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PubMed1976

Azaserine.

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Animals↗
PubMed1989

Photoinhibition of 2-amino-2-carboxybicyclo[2,2,1]heptane transport by O-diazoacetyl-L-serine. An initial step in identifying the L-system amino acid transporter.

Neutral amino acid uptake into mammalian cells occurs predominantly through the L, A, and ASC carrier-mediated transport systems. The proteins responsible for transport by these systems have not been isolated, and the three pathways presently are defined by their amino acid specificity and physiologic parameters. We have found that the amino acid derivative, O-diazoacetyl-L-serine (azaserine), is a potentially useful probe for identification of the L-(leucine-favoring) system transporter in human T-lymphocytes. Uptake of azaserine competitively inhibits the uptake of the prototype L-system amino acid, 2-amino-2-carboxybicycloheptane (BCH). Azaserine undergoes photolytic cleavage with 365 nm incident light to yield a highly reactive carbene intermediate and free N2. Following photolysis of [14C]azaserine in a suspension of lymphocytes, the 14C label is detectable within a crude cytoplasmic membrane preparation, and this process is inhibited by a 50-fold excess of unlabeled azaserine or 2-amino-2-carboxybicycloheptane, suggesting that the 14C-product is associated with the membranes at or near the L-system transport site. Furthermore, photolysis of azaserine in the presence of lymphocytes results in specific irreversible inhibition of L-system transport. Thus, photolysis of azaserine provides an initial step toward the identification of the L-system transporter.

Amino Acid Transport Systems↗
PubMed1996

Increased immunoreactivity and protein tyrosine kinase activity of the protooncogene pp60c-src in preneoplastic lesions in rat pancreas.

This study investigates the possibility that the c-Src protein tyrosine kinase is involved in experimental exocrine pancreatic carcinogenesis. Expression and activity of the protooncogene pp60c-src (c-Src) are investigated in acinar pancreatic (pre-) neoplastic lesions induced in rats by azaserine and compared with normal rat pancreas. Low or absent c-Src immunoreactivity and c-Src tyrosine kinase activity were found in the pancreas of untreated control rats. Compared with these controls, c-Src protein immunoreactivity was increased in "normal" acinar cells and even more in putative preneoplastic atypical acinar cell nodules (AACN) after azaserine treatment. In contrast, more advanced (secondary transformed) acinar cell lesions demonstrated no c-Src immunoreactivity. Rats treated with azaserine showed a 7-fold-higher c-Src tyrosine kinase activity in their pancreas. The level of c-Src tyrosine kinase activity correlated positively with the number of lesions in the pancreas, inasmuch as promotion of azaserine-initiated carcinogenesis by cerulein resulted in a more than 10-fold increase in the number of AACN, which was accompanied by a 6-fold increase in c-Src activity when compared with azaserine treatment alone. c-Src tyrosine kinase activity was responsible, on average, for 40% of the total tyrosine kinase activity in the pancreatic homogenates and was predominantly found in the cytoskeletal subcellular fraction. Furthermore, the transformation from normal to preneoplastic pancreatic tissue in azaserine-treated rats was accompanied by a change in the localization of the c-Src protein. With the use of immunohistochemistry and confocal laser scanning microscopy, the protein was detected in the cytoplasm in morphologically normal pancreatic acini, whereas in AACN it was detected both in the cytoplasm and in the nuclei. It is concluded that the protooncogene c-Src might be involved early in experimental pancreatic carcinogenesis: c-Src probably plays a minor role in pancreatic acinar cells after transformation to malignancy.

Animals↗
PubMed1979

DNA damage and repair induced by diazoacetyl derivatives of amino acids with different mechanism of cytotoxicity. Correlations with mutagenicity and carcinogenicity.

Eight synthetic N-diazoacetyl amino acids, prepared by inserting a diazoacetyl group onto the alpha-nitrogen of a natural amino acid, and two natural diazoazetyl amino acids, azaserine (9-diazoacetyl-L-serine) and DON (6-diazo-5-oxo-L-norleucine), have been studied by autoradiography for their capacity to induce DNA repair synthesis in mouse cells cultivated "in vitro". Dose-dependent unscheduled DNA synthesis was present in cells treated with the eight N-diazoacetyl derivatives, and was absent in cells exposed to approximately equitoxic concentrations of azaserine and DON. Azaserine and DON, unlike N-diazoacetyl derivatives, did not alkylate gamma-(4-nitrobenzyl) pyridine at an appreciable extent. When DNA damage (single stranded breaks or weak points in alkali) was measured by the sensitive technique of alkaline elution, DGA was found about 4 times as potent as azaserine and about 12 times as DON on a molar basis, but about 800 and 17,000 times as potent as azaserine and DON respectively by extrapolating to equitoxic concentrations. Carcinogenicity and mutagenicity seem to follow mainly the capability of inducing DNA damage.

Alkylation↗
PubMed1987

gamma-Glutamyltransferase activity in atypical acinar cell nodules of rat pancreas.

The biochemical and histochemical measurement of the enzyme gamma-glutamyltransferase (GGT) was undertaken in normal rat pancreas and in rat pancreas containing azaserine-induced preneoplastic nodules. A steady decrease in pancreatic GGT activity was observed in the normal animals as they aged from 5 to 34 weeks. The azaserine-induced nodules contained a lower average GGT activity than the control pancreas although a 10-fold variation was noted in the GGT activity of individual nodules. A significant increase in concentrations of both reduced glutathione and oxidized glutathione was noted in pancreatic nodules from azaserine-treated rats compared to concentrations found in both control pancreas from untreated rats and internodular pancreas from azaserine-treated rats. A pancreatic acinar cell carcinoma contained low GGT activity--similar to that found in large nodules and about 10% of the level found in control pancreas. Pancreatic GGT levels were higher in 5- and 7-week-old rats fed chow than in rats fed a purified diet, but this effect of chow was not observed at 34 weeks of age. Feeding a purified diet supplemented with a retinoid, N-2-hydroxyethylretinamide (2-HER), for a period of 2 weeks did not influence the GGT activity level in either normal pancreas or in the azaserine-induced nodules. While decreased GGT activity does not serve as a marker for all atypical acinar cell nodules, deficient activity with concomitant increased glutathione levels appears to correlate generally with increased growth potential.

Animals↗
PubMed1973

Effect of phenylpyruvate on enzymes involved in fatty acid synthesis in rat brain.

1. The effects of azaserine and nicotinamide, agents which inhibit and stimulate hepatic NAD synthesis respectively, on the content of NAD(+) and NADH in isolated rat islets of Langerhans incubated in vitro were studied. The effects of these compounds on the rates of insulin release, from isolated islets incubated in vitro, in response to various secretagogues were also measured. 2. Preincubation of islets in the presence of azaserine (0.3mm) caused a marked depletion of the normal islet-cell content of both NAD(+) and NADH and prevented the secretion of insulin in response to stimulatory concentrations of d-glucose, xylitol, d-xylulose, l-arginine hydrochloride and l-leucine. 3. Preincubation of islets in the presence of nicotinamide (2mm) increased the islet content of NAD(+) and enhanced the rate of release of insulin in response to d-glucose. Also when nicotinamide was present the inhibitory effect of azaserine on insulin release and the azaserine-induced depletion of the islet content of NAD(+) and NADH was prevented. 4. Preincubation with azaserine was without effect on the stimulation of insulin release caused by theophylline or dibutyryl cyclic AMP. 5. It is suggested that insulin release caused by sugars and amino acids is dependent on the maintenance of NAD concentrations, though this may not be the case for release due to theophylline and dibutyryl cyclic AMP.

Journal Article↗
PubMed1967

Mutator gene of Escherichia coli B.

An azaserine-resistant derivative of Escherichia coli B/UV, AZA/R(1), was found to carry a mutator gene. This gene, designated mutS1, was mapped by means of conjugation and P1kc-mediated transduction. The mutS1 gene was cotransduced with argB at a frequency of 2.4%; the gene order in this region of the chromosome is thy argB mutS1. To determine whether a relationship commonly exists between azaserine resistance and the mutator property, 12 additional azaserine-resistant derivatives of B/UV were developed and tested for the mutator phenotype. None of the twelve was a mutator strain. The level of azaserine resistance was not increased over that of the recipient parent when mutS1 was transduced to an azaserine-susceptible strain. Reversion studies indicated that mutS1 induced adenosine-ribosylthymine to guanosine-cytidine and guanosine-cytidine to adenosine-ribosylthymine transitions. Because such mutational changes are suppressible with deoxynucleosides when induced by base analogues, an attempt was made to suppress the mutator activity of mutS1 by the addition of deoxyribonucleosides to the medium. No suppression was found. Recombinants were prepared containing mutS1 and the Treffers mutator gene of E. coli K-12. The effect of the mutator genes appears to be additive.

Chromosome Mapping↗
PubMed1997

Involvement of purine nucleotide synthetic pathways in gonadotropin-induced meiotic maturation in mouse cumulus cell-enclosed oocytes.

This study was carried out to test the hypothesis that purine nucleotide-generating pathways are required for ligand-stimulated oocyte maturation in meiotically arrested cumulus cell-enclosed oocytes. Oocytes from hormonally primed, immature mice were cultured overnight in Eagle's minimum essential medium containing dibutyryl cyclic AMP (dbcAMP) (to maintain meiotic arrest), plus either mycophenolic acid or alanosine (inhibitors of guanyl and adenyl nucleotide production, respectively). Follicle-stimulating hormone (FSH) was added either at the outset of culture or after a 3-hr preincubation period. Under either of these conditions, the inhibitors suppressed FSH induction of germinal vesicle breakdown (GVB). In addition, the potency of FSH as an inducer of GVB was reduced following the 3-hr preincubation period, but this could be prevented if nucleotide precursors such as hypoxanthine, guanosine, or adenosine were included during the first 3 hr. Furthermore, preincubation had little effect on FSH induction of GVB when hypoxanthine was used to maintain meiotic arrest for the entire culture period. The phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine, could not mimic this protective effect of hypoxanthine. Azaserine and aminopterin, inhibitors of purine de novo synthesis, blocked hormone-triggered maturation in dbcAMP-arrested oocytes, but had little effect on hypoxanthine-arrested oocytes. The effect of azaserine on dbcAMP-treated oocytes could be reversed by the inclusion of AICA riboside, a compound that can be taken up by cells and phosphorylated to form AICAR, which can enter the purine de novo pathway at a point distal to the sites of azaserine inhibition. FSH was stimulatory to purine de novo synthesis, while azaserine, aminopterin, hypoxanthine, and AICA riboside all suppressed de novo synthesis in the presence or absence of FSH, with dbcAMP having no effect. HPLC analysis of 14C-hypoxanthine metabolism in oocyte-cumulus cell complexes revealed that changes in the pattern of purine metabolism did not mediate the meiosis-inducing effect of FSH. These data support the conclusion that purine nucleotide-generating pathways are vital participants in the mechanism(s) regulating hormone-induced meiotic maturation, and that either the de novo or salvage pathway can fulfill this nucleotide requirement.

Aminoimidazole Carboxamide↗
PubMed2005

Transgenic expression of CCK2 receptors sensitizes murine pancreatic acinar cells to carcinogen-induced preneoplastic lesions formation.

In humans, initial events of pancreatic carcinogenesis remain unknown, and the question of whether this cancer, which has a ductal phenotype, exclusively arises from duct cells has been raised. Previous studies have demonstrated that transgenic expression of the CCK2 receptor in acinar cells of ElasCCK2 mice plays a role in the development of pancreatic neoplasia. The aim of our study was to examine initial steps of carcinogenesis in ElasCCK2 mice, adding a supplementary defect by using a chemical carcinogen, azaserine. Results of posttreatment sequential immunohistochemical examinations and quantifications demonstrate that mice responded to azaserine. Transition of acinar cells into duct-like cells expressing Pdx1 and gastrin, as well as proliferation of acinar cells, were transiently observed in both transgenic and control mice. The carcinogen also induced formation of preneoplastic lesions, adenomas, exhibiting properties of autonomous growth. Importantly, expression of the CCK2 receptor increased the susceptibility of pancreas to azaserine. Indeed, treated ElasCCK2 mice exhibited larger areas of pancreatic acinar-ductal transition, increased cellular proliferation as well as larger adenomas areas vs. control mice. These amplified responses may be related to auto/paracrine stimulation of CCK2 receptor by gastrin expressed in newly formed duct-like cells. Our results demonstrate that activation of CCK2 receptor and azaserine result in cumulative effects to favor the emergence of a risk situation that is a potential site for initiation of carcinogenesis.

Adenoma↗
PubMed1994

Modulation of growth and cell turnover of preneoplastic lesions and of prostaglandin levels in rat pancreas by dietary fish oil.

In the present study the modulating effects of dietary fish oil (MaxEPA) on unsaturated fat-promoted pancreatic carcinogenesis in azaserine-treated rats were investigated. Three groups of 20 rats (each group comprised five saline-treated and 15 azaserine-treated animals) were fed an AIN76-based purified diet containing (i) 5 wt% fat, (ii) 25 wt% fat including 5 wt% linoleic acid or (iii) 25 wt% fat including 5 wt% linoleic acid and 9.4 wt% (20 cal%) MaxEPA for 6 months. The number and size of pancreatic atypical acinar cell foci was significantly higher (P < 0.01) in azaserine-treated animals maintained on a high fat diet than in those fed a low fat diet. MaxEPA did not influence the promoting effect of the high fat diet. The labeling index of atypical acinar cell foci in animals maintained on both a low fat or a high fat/MaxEPA diet was significantly (P < 0.01) lower than that in rats fed a high fat diet without MaxEPA. The linoleic acid concentration was higher, whereas the arachidonic acid concentration was lower, in blood plasma and to a lesser extent also in the pancreas of animals given MaxEPA in comparison with the other groups. Furthermore, animals fed MaxEPA showed lower 6-keto-prostaglandin F1 alpha, prostaglandin F2 alpha and thromboxane B2 levels, but not prostaglandin E2 levels in pancreatic tissue in comparison with the other groups. It is concluded that a high fat diet containing 5 wt% linoleic acid has a strong promoting effect on pancreatic carcinogenesis in azaserine-treated rats. Dietary MaxEPA did not influence the promoting effect of unsaturated fat on pancreatic carcinogenesis, although it caused a decrease in both cell proliferation in atypical acinar cell foci and prostaglandin levels in the pancreas.

Animals↗