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At least 19 recordsLinked to original sources
PubMed1975

[Eremothecium ashbyii mutants resistant to 8-azaguanine. II. Mutants with different degrees of resistance to 8-azaguanine].

Guanine, unlike adenine and hypoxanthine, can not eliminate the inhibitory effect of adenine analogues on the growth and flavinogenesis of Eremothecium ashbyii. Guanine does not restore riboflavin synthesis inhibited with 5-10(-3) M 8-azaguanine. Low adenine concentrations (10(-4)-3-10(-4) M), which do not influence the inhibitory effect of 5.-10(-3) M 8-azaguanine, restore the riboflavin synthesis in combination with guanine. On the basis of the data obtained as well as the data of biochemical analysis it is concluded that the riboflavin producer studied lacks guanosinemonophosphate reductase. The mutants resistant to various concentrations of 8-azaguanine have been obtained. In all mutants resistant to 8-azaguanine the efficiency of the incorporation of 14C-guanine and 14C-adenine into mycelium is decreased as compared with the susceptible strain. The mutant Azg-R 10 resistant to high (3-10(-3) M) concentrations of 8-azaguanine, 8-azaadenine and 2,6-diaminopurine secretes inosine-like compounds when grown in a synthetic medium. The stepwise increase of the mutant resistance to 8-azaguanine from 10(-4) M TO 3-10(-3) M did not result in further enhancement of riboflavin synthesis.

Ascomycota↗
PubMed1982

[Eremothecium ashbyii mutants resistant to 8-azaguanine. III. Nucleotide pyrophosphorylase activity of mutants with a varying degree of 8-azaguanine resistance].

Eremothecium ashbyii mutants resistant to low and high concentrations of 8-azaguanine (AZG), have been obtained. In low resistant mutants (10(-4) M AZG) isolated by one step selection, the activity of GMP- and AMP-pyrophosphorylases was decreased, as compared with the initial sensitive strain. The stepwise increase of the mutants resistance to AZG resulted in increasing of resistance to 8-azaadenine and decreasing of the activity of GMP-pyrophosphorylase, while this did not affect the level of AMP-pyrophosphorylase. Characteristics of the cross-resistance of mutant to purine analogues and the level of nucleotide-pyrophosphorylases activity were discussed in the light of their possible influence on riboflavin biosynthesis.

Adenine Phosphoribosyltransferase↗
PubMed1981

Specific resistance to 8-azaguanine in cells with normal hypoxanthine phosphoribosyltransferase (HPRT) activity: the role of guanine deaminase.

The role of guanine deaminase in selective cellular resistance to 8-azaguanine was examined, using eight mammalian cell lines and their subclonal derivatives isolated on the basis of increasing resistance to this drug. 8-Azaguanine and 6-thioguanine are synthetic analogs of guanine and are lethal to cells with normal hypoxanthine phosphoribosyltransferase (HPRT) activity. In principle, however, HPRT-positive cells could become selectively resistant to 8-azaguanine if, by any mechanism, the cells expressed higher levels of guanine deaminase. This is because 8-azaguanine, but not 6-thioguanine, is converted by this enzyme to a noncytotoxic metabolite, 8-azaxanthine. Our study shows that HPRT-positive cells inherently resistant to relatively high levels of 8-azaguanine contain high levels of guanine deaminase. In general, guanine deaminase activity was higher in 8-azaguanine-resistant cells, regardless of their HPRT activity. Our results support the view that elevated guanine deaminase activity constitutes a potential mechanism of selective 8-azaguanine resistance in cells with normal HPRT activity. Guanine deaminase levels were significantly elevated in HPRT-positive cells briefly exposed to sublethal concentrations of 8-azaguanine, but this elevation was transient. Long-term exposure of cells to increasingly higher levels of the drug did not lead to high stable levels of guanine deaminase, indicating that 8-azaguanine is not an inducer of guanine deaminase in the cells examined.

Aminohydrolases↗
PubMed1981

Mechanism of cytotoxic action of azaguanine and thioguanine in wild-type V79 cell lines and their relative efficiency in selection of structural gene mutants.

The cytotoxic effects of azaguanine and thioguanine have been compared in two wild-type V79 cells. To achieve equitoxic effects in both cell lines a 10-20-fold higher concentration of azaguanine than thioguanine was required. Affinity of HGPRT for azaguanine was 10-fold lower than for hypoxanthine in both cell lines and was similar to that for thioguanine in V79S cells. Affinity for thioguanine differed by a factor of 3 in the two cell lines. The rate of cell kill by azaguanine was markedly slower than by thioguanine in both cell lines. Reduction of whole cell uptake of [14C]hypoxanthine incorporation by unlabelled azaguanine was only demonstrable after prolonged incubation periods as was incorporation of [14C]azaguanine into acid-insoluble material. Experiments with cell-free extracts indicated that hypoxanthine acts as a non-competitive inhibitor of the enzyme. The slow rate of dissociation of the HGPRT-azaguanine complex is reflected in the slow rate of killing of wild-type cells. Clones resistant to the cytotoxic effects of these analogues have been selected from both cell lines and have been shown to possess HGPRT with altered kinetic properties. Our data suggest that azaguanine and thioguanine may select for mutations at different sites on the HGPRT molecule in V79 cells and provide possible explanations for the differences in effectiveness of these two agents reported in other cell lines.

Animals↗
PubMed1985

Metabolic properties of an azaguanine-resistant variant of Chinese hamster ovary cells (azarts) with normal levels of hypoxanthine-guanine phosphoribosyltransferase activity.

Azarts Chinese hamster ovary cells were 20 to 50 times more resistant to 8-azaguanine and 50 to 10 times more resistant to both 6-thioguanine and 6-mercaptopurine than wild-type cells. Resistance correlated with a failure of azarts cells to incorporate 8-azaguanine into the nucleotide pool and into nucleic acids. The uptake of hypoxanthine and guanine, on the other hand, was about the same in both types of cells and the hypoxanthine-guanine phosphoribosyltransferase of the azarts cells as measured in cell lysates was unaltered both in concentration and kinetic properties with hypoxanthine as well as 8-azaguanine as substrate. Plasma membrane permeability to 8-azaguanine and the regulation of intracellular pH were also not altered in azarts cells and there was no significant degradation of 8-azaguanine or azaguanine nucleotides. We conclude therefore that in azarts cells the phosphoribosylation of 8-azaguanine per se is specifically blocked but that this effect is abolished upon cell lysis.

Animals↗
PubMed1964

DIFFERENTIATION OF PATHOGENIC AND SAPROPHYTIC LEPTOSPIRES WITH 8-AZAGUANINE.

Johnson, Russell C. (University of Minnesota, Minneapolis), and Palmer Rogers. Differentiation of pathogenic and saprophytic leptospires with 8-azaguanine. J. Bacteriol. 88:1618-1623. 1964.-The use of the purine analogue, 8-azaguanine, as a differential agent for the separation of pathogenic and saprophytic leptospires was investigated. Growth of strains of the saprophyte Leptospira biflexa was almost insensitive to the bacteriostatic action of 8-azaguanine at concentrations varying from 25 to 600 mug/ml; these saprophytic leptospires were serially transferred five times in media containing 225 mug without any change in growth rate or cell yield. In contrast, decreased growth rate and cell yield of the pathogenic serotypes were observed with 25 to 50 mug/ml of 8-azaguanine. Complete inhibition of growth occurred at concentrations of 100 mug/ml and above. A medium containing 225 mug/ml of 8-azaguanine was successfully used to differentiate 20 serotypes of pathogenic leptospires and 10 saprophytic strains. L. andaman CH11, L. semarang Veldrat S1 73, and L. andaman Correa, were classified with the L. biflexa strains on the basis of their growth response to 8-azaguanine.

Antimetabolites↗
PubMed1981

Facilitated transport of 6-mercaptopurine and 6-thioguanine and non-mediated permeation of 8-azaguanine in Novikoff rat hepatoma cells and relationship to intracellular phosphoribosylation.

6-Mercaptopurine and 6-thioguanine strongly inhibited the zero-trans entry of hypoxanthine into Novikoff rat hepatoma cells which lacked hypoxanthine/guanine phosphoribosyltransferase, whereas 8-azaguanine had no significant effect. 6-Mercaptopurine was transported by the hypoxanthine carrier with about the same efficiency as its natural substrates (Michaelis-Menten constant = 372 +/- 23 microM; maximum velocity = 30 +/- 0.7 pmol/microl cell H2O per s). 8-Azaguanine entry into the cells, on the other hand, showed no sign of saturability and was not significantly affected by substrates of the hypoxanthine/guanine carrier. The rate of entry of 8-azaguanine at 10-100 microM amounted to only about 5% of that of hypoxanthine transport and was related to its lipid solubility in the same manner as observed for various substances whose permeation through the plasma membrane is believed to be non-mediated. Only the non-ionized form of 8-azaguanine (pKa = 6.6) permeated the cell membrane. Studies with wild type Novikoff cells showed that permeation into the cell was the main rate-determining step in the conversion of extracellular 8-azaguanine to intracellular aza-GTP and its incorporation into nucleic acids. In contrast, 6-mercaptopurine was rapidly transported into cells and phosphoribosylated; the main rate-determining step in its incorporation into nucleic acids was the further conversion of 6-mercaptopurine riboside 5'-monophosphate.

Animals↗
PubMed1962

Effect of 8-azaguanine on growth and viability of Bacillus megaterium.

Mangalo, R. (University of Illinois, Urbana) and J. T. Wachsman. Effect of 8-azaguanine on growth and viability of Bacillus megaterium. J. Bacteriol. 83:27-34. 1962.-The addition of 8-azaguanine to exponentially growing cells of Bacillus megaterium results in an inhibition of growth after a lag of approximately 30 min. However, 8-azaguanine-2-C(14) is incorporated into the nucleic acids in a linear fashion without a detectable lag. The inhibitory action is reversed by purines and their derivatives, but not by uridine, thymidine, or cytidine. 8-Azaguanine is bactericidal, especially under conditions where growth (ribonucleic acid synthesis) is possible. Growth in the presence of a complete amino acid mixture, either before or during exposure to 8-azaguanine, increases the rate of killing. Chloramphenicol has little or no effect on the bactericidal action of the analogue.

Amino Acids↗
PubMed1976

Purine uptake by azaguanine-resistant Chinese hamster cells.

In this study the resistance of a number of lines of Chinese hamster ovary cells to azaguanine is examined. Those which are drug resistant by virtue of a deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT) fail to take up any exogenous hypoxanthine or azaguanine. A second class of drug resistant cells which grow in the reverse selective HAT medium and have levels of HPRT in the range of the wild type parent line take up these purines at lower rates than the nonresistant cells and incorporate smaller amounts of them into trichloracetic acidinsoluble constituents. The results suggest that their basis for resistance resides in lowered incorporation of azaguanine into DNA and RNA, possibly due to a mofified HPRT molecule which accepts hypoxanthine, but not azaguanine as a substrate.

Amino Acids↗
PubMed1975

Mechanisms of action of 6-thioguanine, 6-mercaptopurine, and 8-azaguanine.

The effects of 6-thioguanine on purine biosynthesis and cell viability have been examined in H.Ep. 2 cells grown in culture. Toxicity is not reversed by aminoimidazolecarboxamide, suggesting that inhibition of purine biosynthesis de novo is not the sole mechanism of toxicity. Also, 6-(methylmercapto)purine ribonucleoside, a potent inhibitor of purine biosynthesis de novo, produces more marked reductions in cellular pools of purines than does 6-thioguanine without killing cells. There is no apparent inhibition by 6-thioguanosine 5'-monophosphate of other enzymes leading to the synthesis of guanosine 5'-triphosphate as determined in whole cells by measurements of radioactive hypoxanthine or guanine incorporation. Inhibition of DNA synthesis by 1 mM thymidine protects cells from 6-mercaptopurine or 6-thioguanine but fails to protect cells from 8-azaguanine toxicity. On the other hand, inhibition of RNA synthesis by 6-azauridine plus deoxycytidine protects cells against 8-azaguanine but does not protect against 6-thioguanine or 6-mercaptopurine toxicity. In agreement with the in vitro data, arabinosylcytosine (a potent inhibitor of DNA synthesis) fails to protect mice against 8-azaguanine but has previously been shown to protect mice from 6-mercaptopurine or 6-thioguanine toxicity. The results support the hypotheses of others that incorporation into DNA (as 6-thioguanine nucleotide) is a mechanism of toxicity for these thiopurines, whereas 8-azaguanine is toxic due to its incorporation into RNA.

Azaguanine↗
PubMed1965

CHARGE-TRANSFER SELF-COMPLEX FORMED BY 8-AZAGUANINE.

The perpendicular distance between the planes of successive molecules of 8-azaguanine, in crystals of 8-azaguanine monohydrate, is 3.25 A. This distance indicates intermolecular interaction of the charge-transfer type. 8-Azaguanine may act as a cell poison by forming a charge-transfer complex within the bacterial RNA.

Azaguanine↗
PubMed1964

ACCUMULATION OF RIBONUCLEIC ACID IN BACTERIAL NUCLEAR PREPARATIONS DURING TREATMENT OF WHOLE CELLS WITH 8-AZAGUANINE, TETRACYCLINES, AND OTHER INHIBITORS.

Ezekiel, David H. (Albert Einstein Medical Center, Philadelphia, Pa.). Accumulation of ribonucleic acid in bacterial nuclear preparations during treatment of whole cells with 8-azaguanine, tetracyclines, and other inhibitors. J. Bacteriol. 87:755-760. 1964-Ribonucleic acid (RNA), synthesized in Bacillus megaterium KM during chloramphenicol treatment, accumulates in the chromatin-containing cell fraction obtained by lipase treatment of protoplasts. To determine whether this phenomenon is the cause or an effect of the inhibition of protein synthesis, or neither, other inhibitors of protein synthesis were studied. Chloramphenicol, tetracyclines, azaguanine, and, to a lesser extent, 7-azatryptophan permitted RNA synthesis while inhibiting protein synthesis. In each case, RNA accumulated in the chromatin body fraction. Azaguanine at 5 mug/ml causes more RNA accumulation than at 15 mug/ml, but allows some protein synthesis. Other inhibitors of protein synthesis inhibit RNA synthesis as well, and no accumulation is seen. The evidence favors the hypothesis that inhibition of protein synthesis causes the accumulation in the nuclear fraction. The possible nature and intracellular locus of the RNA accumulation are discussed briefly.

Anti-Bacterial Agents↗
PubMed1986

Mutagenic and cytotoxic potencies of a series of anthracycline derivatives as measured by His+ reversion, 8-azaguanine resistance and direct plating cytotoxicity tests in Salmonella typhimurium.

His+ reversion at multiple his- loci, 8-azaguanine resistance, and a previously reported direct plating cytotoxicity test were used to measure the genotoxic potencies of a series of anthracycline derivatives in Salmonella typhimurium. N-demethylated amino sugar monosaccharide anthracyclines reverted most his- tester strains and were positive with 8-azaguanine selection. Reversion of strain TA98 was the most sensitive end point for measuring the mutagenic activity of the N-demethylated anthracyclines. N,N-dimethyl amino sugar derivatives of Adriamycin and daunomycin were negative as measured by His+ reversion in tester strain TA98, but generated positive responses in tester strain TA102 that were equal to or greater than those of the demethylated parent compounds. Similarly, N,N-dimethyl amino sugar derivatives of pyrromycinone and 1-deoxypyrromycinone had no mutagenic activity as measured by His+ reversion except in tester strains TA102 and TA104. These later compounds also gave positive responses with 8-azaguanine selection. In view of these results, the importance of amino sugar dialkylation and anthracycline mechanisms of mutagenesis are discussed.

Anti-Bacterial Agents↗
PubMed1985

A simple method for efficiently establishing 8-azaguanine-resistant mutant human leukemia and myeloma cell lines.

A simple and convenient method for efficiently establishing 8-azaguanine-resistant mutant leukemia and myeloma cell lines (for example, the T cell lines Jurkat and CCRF-CEM, human myeloid/macrophage-like cell lines HL60 and U937, Burkitt lymphoma line Raji and the human myeloma line RPMI 8226), is described. The method relies on culturing the cell lines in RPMI 1640 medium containing 8-azaguanine and supplemented with 15% heat-inactivated fetal calf serum and large amounts of amino acids and vitamins, and removes the necessity for pretreatment with mutagenic reagents such as ethyl methylsulfonate or X-irradiation. The possibility of obtaining mutant cell lines using the method described here is about 15 times greater than using media without high levels of amino acids and vitamins. Hybridomas produced between mitogen-activated human peripheral blood lymphocytes and an 8-azaguanine-resistant Jurkat mutant cell line (established by this method) were shown to produce soluble T cell-derived macrophage activating factor (MAF)-like material.

Antigens, Surface↗
PubMed1983

8-Azaguanine versus 6-thioguanine: influence on frequency and expression time of induced HGPRT- mutations in Chinese hamster V79 cells.

Chinese hamster V79 cells were mutagenized with ethyl methanesulfonate at various concentrations. Clones resistant to 8-azaguanine (20 and 80 micrograms/ml) or 6-thioguanine (4 micrograms/ml) were selected at different times after the treatments. The total yield of induced mutations was only slightly affected by the kind and concentration of purine analog used in the selection. However, full phenotypic expression of the mutants selected with 8-azaguanine was achieved earlier than that of mutants resistant to 6-thioguanine. This result seems to be best explained by the reported lower affinity of 8-azaguanine for the wild-type HGPRT enzyme, thus providing evidence that, in this gene-mutation assay, the phenotypic expression time has a physiological component.

Animals↗
PubMed1975

8-azaguanine and flavinogenesis in Eremothecium ashbyii.

8-Azaguanine (10- minus 4 M) supplementation in synthetic medium inhibited flavinogenesis in Eremothecium ashbyii to far greater extent (68per cent) than the growth (25 per cent). That enzymes comprising the biosynthetic pathway of riboflavin are synthesized during early growth phase of the organism is supported by the data presented. 8-Azaguanine mediated inhibition in flavinogenesis was closely related with decreased levels of ribose-5'-phosphatase, ribose reductase and ribitol kinase, the enzymes involved in supplying ribitol for flavinogenesis. Addition of guanine and not ribitol during early growth phase to 8-azaguanine-added cultures released the inhibition of riboflavin synthesis and restored the enzyme levels in the presence of the antimetabolite.

Alcohol Oxidoreductases↗
PubMed1985

Interaction energy studies of an antimetabolite 8-azaguanine during transcription.

The possible incorporation of 8-azaguanine during transcription has been examined in the light of the model of transcription developed earlier by Sanyal et al. Electrostatic energy of interaction has been calculated for the nucleoside analogue (8-azaguanine) base for the entire space inside the deep groove of the DNA double helix. The interaction energy values and the location of the possible sites of association are compared with the recommended configurations of RNA transcription. It is concluded that 8-azaguanine is capable of replacing guanine during transcription. These conclusions are in general agreement with the experimental results.

Azaguanine↗