes were incubated in mixtures containing the precursors--2,3-2(3)H-aspartic and 2-14C-orotic acids as well as 5-3H-uridine. Effect of adenosine on the activity of key enzymes of pyrimidine nucleotide synthesis (orotidine monophosphate pyrophosphorylase and uridine kinase) was studied. The enzymatic activity was estimated using radiochemical procedures in extracts of lymphocytes stored at -20 degrees after acetone drying. Adenosine similarly inhibited synthesis of pyrimidine nucleotides and RNA in normal and leukemic leukocytes. One of the mechanisms, by means of which the inhibitory effect of adenosine was realized, was related to the enzymatic activity of orotidine monophosphate pyrophosphorylase and uridine kinase.

Adenosine↗

PubMed1982

Effects of caffeine on pyrimidine biosynthesis and 5-phosphoribosyl 1-pyrophosphate metabolism in Chinese hamster cells.

Caffeine, at doses which enhance killing by UV light, inhibits the biosynthesis of pyrimidines in Chinese hamster ovary cells (K1) in culture. This inhibition was measured as a decrease in [14C]UTP and [14C]CTP accumulation after a 3-h incubation with [14C]aspartate or [14C]orotate and a similar decrease in Urd-A cells (which lack the first three enzymes of the pathway) using [14C]orotate as substrate. There was no such inhibition in Urd-C cells (which lack the last two enzymes) using [14C]aspartate as substrate and measuring accumulation of orotate. There is some inhibition of the fifth enzyme of the pathway, orotate phosphoribosyltransferase by caffeine in vitro and this is most striking at low 5-phosphoribosyl 1-pyrophosphate concentrations. The level of 5-phosphoribosyl 1-pyrophosphate is decreased in Chinese hamster ovary K1 cells by about 20% after 3 h and by about 70% after 16 h in the presence of caffeine. It is suggested that inhibition of pyrimidine biosynthesis by caffeine over a 16-h period may be due mainly to decreased intracellular 5-phosphoribosyl 1-pyrophosphate levels but that in the decrease in pyrimidine accumulation over 3 h, direct inhibition of orotate phosphoribosyltransferase by caffeine may also play a role.

Animals↗

PubMed1980

Comparison of the cleavage of pyrimidine dimers by the bacteriophage T4 and Micrococcus luteus UV-specific endonucleases.

A comparison was made of the activity of the UV-specific endonucleases of bacteriophage T4 (T4 endonuclease V) and of Micrococcus luteus on ultravilet light-irradiated DNA substrates of defined sequence. The two enzymes cleave DNA at the site of pyrimidine dimers with the same frequency. The products of the cleavage reaction are the same, suggesting that the scission of DNA by T4 endonuclease V occurs via the combined actin of a pyrimidine dimer specific DNA glycosylase and an apyrimidinic-apurinic (AP) endonuclease as was recently shown for the M. luteus enzyme. The pyrimidine dimer DNA-glycosylase activity of both enzymes is more active on double-stranded DNA than it is on single-stranded DNA.

Base Sequence↗

PubMed1984

[Synthesis of various acyclic analogs of pyrimidine nucleosides].

As acyclic analogues of pyrimidine nucleosides, 1-[2-(2,3- dihydroxypropyloxy )ethyl]pyrimidines (III a-c) and 1-[[3-(2,3- dihydroxypropyloxy )-2-hydroxy]propyl]pyrimidines (III d-f) were synthesized and tested for in vitro activity against herpes simplex virus type 1. The compounds exhibited no significant antiherpetic activity.

Antiviral Agents↗

PubMed1983

Hormonal regulation of de novo pyrimidine synthesis and utilization in human breast cancer cells in tissue culture.

The hormonal regulation of pyrimidine synthesis and utilization is examined in the estrogen-responsive MCF-7 human breast cancer cell line. [14C]Acetate is used as a novel marker in assaying the incorporation of pyrimidine nucleotides derived through de novo synthesis into DNA. Technical verification of the validity of this tracer in DNA synthesis is presented. The experimental conditions permitting extrapolation from radioactivity incorporated into DNA to pmol of DNA synthesized/unit of time are discussed. We observe that estrogen administration increases the incorporation of [14C]acetate into DNA, and this effect is most evident after 36 hr of exposure to hormone. Treatment with the antiestrogen tamoxifen produces substantial reductions in the rate of incorporation of [14C]acetate into DNA. Incorporation correlates well with net rates of DNA synthesis, as measured by 32Pi incorporation into DNA. Concomitant administration of thymidine in concentrations in excess of 10(-7)m partially relieves tamoxifen inhibition of net DNA synthesis and increases the apparent stimulation of net DNA synthesis following 18 to 32 hr of estrogen treatment. Activity of de novo enzymes such as carbamylphosphate synthetase, aspartate transcarbamylase, orotidine pyrophosphorylase, and orotidine decarboxylase also varies with hormone treatment. All characteristically increase following estrogen treatment and decrease after tamoxifen administration. These results suggest that changes in de novo pyrimidine synthesis after hormone treatment are directly linked to hormone-induced alterations in the activity of specific-enzymes in the de novo pathway.

Acetates↗

PubMed1982

Incorporation of molecular oxygen into pyrimidine cofactors by phenylalanine hydroxylase.

The 5-amino substituents of two pyrimidine cofactors of rat liver phenylalanine hydroxylase, 2,5,6-triamino-4-pyrimidinone (TP) and 5-benzylamino-2,6-diamino-4-pyrimidinone (BDP), have been shown to be cleaved quantitatively by enzyme (Bailey, S. W., and Ayling, J. E. (1980) J. Biol. Chem. 255, 7774-7781). That the pyrimidine product of this process (when carried out in the presence of 2-mercaptoethanol) is 2,6-diamino-5-hydroxy-4-pyrimidinone (divicine) is further confirmed by mass spectrometry of an isolated t-butyldimethylsilyl derivative. The origin of the oxygens in this divicine was studied with enzyme reactions containing 18O2. Corrected for the loss in the controls, the divicine generated by phenylalanine hydroxylase from TP and BDP incorporated one atom of 18O with an efficiency of 98 +/- 5% and 100 +/- 3%, respectively, even though these reactions are partially uncoupled. The position of the isotope was unambiguously assigned to the 5-hydroxyl group by the simultaneous use of [18O] TP and 18O2, the divicine from which was found to be doubly labeled. o-Methylphenylalanine stimulates a rate of cofactor oxidation at least 10-fold greater than its own rate of hydroxylation. The majority of divicine isolated from phenylalanine hydroxylase incubations with o-methyl substrate analog was labeled with oxygen from 18O2. The demonstration, with phenylalanine hydroxylase, that one atom of molecular oxygen remains attached to position 5 of pyrimidine cofactor, provides the first strong evidence for activation of oxygen by aromatic amino acid monooxygenases via covalent addition to C4a of tetrahydrobiopterin.

Animals↗

PubMed1982

Enzymatic repair of pyrimidine dimer-containing DNA. A 5' dimer DNA glycosylase: 3'-apyrimidinic endonuclease mechanism from Micrococcus luteus.

A pyrimidine dimer-DNA glycosylase has been purified 20,000-fold from Micrococcus luteus. The enzyme is a single polypeptide chain with Mr = 18,000 that acts specifically on pyrimidine dimers, preferring those in double-stranded DNA to those in single-stranded DNA. The glycosylase cleaves the 5' residue of a pyrimidine dimer generating an apyrimidinic site and a mixed pyrimidine/pyrimidine nucleotide dimer. Under conditions of substrate excess, dimers containing a 5'-thymine are preferred to those with a 5'-cytosine residue. The glycosylase has an associated apyrimidinic/apurinic (AP) endonuclease that prefers apyrimidinic sites at the site of glycosylase action to either apurinic or apyrimidinic residues. This endonuclease is a Class I AP endonuclease in that it cleaves 3' to the AP site generating a 3'-deoxyribose moiety and a 5'-phosphate.

DNA Glycosylases↗

PubMed1980

Use of alpha-secondary isotope effects in nucleophile-promoted reactions of pyrimidine derivatives; evidence for transient 5,6-dihydropyrimidine intermediates.

alpha-Secondary isotope effect provides a useful tool for detection of transient 5,6-dihydropyrimidine intermediates which have been indirectly implicated in a number of chemical and enzymic conversions of pyrimidine heterocycles. The method involves the use of kinetic secondary alpha-hydrogen isotope effects which are expected to accompany sp2 to sp3 rehybridization of C-6 of the pyrimidine ring if they occur prior to or at the rate determining step. Thus, using 6-tritiated pyrimidines, and measurement of the isotopic ratio of reactant and products, kT/kH values of 1.15 or greater would be indicative of rehybridization. Using this method, we have studied the inhibition of thymidylate synthetase by 5-fluorodeoxyuridylate and 5-nitro-deoxyuridylate as well as the chemical and enzymic dehalogenation of 5-bromodeoxyuridine and 5-bromodeoxyuridylate. Large secondary isotope effects observed in all of these reactions provided strong evidence for the formation of 5,6-dihydropyrimidine intermediates.

Bromodeoxyuridine↗

PubMed1978

Photoreactivation: evaluation of pyrimidine dimers in ultraviolet radiation-induced cell transformation.

The PRE repairs DNA by the specific and exclusive monomerization of pyrimidine dimers. Photoreactivation thus provides an analytical test for determining the role of pyrimidine dimers in UV damage to biologic systems. We have shown the first UV transformation of cultured human cells (judged by ability to grow in soft agar). Preliminary results indicate that 1) lesions leading to cell transformation are subject to photoreactivation and 2) pyrimidine dimers may well be important in solar carcinogenesis.

Animals↗

PubMed1979

Characterization of a mutant mouse lymphoma cell with deficient transport of purine and pyrimidine nucleosides.

A clone (AE1) of cells resistant to adenosine cytotoxicity was isolated from a mutagenized population of mouse T-lymphoma (S49) cells. These adenosine-resistant cells cannot transport adenosine or any other purine or pyrimidine nucleoside tested, but their transport of purine bases is intact. The AE1 cells also have an impaired ability to salvage thymidine. Kinetic analyses of the uptake of purine and pyrimidine nucleosides further substantiate the evidence that the facilitated transport of purine and pyrimidine nucleosides in S49 cells is mediated by the same carrier. Growth rate and transport studies indicate that the lack of expression of the nucleoside transport in AE1 cells is recessive in intraspecies cell-cell hybrids.

Animals↗

PubMed1995

[Effect of 5-FU on the utilization of purine and pyrimidine by human gastric cancer cells (KATO III)].

Effect of utilization of purine and pyrimidine in the culture medium by human gastric cancer cells (KATO III) was evaluated. Nucleosides mixture solution (OG-VI), consisting of inosine, guanosine 5' monophosphate (5'GMP), cytidine, uridine and thymidine (4: 4: 4: 3: 1 in molar ratio) was used and their levels in the culture medium was measured by HPLC after 3 day culture. Purine, inosine and 5' GMP, in the medium almost decreased and purine base, xanthine and hypoxanthine levels increased, but changes in pyrimidine level were minimal. 5-FU decreased purine and increased pyrimidine consumption. Addition of nucleosides mixture did not enhance the cellular proliferation, but inhibited growth when given in higher concentrations. Nucleoside mixture solution enhanced growth inhibition by 5-FU and it is a potential biochemical modulator of 5-FU metabolism in human cancer cells.

Cell Division↗

PubMed1975

Distribution of bromouracil in the pyrimidine oligonucleotides of Drosophila DNA.

DNA was isolated from Drosophila melanogaster larvae fed radioactive thymidine (TdR), bromodeoxyuridine (BUdR), or one of these nucleosides together with 5-fluorouracil (FU) under identical conditions. The four DNA samples designated T-DNA, B-DNA, T(F)-DNA, and B(F)-DNA respectively were hydrolyzed with formic acid-diphenylamine, and the pyrimidine oligonucleotides of various chain lengths (isotichs) were ractionated by DEAE-celluclose chromatography. The distributions of the labeled thymine and bromouracil (BU) residues among the pyrimidine isostichs were determined, and compared for the four DNAs. These comparisons indicated the following: (1) Similarity of T-DNA and T(F)-DNA with respect to labeled thymine distribution among the pyrimidine isostichs (using the mononucleotide to pentanucleotide tracts for statistical comparisons) showed that TdR entering DNA synthesis via the salvage pathway has the same distribution whether the synthetic pathway is operating normally or is inhibited by FU treatment. (2) Quantitative comparison of the distribution of BU among the isostichs of B-DNA and B(F)-DNA with the distribution of labeled thymine in T-DNA showed significant differences, indicating that the organism does not accept BUdR indiscriminately at all thymine sites for DNA synthesis. (3) Comparison of the distribution of BU in B-DNA and B(F)-DNA showed that isostichs 1 and 3 differ significantly. The elution profiles of the isostichs also differed qualitatively between these DNAs. This analysis confirms differential incorporation of BUdR into Drosophila DNA in the presence of a thymidylate inhibitor. The observations on BUdR incorporation in Drosophila DNA have been discussed with relation to the high frequency of somatic cell mutations induced in imaginal disc cells by treatment with the analog in the presence of inhibitors of thymidylate synthetase.

Animals↗

PubMed1993

Pyridoxine is a precursor of the pyrimidine moiety of thiamin in Saccharomyces cerevisiae.

We studied the origin of the N-1 atom of the pyrimidine moiety of thiamin in a eucaryote, Saccharomyces cerevisiae. The competitive effects of 14N-compounds on the incorporation of 15N-NH4Cl into the pyrimidine moiety were examined. Amino acids, the bases of nucleic acids and glucosamine did not decrease 15N incorporation, but pyridoxine did. We conclude that the N-atom of pyridoxine is the origin of the N-1 atom of the pyrimidine of thiamin synthesized by S. cerevisiae. We also suggest that the N-atom of pyridoxine is derived from glutamine.

Amino Acids↗

PubMed1993

New heterocyclic structures. thiazolo[3,2-a][1,2,5] thiadiazolo[3,4-d]pyrimidine and [1,2,5]thiadiazolo[3',4':4,5] pyrimido[2,1-b][1,3]thiazine. biological assays.

6,7-Dihydro-9H-thiazolo[3,2-a][1,2,5]thiadiazolo [3,4-d]pyrimidin-9-one, 7,8-dihydro-6H,10H-[1,2,5]thiadiazolo[3',4':4,5]pyrimido [2,1-b][1,3]thiazin-10-one and its 3-methyl derivative were prepared by reacting 6,7-diamino-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidin-5-one, 7,8-diamino-3,4-dihydro-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one or its 3-methyl derivative with N-thionylaniline. A reaction mechanism is proposed. The compounds and the sodium salts of (7-amino-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidin-5-on-6-yl)sulfamic acid, (8-amino-3,4-dihydro-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-on-7-yl) sulfamic acid and its 3-methyl derivative were tested for antimicrobial and antimycotic activity on a number of strains, namely: E. Coli, Proteus mirabilis, P. vulgaris, Pseudomonas aeruginosa, Salmonella spp, Staphylococcus spp, Streptococcus faecalis, Bacillus subtilis, Sarcina lutea, Candida albicans, and for antiviral activity on Herpes simplex virus type 1 and Vescicular stomatitis virus. None of the compounds showed antiviral activity or exhibited biological activity against gram-negative, gram-positive bacteria or against mycetes.

Animals↗