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At least 19 recordsLinked to original sources
PubMed1977

Studies on the modes of action of azaserine in Escherichia coli. Mechanism of resistance to azaserine.

Growth of wildtype Escherichia coli was inhibited by azaserine. There was an inverse relationship between the initial rate of uptake of phenylalanine and the azaserine concentration. Moderately azaserine-resistant mutants exhibited an initial rate that was similar to that of an aroP mutant, but highly azaserine-resistant mutants exhibited little, if any, uptake of phenylalanine. All of the azaserine-resistant organisms tested harboured a mutation in the aroP+ gene. However, resistance to the antibiotic was not due solely to this lesion.

Aspartic Acid↗
PubMed1959

Mutagenic effect of azaserine in relation to azaserine resistance in Escherichia coli.

For demonstration of the mutagenic effect of azaserine (mutation from streptomycin dependence to nondependence), higher concentrations of this antibiotic are required with azaserine-resistant Escherichia coli than with the sensitive, parental strain. At barely toxic concentrations of azaserine, however, the mutagenic response of the resistant strain is many times higher than that of the sensitive strain.

Anti-Bacterial Agents↗
PubMed1982

The effect of azaserine upon the proline and methyl alpha-D-glucoside transport systems of rat renal brush-border membranes.

An inhibitory effect of azaserine on Na+ dependent proline and methyl alpha-D-glucoside transport of the rat renal brush-border membrane vesicles has been demonstrated. The inhibitory effects of azaserine were not the results of the drug disrupting the membrane vesicles as shown in osmolarity studies, nor did it affect the transport systems' affinities for Na+. Azaserine acts as a non-competitive inhibitor for the proline transport system in renal brush-border membranes by lowering 37% and 27% in the Vmax1 and Vmax2, respectively, when compared to that of control proline transport system. Azaserine had no effect upon the two Km values for proline uptake. Azaserine inhibition of methyl alpha-D-glucoside uptake by vesicles in the presence of 7.2 mM azaserine at 22 degrees C resulted in 66% increase in Km1 value and 44% decrease in Vmax1 as compared to that of control vesicles. There was no detectable effect upon the Km2 and Vmax2 of the methyl alpha-D-glucoside transport system. No effect of the drug was observed when sodium was equilibrated across the membrane, indicating that azaserine altered the driving force exerted by a sodium gradient. Azaserine only slightly affected the relative contribution of the two Km systems to total proline uptake. Contrary to the observed effect of azaserine upon the proline transport system, azaserine exerted a distinct effect upon the relative contribution to total uptake by the two Km systems in the low methyl alpha-D-glucoside concentration range. In the presence of 7.2 mM azaserine, the low-affinity, high-Km transport system becomes the major contributor to total methyl alpha-D-glucoside uptake by isolated renal brush-border vesicles.

Animals↗
PubMed1996

Autoradiographic localization of cholecystokinin (CCK) receptor expression during the development of azaserine-induced rat pancreatic carcinoma.

The peptide hormone cholecystokinin (CCK) has been shown to stimulate the growth of azaserine-induced preneoplastic nodules in the rat pancreas. Previously, our labortory demonstrated by classical binding studies that CCK receptors are overexpressed in azaserine-induced rat pancreatic neoplasms. In the present study, we utilized autoradiography to determine the temporal course of this increased receptor binding. Male Lewis rats were given azaserine or saline injections and sacrificed at 2, 4, 8, 12, and 18 months of age. Pancreatic tissue was harvested and autoradiography using 125l-labeled. CCK-8 was performed. Densitometry measurements of azaserine-induced pancreatic nodules, internodular pancreas, and normal pancreatic tissue (from saline-treated controls) of each age group were taken with an image analyzer. There was no statistically significant difference in CCK binding to internodular pancreas and normal pancreas at any age. At 2 months of age, there was no significant increase in CCK binding to azaserine-induced pancreatic nodules. However, at 4, 8, 12, and 18 months of age there was significantly greater CCK binding to azaserine-induced pancreatic nodules than to both internodular pancreas and normal pancreas (p < 0.001 for all groups). At 18 months of age, one azaserine-treated animal developed a pancreatic acinar cell carcinoma, which likewise exhibited significantly greater CCK binding than internodular pancreas or normal pancreas (p < 0.001 for both). These findings demonstrate increased CCK binding in azaserine-induced preneoplastic pancreatic nodules and pancreatic acinar cell carcinoma, compatible with our previous demonstration of receptor overexpression in these tissues. Increased CCK binding first becomes apparent by 4 months following exposure to azaserine. These result suggest that overexpression of CCK receptors, located specifically on preneoplastic and neoplastic pancreatic lesions, results in increased CCK binding and is involved in the mediation of CCK-stimulated growth during azaserine-induced pancreatic carcinogenesis.

Animals↗
PubMed1987

Effect of bombesin and caerulein on early stages of carcinogenesis induced by azaserine in the rat pancreas.

This study was designed to analyze the effect of two pancreaticotrophic peptides on pancreatic carcinogenesis in the azaserine-rat model. The rats were treated with bombesin or caerulein for 16 weeks after initiation with azaserine. Two-week-old Lewis rats were given injections of a single dose of azaserine (30 mg/kg) and the control pups received an injection of saline. They were divided into ten groups for peptide treatment as follows: Group 1, azaserine-saline; Group 2, azaserine-bombesin, 10 micrograms/kg; Group 3, azaserine-bombesin, 30 micrograms/kg; Group 4, azaserine-caerulein, 5 micrograms/kg; Group 5, azaserine-caerulein, 15 micrograms/kg; Group 6, control-saline; Group 7, control-bombesin, 10 micrograms/kg; Group 8, control-bombesin, 30 micrograms/kg; Group 9, control-caerulein, 5 micrograms/kg; and Group 10, control-caerulein, 15 micrograms/kg. At 3 weeks of age, they were weaned. Peptides or saline were injected 3 consecutive days a week for 16 weeks. Rats were autopsied 4 months after the administration of azaserine. Pancreatic weight was increased by bombesin and decreased by caerulein treatment. Quantitative histological analysis of azaserine-induced atypical acinar cell nodules in the pancreas showed that the size and number of atypical acinar cell nodules were increased in both bombesin- and caerulein-treated groups. Thus, these peptides appear to stimulate the growth of preneoplastic acinar cell lesions.

Animals↗
PubMed1996

Gastrin receptor expression during azaserine-induced rat pancreatic carcinogenesis.

The hormone gastrin is thought to stimulate the growth of certain pancreatic carcinoma cell lines. We have previously detected the presence of the gastrin receptor in rat pancreatic carcinoma cell lines but not in normal rat pancreas. We had not, however, previously demonstrated that gastrin receptor is expressed in pancreatic carcinomas developing in the rat in vivo. Therefore, in the present study, we examined rat pancreatic tissue at various stages in azaserine-induced pancreatic carcinogenesis for gastrin binding and for the presence of gastrin receptor mRNA to determine the temporal expression pattern of the gastrin receptor during the in vivo development of pancreatic cancer. Autoradiography of pancreatic tissue using (125)I-gastrin-17-I from all azaserine-treated and control animals at 2, 4, 8, and 12 months of age demonstrated no specific gastrin binding. At 18 months of age, normal pancreas, azaserine-induced premalignant pancreatic nodules, and internodular pancreas demonstrated no specific gastrin binding. One of three azaserine-treated animals developed an area of pancreatic acinar cell carcinoma at 18 months of age which exhibited significant specific gastrin binding of 141.8 - 32.8 fmole/gm of tissue. Southern blot analysis of pancreatic RNA isolated from animals at 12 months of age revealed no gastrin receptor mRNA; however, by 18 months of age, gastrin receptor mRNA was present in all azaserine-treated animals but absent in control animals. In summary, specific gastrin binding is present in in vivo azaserine-induced pancreatic acinar cell carcinoma but absent in normal pancreas and azaserine-induced premalignant pancreatic nodules. Gastrin receptor mRNA is first expressed in azaserine-treated rat pancreas at some point between 12 and 18 months of age. These results demonstrate that expression of gastrin receptor is altered in azaserine-treated rat pancreas and may play a role in the development of pancreatic cancer.

Animals↗
PubMed1984

The function of gamma-glutamyl transpeptidase as a determinant in cell sensitivity to azaserine toxicity.

The enzyme gamma-glutamyl transpeptidase (GGT) is characteristically present at high levels in mammalian cells that are vulnerable in vivo to the selectively toxic and carcinogenic effects of the naturally occurring diazo amino acid L-azaserine. The possible role of GGT as a determinant of cellular sensitivity to azaserine toxicity was investigated. No correlation was found between GGT activity and the abilities of different cell lines or GGT-deficient cell strains of TuWi, a human nephroblastoma-derived line high in GGT, to accumulate azaserine. However, the thiols glutathione and cysteine were found to inhibit the toxicity of azaserine in cultures of TuWi. In addition, maleate lowered both intracellular and extracellular glutathione levels and enhanced sensitivity of TuWi cells to azaserine, while serine-borate, a potent inhibitor of GGT, increased extracellular glutathione levels and inhibited azaserine toxicity. Since extracellular glutathione accumulation, which may reflect the rate of cellular glutathione turnover, is increased in cultures of azaserine-resistant, GGT-deficient strains of TuWi, we propose that GGT enhances cellular sensitivity to azaserine primarily by increasing the rate of glutathione turnover, thus removing the glutathione from detoxification pathways.

Animals↗
PubMed1995

Dissimilar effect of the carcinogenic agent azaserine on pancreatic and hepatic polyamine metabolism in rats.

The present study was designed to investigate the effects of the carcinogenic agent azaserine on the induction of pancreatic and hepatic polyamine metabolism in rats. One single injection of 30 mg azaserine/kg body weight i.p. is known to induce adenoma and subsequently carcinoma, predominantly in the pancreas, after several months. Male Lewis rats were treated with either azaserine (30 mg/kg body weight i.p.) or saline and 5-10 animals per group were sacrificed 2, 6, 9, 12, 18, 24, and 48 h later. Furthermore, animals were simultaneously treated with the ornithine decarboxylase (ODC) inhibitor alpha-difluoromethylornithine (DFMO) or the polyamine oxidase inhibitor MDL 72527 and killed 6 and 12 h after azaserine injection. The azaserine-induced significant increase in pancreatic putrescine concentrations was accompanied by an increase in spermidine/spermine N1-acetyltransferase but unchanged ODC and was significantly inhibited by N, N'-bis(2,3-butadienyl)putrescine (MDL 72527) but not by DFMO. S-Adenosylmethionine decarboxylase (SAM-DC) activity was significantly decreased in the pancreata of azaserine-treated animals compared to controls. In contrast, the azaserine-induced significant increase in hepatic putrescine was lower and transient, was accompanied by an increase in ODC and SAM-DC, and was completely inhibited by simultaneous DFMO treatment but not by MDL 72527. These data show completely different patterns of activation of polyamine metabolism in the pancreas and in the liver: Azaserine treatment forms putrescine in the liver by de novo synthesis via ODC only, while azaserine-induced pancreatic putrescine is exclusively produced by the interconversion pathway via oxidation of N1-acetylspermidine.

Animals↗
PubMed1981

A single-dose protocol for azaserine initiation of pancreatic carcinogenesis in the rat.

Previously, the induction of pancreatic carcinogenesis in the rat using azaserine has involved a multiple-dose treatment protocol. The objective of the present study was to determine the effect of multiple azaserine treatments on pancreatic DNA synthesis and to develop a protocol for a single-dose initiation of pancreatic carcinogenesis by azaserine in the rat. Pancreatic DNA synthesis in young rats, which was determined by measuring the amount of [3H]-thymidine incorporation into DNA, was found to be elevated at 4.3 weeks of age and to decrease to a baseline level by 6.3 weeks. Treatment of 4-week-old rats with azaserine resulted in a dose-dependent inhibition of [3H]-thymidine incorporation into both pancreatic and liver DNA. Maximum inhibition was seen at 10 mg/kg body weight. This inhibition was followed by a gradual return of incorporation to normal values over a 48 h period. One week following pretreatment with four weekly injections of azaserine at 30 mg/kg, [3H]-thymidine incorporation into pancreatic and liver DNA was significantly elevated, suggesting that multiple injection protocols caused enhanced DNA synthesis which could have a co-carcinogenic and/or promotional effect. Single-doses of azaserine (10, 30 and 60 mg/kg) given at 7 weeks of age caused the appearance of more atypical acinar cell nodules (AACN) than when given at 5 weeks of age. The most effective dose was 30 mg/kg. Using alkaline elution, we determined that this response was due to the occurrence of more DNA damage in the 7-week-old animals. Thus, these results demonstrate a rationale for the use of single-dose initiation protocols in the pancreas. An effective single-dose protocol for induction of AACN in azaserine-treated rats fed semi-synthetic diet is presented.

Animals↗
PubMed1984

Azaserine: further evidence for DNA damage in Escherichia coli.

Azaserine causes DNA damage in stationary-phase cells. In our investigation of this damage, we used strains of Escherichia coli differing in repair capabilities to study azaserine-induced DNA damage, detected as DNA strand breaks by sucrose gradient sedimentation techniques. Reduced sedimentation in alkaline and neutral sucrose gradients indicated the presence of both alkali-labile sites and in situ strand breaks. Azaserine induced DNA single-strand breaks (SSBs) abundantly in all but the recA strain, in which SSBs were greatly reduced. Treatment of purified DNA with azaserine from bacteriophages T4 and PM2 produced no detectable SSBs. Several other studies also failed to detect DNA damage induced directly by azaserine. Increased levels of beta-galactosidase were induced in an E. coli strain possessing a rec::lac fusion, providing further evidence for azaserine induction of the recA gene product. In addition, azaserine induced adaptation against killing but not against mutagenesis in wild-type E. coli strain.

Azaserine↗
PubMed1995

Gut peptide receptors in pancreata of azaserine-treated and normal control rats.

Gut peptides are involved in the growth and carcinogenesis of the exocrine pancreas of rats after treatment with azaserine. However, little is known about the influence of azaserine on expression of gut peptide receptors in the pancreas of the rat. Cholecystokinin, bombesin, somatostatin, secretin, and vasoactive intestinal peptide receptors were therefore visualized and quantified by storage phosphor autoradiography in pancreata of either saline control or azaserine-treated rats. As expected, putative preneoplastic lesions were formed in the pancreata of the azaserine-treated but not in the control animals. The pancreata of control rats contained receptors for cholecystokinin, bombesin, somatostatin, secretin, and vasoactive intestinal peptide. Cholecystokinin receptors were of the A-type and showed, in contrast to the other receptors, a heterogeneous expression due to variability of the high-affinity receptors. In the pancreata of azaserine-treated animals a significantly increased binding capacity of high-affinity receptors fro cholecystokinin was found not only in atypical acinar cell nodules but also in non-nodular pancreas when compared to pancreas of control rats (P < 0.05). Neither atypical acinar cell nodules nor non-nodular pancreas of rats treated by azaserine were shown to possess receptors for the other four types of gut peptide receptors. The spectrum of peptide receptors in pancreas of control and azaserine-treated rats in this study may help to understand the mechanism whereby gut hormones may modulate pancreatic carcinogenesis.

Animals↗
PubMed1995

Transforming growth factor-alpha and epidermal growth factor expression in the exocrine pancreas of azaserine-treated rats: modulation by cholecystokinin or a low fat, high fiber (caloric restricted) diet.

Expression of transforming growth factor-alpha (TGF-alpha) and epidermal growth factor (EGF) was studied in normal pancreatic tissue and in (pre)neoplastic pancreatic lesions of azaserine-treated rats. They were given either a low fat, high fiber (low caloric) diet, to inhibit carcinogenesis, or a low fat diet combined with injections of the cholecystokinin analog caerulein to enhance carcinogenesis. The control groups, maintained on a low fat diet, were injected with azaserine or were not treated at all. Autopsy was performed at 6 and 15 months after the last azaserine injection. After both 6 and 15 months immunohistochemistry revealed a weak expression of EGF and TGF-alpha peptides in the acinar cells, and a stronger expression in the ductular and centroacinar cells. TGF-alpha peptide expression was reduced in both putative preneoplastic and neoplastic acinar cell lesions, but no differences in EGF peptide expression were observed between the various stages of exocrine pancreatic carcinogenesis. After 16 months an increase in TGF-alpha mRNA due to treatment with azaserine was detected by semi-quantitative PCR in total pancreatic homogenates, whereas EGF mRNA expression had decreased. TGF-alpha mRNA levels in macroscopically isolated tumors were significantly lower, but EGF mRNA levels were significantly higher, than in total pancreatic homogenates from azaserine-treated rats. Furthermore, EGF and TGF-alpha mRNA levels in isolated tumors did not differ significantly from mRNA levels in non-carcinogen-treated rats. Neither with immunohistochemistry nor with PCR were differences in EGF or TGF-alpha expression observed due to either inhibition or stimulation of carcinogenesis. It is concluded that putative preneoplastic acinar cell lesions induced in rat pancreas by azaserine may develop into acinar adenocarcinomas independently of TGF-alpha and EGF. The results suggest involvement of these growth factors at the early stage of the carcinogenic process, during the initiation of normal acinar cells into putative preneoplastic cells. However, modulation of azaserine-induced pancreatic carcinogenesis by cholecystokinin or a low fat, high fiber (caloric restricted) diet appeared not to be regulated by EGF or TGF-alpha.

Animals↗
PubMed1984

Effect of pyridoxal deficiency on pancreatic DNA damage and nodule induction by azaserine.

The effects of pyridoxal deficiency on the genotoxicity and nodule inducing ability of azaserine in rat pancreas were examined. Azaserine at a dose of 10 mg/kg body weight which causes substantial DNA damage in normal rat pancreas, failed to induce DNA damage detectable by alkaline elution in the pancreas of pyridoxal-deficient rats. Studies of the distribution of [14C]azaserine in rat tissues revealed that uptake of azaserine in pancreas of pyridoxal deficient rats was not significantly different from that of normal rats. The ability of a structurally unrelated amino acid carcinogen N delta-(N-methyl-N- nitrosocarbamoyl )-L-ornithine to damage rat pancreatic DNA was not affected by pyridoxal deficiency. In another study, the pyridoxal antagonist 4'-deoxypyridoxine was administered i.p. to rats prior to and during azaserine treatment. Four months later, quantitative sterological analysis of atypical acinar cell nodules revealed that there was a significant reduction in the number but not size of nodules in the pancreases of 4'-deoxypyridoxine-treated rats. These results confirm the relationship of the induction of DNA damage by azaserine to its ability to induce pancreatic tumors, and support previous studies of azaserine metabolism, strongly suggesting that the in vivo activation of this carcinogen is pyridoxal dependent.

Animals↗
PubMed1987

Mutagenicity of L-azaserine for V79 cells in a pancreatic acinar cell-mediated mutagenesis assay.

The mutagenicity of azaserine was determined in a pancreatic acinar cell-mediated mutagenesis assay using V79 cells as the responder cell line. The mutation frequency of V79 cells was increased in direct culture with azaserine as well as in coculture with rat and hamster pancreatic acinar cells. Although slightly higher mutation frequencies were seen with coculture, the mutation frequency induced by azaserine in coculture was not significantly enhanced over that observed in direct culture. Thus, azaserine cannot be used as a positive control to monitor the level of acinar cell metabolism in such cell-mediated mutagenesis assays. Statistical analysis suggested that hamster acinar cell cocultures were more effective at increasing the mutation frequency of azaserine as compared to rat acinar cell cocultures. Hamster acinar cell cocultures, but not rat acinar cell cocultures, increased the mutagenicity of azaserine in a dose-response fashion. These results suggest that azaserine may be a pancreatic carcinogen for the hamster as well as the rat.

Animals↗