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PubMed1986

Effects of corn oil and benzyl acetate on number and size of azaserine-induced foci in the pancreas of LEW and F344 rats.

The response of LEW and F344 strain rats to the pancreatic carcinogen azaserine was compared using the size and number of azaserine-induced acidophilic acinar cell foci and nodules as parameters in a 4-month experiment. A second experiment compared the effect of corn oil intake by gavage and dietary routes on the growth of azaserine-induced pancreatic lesions in LEW rats. A third experiment tested the activity of benzyl acetate in regard to its ability to induce acinar cell foci or to promote the growth of such foci in azaserine-treated rats. The results showed that equivalent doses of azaserine induce two to seven times more foci in LEW than in F344 rats, and that LEW rats have a higher incidence of "spontaneous" foci than F344 rats. Azaserine-treated LEW rats that were given 5 mL corn oil/kg body weight 5 days per week by gavage developed more acinar cell foci than rats fed a basal diet (chow). Addition of an equivalent amount of corn oil to chow had a similar effect of enhancing the development of foci. Rats of neither strain developed acinar cell foci when benzyl acetate was given by gavage or in the diet nor was there evidence that benzyl acetate has a significant effect on the development of foci in azaserine-treated rats. These studies also demonstrate that the azaserine/rat model of pancreatic carcinogenesis which was developed in LEW rats can be adapted for use with F344 rats.

Animals↗
PubMed1990

Potentiation of azaserine by cholestyramine in the rat.

In the rat, when pancreatic growth is stimulated there is an increased incidence of spontaneous pancreatic neoplasms and marked potentiation of the pancreatic carcinogen azaserine. Since previous studies showed that cholestyramine caused pancreatic growth in this species we have now studied the effect of azaserine in rats fed soya flour diets containing cholestyramine. Two groups, each of eight rats, were fed either heated soya flour (HSF) or raw soya flour (RSF). Two further groups, each of 12 rats, received the same diets containing 2% cholestyramine (HSF + C, RSF + C). In each group, four rats received azaserine (30 mg/kg i.p.) and the remainder saline, weekly, for the first 5 weeks. Animals were killed after 24 weeks and pancreatic growth and the number and size of pancreatic neoplastic nodules was measured. RSF caused a significant increase in pancreatic weight, protein, RNA and DNA, compared with HSF and cholestyramine caused a further significant increase in pancreatic weight, protein and RNA but not DNA. Azaserine did not affect pancreatic growth. In azaserine-injected rats significantly more nodules were seen and the nodules were larger and the tumour burden greater in rats fed HSF + C than in rats fed HSF alone. However, the nodule count and other nodule parameters were not significantly different in RSF and RSF + C fed rats. It is concluded that 2% cholestyramine enhances pancreatic growth when added to soya flour diets and in rats fed HSF it potentiates the action of azaserine on the pancreas. It does not increase the potentiation of azaserine seen with RSF up to 24 weeks.

Animals↗
PubMed1993

Effects of the purine biosynthesis pathway inhibitors azaserine, hadacidin, and mycophenolic acid on the developing ovine corpus luteum.

De novo synthesis precursors of the purine second messengers adenosine, guanosine and inosine are adenosine, guanosine and inosine monophosphate (AMP, GMP, IMP), respectively. Inhibitors of the de novo purinergic synthesis pathways for AMP, GMP and IMP by hadacidin, mycophenolic acid and azaserine, respectively, or adenosine, guanosine or inosine alone or in combination were given every 4 or 6 hours in vivo. Treatments were given into the ovarian vascular pedicle sheath adjacent to the luteal-bearing ovary in three separate experiments to determine whether purines were involved in development of the corpus luteum. Hadacidin lowered AMP (p < or = 0.01) and azaserine tended to lower IMP and the GMP: AMP ratio (p < or = 01) while mycophenolic acid tended to lower the GMP:AMP ratio (p < or = 0.1) in luteal tissue. Azaserine (150 mg) increased progesterone (p < or = 0.01) on some days but guanosine or inosine had no effect on profiles of progesterone in jugular blood of the developing corpus luteum (p > or = 0.1). Azaserine (500 micrograms) tended to lower progesterone in jugular blood (p < or = 0.1) while profiles of progesterone did not differ among guanosine or inosine or adenosine, guanosine and inosine plus hadacidin, mycophenolic acid and azaserine treatment groups compared to controls (p > or = 0.1). Weights of corpora lutea or composition of cell types in the corpus luteum or their viability were not affected by adenosine, guanosine, inosine, hadacidin, mycophenolic acid or azaserine (p > or = 0.1). Since profiles of jugular progesterone did not differ between treatments during development of the corpus luteum, these results suggest that progesterone production by the developing corpus luteum is a) less dependent on de novo synthesized purines or b) there may be a non-purinergic-dependent second messenger system controlling biosynthesis of steroids in the developing ovine corpus luteum.

Adenosine Monophosphate↗
PubMed1984

Enhancing activity of rat tissue extracts for induction of lambda prophage by L-azaserine.

We studied the effect of rat tissue extracts on induction of lambda prophage in Escherichia coli (lambda) by L-azaserine. Hepatic and pancreatic extracts, primarily the cytosolic fraction, markedly increased the rate of induction. Hepatic extracts from lipotrope-deficient rats were somewhat more active than extracts from normal rats. The enhancing activity in normal rat hepatic cytosol was partially characterized. It reduced by about one-half the dose of azaserine required for a given purpose. The enhancement was increased by preincubating the bacterial cells with cytosol; cells retained the effect after cytosol was removed. Enhancing activity was inhibited strongly by the amino acids phenylalanine, tryptophan, and tyrosine; to lesser extents by leucine, methionine, and serine; and not at all by proline or glutamine. It was eliminated by dialysis of the cytosol and reduced by omission of nicotinamide adenine dinucleotide phosphate (NADP) from the reaction mixture. Heating the cytosol to 60 degrees C or 80 degrees C or varying the pH of the reaction mixture from 6 to 8 had no significant effect. Treating the cytosol with trypsin appeared to release an inhibitor of the activity. Glutathione, cysteine, and beta-mercaptoethanol also enhanced lambda induction by azaserine, but the cytosolic activity was not affected by the thiol-inactivating compound diethylmaleate (DEM). The results suggest that factors in cytosol interact with bacterial cells to facilitate transport of azaserine into the cells, primarily through the aromatic amino acid transport system. A small molecule, not a free thiol compound, appears to be involved. It may serve to establish reducing conditions protective for azaserine, the probable mechanism of action of sulfhydryl compounds.

Animals↗
PubMed1982

Azaserine: survival and mutation in Escherichia coli.

Azaserine in an antineoplastic agent, mutagen and carcinogen that is known to inhibit purine metabolism. Comparison of mutation in stationary-phase cultures of E. coli WP2 and a series of its DNA repair-deficient mutants exposed to azaserine showed that the effects of the compound closely mimicked those caused by UV light indicating, therefore, that azaserine-induced mutagenesis occurred via pathways dependent upon the recA and lexA genes. Comparison of survival of these strains showed that potentially lethal DNA lesions induced by azaserine were corrected by the excision, recombination, and rec-lex repair systems. These results show that azaserine causes DNa damage as well as inhibition of purine metabolism.

Azaserine↗
PubMed1981

Studies of pancreatic nodule induction and DNA damage by D-azaserine.

The ability of the D-isomer of azaserine to induce atypical acinar cell nodules (AACN) in pancreas and to cause DNA damage in pancreas and liver was evaluated. Rats were injected with equivalent doses of D- or L-azaserine and numbers of AACN were counted after 4 months. DNA damage in pancreas and liver of rats treated in vivo, and in pancreatic acinar cells treated in vitro with D- or L-azaserine was determined by alkaline elution. Results show that D-azaserine does not significantly induce AACN in pancreas, nor does it cause extensive DNA damage in comparison with L-azaserine, suggesting that the differential effect of the 2 isomers is related to stereospecificity in either transport or metabolism.

Animals↗
PubMed2004

The LIV-I/LS system as a determinant of azaserine sensitivity of Escherichia coli K-12.

The growth of Escherichia coli is inhibited by an antibiotic compound, azaserine (O-diazoacetyl-L-serine). Previous studies revealed the biochemical properties of azaserine, which involves inhibition of various enzymatic reactions as well as introduction of DNA breakage. However, genetically, nothing has been elucidated except that all the azaserine-resistant strains isolated so far carry lesions in the aroP gene as a primary determinant. Here, we demonstrate that, in addition to AroP, the LIV-I/LS system, an ATP-binding cassette type transporter, is involved in azaserine sensitivity of E. coli, by genetic analysis and transport studies, in which Ki value for azaserine was determined to be approximately 10(-3) M.

Amino Acid Transport Systems↗
PubMed1987

Histochemical studies on gamma-glutamyltranspeptidase activity of pancreatic acinar cell lesions induced by 4-hydroxyaminoquinoline 1-oxide and/or azaserine in rats.

The utility of gamma-glutamyltranspeptidase (gamma-GTP) as an enzyme marker during pancreatic acinar cell carcinogenesis in rats was assessed by measuring its enzyme-histochemical performance in pancreatic acinar cell lesions induced by 4-hydroxyaminoquinoline 1-oxide (4-HAQO) and/or azaserine in partially-pancreatectomized Fischer 344 and Wistar rats. Rats were given a single intravenous injection of 4-HAQO (10 or 7 mg/kg body weight) 3 days after partial pancreatectomy followed by intraperitoneal injections of azaserine (30 mg/kg) once a week for 10 weeks, or the same treatment without azaserine. The animals were sacrificed at 3, 6, 10, 12 and 18 months. 4-HAQO predominantly induced basophilic foci in Fischer rats, while in Wistar rats acidophilic foci and acidophilic hyperplastic nodules were predominant. A preferential enhancement of the induction of acidophilic foci and hyperplastic nodules was exhibited in Fischer rats following co-administration with azaserine. Normal acinar cells were positive for gamma-GTP. 90 to 100% of basophilic foci were either negative or slightly positive for gamma-GTP, whilst 68 to 98% of acidophilic foci were positive. The gamma-GTP activities of acidophilic hyperplastic nodules were more variable between nodules than within nodules, and either co-administration of azaserine or extension of experimental duration time appeared to increase the gamma-GTP positive nodules. Between the gamma-GTP positive and decreased nodules, no histological but some morphometrical differences were observed. As far as the nodules induced by 4-HAQO in Fischer rats were concerned, all of the gamma-GTP decreased nodules had thin fibrous capsules and exhibited ultrastructurally more atypia than the positive ones. Present study thus revealed that gamma-GTP is neither a useful nor invariable enzyme marker during pancreatic acinar cell carcinogenesis in rats.

4-Hydroxyaminoquinoline-1-oxide↗
PubMed1980

The effect of azaserine on glutamine uptake by rat renal brush-border membranes.

Azaserine added directly to isolated rat renal brush-border membrane vesicles inhibits uptake of L-glutamine. Azaserine acts as a non-competitive inhibitor of the low-Km system for glutamine transport, but has no effect on the high-Km system. Preincubation of the vesicles with azaserine at 37 degrees C min is not required for transport inhibition to occur, although it is a requirement for gamma-glutamyl transpeptidase inhibition. Removal of azaserine from the vesicle preparation by repeated resuspensions in buffer results in a reversal of the transport inhibition but not in reversal of enzyme inhibition. Azaserine also inhibits vesicle uptake of L-proline and alpha-methyl D-glucoside, indicating a generalized effect on membrane transport systems. The data cast doubt on the postulate that gamma-glutamyl transpeptidase might act as the carrier mechanism for glutamine reabsorption by renal cortical cells.

Animals↗
PubMed1999

The cytotoxicity of DNA carboxymethylation and methylation by the model carboxymethylating agent azaserine in human cells.

Carboxymethylating agents are potential sources of endogenous DNA damage that have been proposed as possible contributors to gastrointestinal carcinogenesis. The cytotoxicity of the model DNA carboxymethylating agent azaserine was investigated in human cells. Expression of the DNA repair enzyme O(6)-methylguanine-DNA methyltransferase (MGMT) did not affect sensitivity to the drug in two related Raji Burkitt's lymphoma cell lines. DNA mismatch repair-defective variants of Raji cells which display increased tolerance to DNA methylation damage were not selectively resistant to azaserine. Complementary results were obtained with a second carboxymethylating agent, potassium diazoacetate. In contrast, lymphoblastoid cell lines representative of each of the xeroderma pigmentosum complementation groups, including the variant, were all significantly more sensitive to azaserine than nucleotide excision repair-proficient cells. The hypersensitivity of XP cells was not due to systematic differences in the concentrations of intracellular thiol compounds or related thiol metabolizing enzymes. The data indicate that of the two types of potentially lethal DNA damage which azaserine introduces, carboxymethylated bases and O(6)-methylguanine, the former are repaired by nucleotide excision repair and are a more significant contributor to azaserine lethality in human cells.

Adenine↗
PubMed1990

Cyclosporine inhibition of azaserine-induced atypical acinar cell foci in rat pancreas.

The effects of cyclosporine (CsA), an immunosuppressive agent, on azaserine-induced pancreatic carcinogenesis in rats were investigated using the short-term assays of the quantitation of atypical acinar cell foci. Male Lewis rats at 14 days of age were given a single intraperitoneal injection of azaserine (30 mg/kg). At 25 days of age, the treated rats were weaned and divided into two groups fed either basal diet or the same diet containing 0.011% CsA. Saline-injected rats were also fed the CsA diet. Rats were killed 4 months after azaserine injection and acidophilic and basophilic foci in the pancreas were quantified. The pancreas of the rats given saline injection and maintained on the CsA diet showed no significant histological alterations. The dietary CsA after the injection of azaserine markedly reduced the number of both acidophilic and basophilic foci. It is concluded that addition of CsA to the diet inhibits the growth of initiated cells to form foci in the pancreas of azaserine-treated rats. The experimental model is useful in analyzing the modifying role of this immunosuppressant in the induction and growth of epithelial cell tumors.

Animals↗
PubMed1989

Inhibitory effects of estrogen and castration on the early stage of pancreatic carcinogenesis in Fischer rats treated with azaserine.

Effects of sex steroids on pancreatic carcinogenesis during the early stage were studied in azaserine-treated rats of both sexes. Fischer rats were given weekly i.p. injections of azaserine (30 mg/kg) [CAS:115-02; diazoacetate serine(ester)] at 2 and 3 weeks of age and were divided into six groups. Castration, ovariectomy, and s.c. implantations of either a 0.3-mg or a 1.0-mg 17 beta-estradiol (CAS:50-28.2; estradiol) pellet were performed at 7 weeks of age. The groups were as follows: group 1, intact male; group 2, castrated; group 3, castrated plus 0.3 mg estradiol; group 4, castrated plus 1.0 mg estradiol; group 5, ovariectomized; and group 6, intact female. Rats were killed 4 months after the last injection of azaserine. Azaserine treatment induced atypical acinar cell foci and nodules (AACN) in both sexes. The acidophilic AACN are considered preneoplastic lesions. An apparent sex difference was observed; the number of acidophilic AACN was greater in male rats than in female rats. Castration caused a significant decrease in both the serum testosterone levels and the number of acidophilic AACN, which were comparable to those in ovariectomized female rats. Furthermore, when estradiol treatment was administered to the castrated male rats, a linear decrease in the number of acidophilic AACN and an elevation in the serum estradiol levels were observed and were dose dependent. There were also positive relationships between estradiol treatments and the mean pituitary and pancreas weights. These results showed that estradiol treatment and the drop in testosterone levels caused by castration were highly effective in inhibiting the development and growth of preneoplastic lesions of the pancreas of the rats treated with azaserine. This estradiol effect was dose dependent. The present study, therefore, provides evidence that estrogen may act as an inhibitor and androgen as a promoter in the early stage of pancreatic carcinogenesis in rats.

Animals↗
PubMed1980

Pathologic and biochemical effects of azaserine in inbred Wistar/Lewis rats and noninbred CD-1 mice.

Inbred W/LEW rats and noninbred CD-1 mice were compared for responsiveness to induction of pancreatic adenocarcinomas by azaserine. At 1 year following the first of 15 weekly ip injections of 10 mg azaserine/kg body weight, the rats had a pancreatic adenoma incidence of 71% (12/17) and a pancreatic adenocarcinoma incidence of 35% (6/17), with 1 invasive adenocarcinoma. The mice showed none of these advanced lesions, although numerous pancreatic atypical acinar cell nodules (AACN) were present. An examination of the number and size of the AACN showed the rats to hve more and larger AACN thatn did the mice. The concentration of [14C]azaserine and/or its metabolites was greater in rat pancreas than in mouse pancreas. Alkaline sucrose gradients were used to compare azaserine-induced pancrewtic and liver DNA damage in W/LEW and F344 rats, the CD-1 mouse, the Syrian golden hamster, and the strain 13 guinea pig. DNA damage was detected 1 hour following azaserine administration in both pancreata and livers of all animals tested and persisted for at least 1 week in the pancreata of all animals except the CD-1 mouse; however, neither the degree nor persistence of DNA damage accurately reflected the differing responsiveness of these species to induction of pancreatic AACN or neoplasms by azaserine.

Adenocarcinoma↗
PubMed1998

Inhibition by galanin of experimental carcinogenesis induced by azaserine in rat pancreas.

The effects of galanin on pancreatic carcinogenesis induced by azaserine and on the norepinephrine concentration in the pancreas were investigated in male Wistar rats. Rats were given weekly injections of 10 mg/kg body weight of azaserine for 25 weeks and 8 microg/kg body weight of galanin in depot form every other day for 62 weeks. Azaserine-induced pancreatic lesions were examined with hematoxylin and eosin and histochemical techniques. In week 62, quantitative histological examination showed that prolonged administration of galanin significantly reduced the number and size (as percent of parenchyma) of adenosine triphosphatase-positive pancreatic lesions, which are correlated closely with the ultimate development of pancreatic cancer. The number of pancreatic adenocarcinomas in rats treated with galanin was significantly less than in controls. Galanin also significantly decreased the bromodeoxyuridine-labeling index of azaserine-induced pancreatic lesions and the norepinephrine concentration in the pancreas. Our findings indicate that galanin inhibits pancreatic carcinogenesis and that such inhibition may be related to the suppression of sympathetic nervous system activity and subsequently to the inhibition of cell proliferation in neoplastic lesions of the pancreas.

Animals↗
PubMed1990

Expression of c-myc, c-raf-1, and c-Ki-ras in azaserine-induced pancreatic carcinomas and growing pancreas in rats.

We examined the pattern of expression of several proto-oncogenes during nonneoplastic growth and in acinar cell neoplasms in the rat pancreas. The levels of c-myc, c-raf-1, and c-Ki-ras mRNAs were increased in regenerating pancreata following surgical partial pancreatectomy and following administration of camostat. We also investigated proto-oncogene expression associated with the progression of pancreatic cancers in azaserine-treated rats. Injection of a single dose (30 mg/kg) of azaserine (O-diazoacetyl-L-serine) to 14-d-old rats leads to a variety of neoplastic lesions in the rat pancreas. Total RNA was isolated from lesions in various stages of tumor progression, including adenomas, carcinomas in situ, and invasive carcinomas. We observed increased expression of c-myc, c-raf-1, and c-Ki-ras in azaserine-induced adenomas and carcinomas. Actin expression was also increased in these tissues, whereas amylase expression was variable. However, when compared to the normal growing pancreas, the level of proto-oncogene expression in the adenomas and carcinomas was disproportionate to the degree of cellular division in those tissues. Thus, the alterations induced by azaserine apparently caused a deregulated increase in expression of cellular oncogenes associated with growth regulation.

Adenoma↗
PubMed1995

Mutagenicity of O-diazoacetyl-L-serine (azaserine) and 6-diazo-5-oxo-L- norleucine (DON) in a soybean test system.

The mutagenicity of O-diazoacetyl-L-serine (azaserine) and 6-diazo-5-oxo-L-norleucine (DON), glutamine analogues, were assayed in heterozygous soybean plants (Y11y11), according to the appearance of mutational spots (yellow, dark green and twin) on the leaves. The mutagenicity of azaserine was detected at 0.1 mg/ml, and that of DON, at 0.05 mg/ml. DON was strongly cytotoxic at doses exceeding 0.1 mg/ml. After azaserine and DON treatment, large spots which occupied more than half the leaflet were found in the first and second compound leaves. The glutamine analogues increased the frequency of yellow spots much more than dark green spots or twin spots. Light green spots were observed on y11y11 plants. Azaserine and DON induce somatic crossing over, point mutation and segmental loss as major effects.

Azaserine↗
PubMed1981

Studies of DNA damage in rat pancreas and liver by 6-diazo-5-oxo-L-norleucine, ethyl diazoacetate and azaserine.

One hour following intraperitoneal injection of the pancreatic and liver carcinogen azaserine, 10 mg/kg (0.06 mmol/kg), DNA damage is present in both pancreas and liver of Wistar/Lewis rats as determined with alkaline sucrose gradients. Single injections (0.06 mmol/kg) of either of 2 structural analogues of azaserine, 6-diazo-5-oxo-L-norleucine (DON) and ethyl diazoacetate (EDA), do not damage pancreatic or liver DNA. EDA administered at 0.5 mmol/kg damages liver DNA, but not pancreatic DNA. Total radioactivity in pancreas and liver of Wistar rats 1 h after intravenous injection of [14C]azaserine, (10 microCi/kg), is 2.8 and 1.3 times respectively, the level of 14C-activity in pancreas and liver following injection [14C]EDA. Three to four times as much [14C]EDA localizes in the liver of Wistar rats as in the pancreas. Azaserine (0.06 mmol/kg weekly for 6 weeks) induces atypical acinar cell nodules (AACN) in pancreas of Wistar/Lewis rats. DON (0.06 mmol/kg weekly for 6 weeks) induces an elevated incidence, but low number of AACN in pancreas. EDA (0.10 mmol/kg weekly for 6 weeks) does not induce pancreatic AACN.

Animals↗
PubMed1979

Induction of foci of altered hepatocytes by a single injection of azaserine to rats.

The induction of foci of altered, gamma-glutamyltranspeptidase (GGT)-positive hepatocytes by azaserine was investigated. After injection of a single dose of azaserine, many foci developed in male Wistar rats fed a choline-devoid (CD) diet containing acetylaminofluorene (AAF), but only a few in rats fed a choline-supplemented (CS) diet containing AAF. Similar results were obtained in rats fed a plain CD diet or a plain CS diet and injected with a single dose of azaserine after a partial hepatectomy. These findings indicate that azaserine is an effective initiator of liver carcinogenesis in rats, and that a CD diet acts as a strong promoter of the evolution initiated liver cells to foci of altered, GGT-positive hepatocytes.

2-Acetylaminofluorene↗