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PubMed1986

Cellular toxicity of pancreatic carcinogens.

Azaserine (CAS: 115-02-6), streptozocin (CAS: 18883-66-4; streptozotocin), and N-nitrosobis(2-oxopropyl)amine [(BOP) CAS: 60599-38-4] produce different types of pancreatic tumors in rodents. We have investigated the toxic effects of these compounds on pancreatic tissues from Wistar rats and Syrian hamsters. Inhibition of protein synthesis was used as a measure of toxicity. Pancreatic islets and acinar cells from rat and hamster were labeled with [3H]leucine for 60 minutes in vitro in the presence of the various carcinogens. Azaserine, which produces acinar cell tumors in the rat, inhibited synthesis by all tissues; rat acinar cells, however, were most sensitive. Glutamine, but not serine, provided some protection against azaserine toxicity. Streptozocin inhibited synthesis by islets of both species and acinar cells from hamster; islets were the most sensitive. BOP and N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine, which induce ductal tumors in the hamster, had no effect on any of the tissues examined. These results indicate that the specificities of the cellular toxicities of the pancreatic carcinogens parallel, to some degree, their tumorigenic effects.

Animals↗
PubMed1994

Dietary modulation of pancreatic carcinogenesis: calories and energy expenditure.

Physical activity (exercise) is a lifestyle factor that has received little attention with regard to its role in the etiology and/or prevention of cancer. These studies examined the effects of treadmill exercise on the early stages of pancreatic carcinogenesis initiated by azaserine in rats. Male Lewis rats were treated with azaserine at 2 weeks of age and weaned to experimental protocols at 3 weeks of age. Two experiments were undertaken; treadmill exercise began at 6 weeks of age (Experiment 1) or at 13 weeks of age (Experiment 2). Rats were exercised for 15-20 min/day and for 3-5 days/week. Treadmill speed and angle of incline were adjusted to afford a range of exercise intensities. The development of putative preneoplastic lesions of the pancreatic acinar cells (henceforth termed foci) was evaluated by quantitative stereological analysis using light microscopy. In Experiment 1, exercise resulted in a known paradoxical reduction in food intake by about 15% of the intake of the sedentary group fed ad libitum. The burden of azaserine-induced foci was decreased by approximately 37%, and this was attributed to the well known effects of reduced caloric intake in these young, rapidly growing rats. In Experiment 2, the higher intensity treadmill exercise group had an increased focal burden, compared to their sedentary pair-fed controls. Importantly, this enhancement occurred despite a reduction in food intake and body fat stores in this treadmill exercise group. These experiments demonstrate that exercise may suppress or promote carcinogenesis, depending upon the stage in the life cycle of the animal.

Aging↗
PubMed1993

The use of methylthioadenosine phosphorylase activity to select for human chromosome 9 in interspecies and intraspecies hybrid cells.

Methylthioadenosine phosphorylase (MTAP) is an enzyme that functions in a salvage pathway for adenine synthesis. The locus that encodes MTAP activity has been mapped to human chromosome 9 (9q12-9pter) by analysis of mouse x human somatic cell hybrids. Cells that have MTAP activity will stop proliferating, and eventually die in the presence of azaserine, an inhibitor of de novo purine synthesis, but can be rescued by the addition of methylthioadenosine (MTA) to the culture medium. Some mouse and human tumor cells lack MTAP activity and can not grow in the presence of azaserine and MTA. We fused MTAP competent human fibroblast cells to MTAP deficient mouse L-cells and selected for somatic cell hybrids, containing MTAP activity, in medium containing azaserine and MTA. In a separate experiment, a CHO cell x human fibroblast somatic cell hybrid, containing a normal copy of human chromosome 9, was used to prepare microcells, which were fused to an MTAP-deficient human leukemic cell line, CCRF-CEM. Somatic cell and microcell hybrids were shown to retain human chromosome 9 by fluorescence in situ hybridization using probes that hybridize to the interferon-alpha and -beta 1 genes on human chromosome 9 (9p21), and the centromere of human chromosome 9. This is the first report of complementation for MTAP activity being used to select for somatic cell hybrids and microcell hybrids that retain a human chromosome 9.

Animals↗
PubMed1982

Effect of temperature on mutation in cultured human skin fibroblasts.

Because clothing enhances the gonadal temperature in the human male and because as a consequence of that the spontaneous mutation rate might be increased, a study was undertaken to determine the effect of temperature on mutation towards HPRT deficiency in human diploid skin fibroblasts. Culturing of the cells in HAT medium containing azaserine, to remove pre-existing mutants, was highly mutagenic. Some results suggested that azaserine acts as an indirect mutagen. The mutational process in the presence of azaserine was influenced by temperature, a rise in temperature from 33 to 37 degrees C leading to a more than 10-fold increase in mutation rate per cell generation. This temperature dependence, taken as a starting point for the estimation of the consequences of the rise in gonadal temperature, could be responsible for an increase of 135% in the incidence of a sex-linked lethal (Lesch-Nyhan) in the human population. Epidemiological data on the frequency of Lesch-Nyhan disease and on the ratio of paternal and maternal mutations leading to Lesch-Nyhan disease do not contradict the findings in the cultured cells.

Cells, Cultured↗
PubMed1991

Effects of dietary soya bean trypsin inhibitor concentrate on initiation and growth of putative preneoplastic lesions in the pancreas of the rat.

Two studies evaluated the effects of soya bean trypsin inhibitor concentrate (STIC) on early stages of pancreatic carcinogenesis in Wistar rats. In experiment 1, the effects of a 3-month administration of diets containing 3.7% STIC were compared with the effects of administration of diets containing 20% corn oil, in rats pretreated with a single azaserine injection sufficient to initiate putative preneoplastic atypical acinar cell foci. Experiment 2 investigated the capacity of STIC to initiate pancreatic carcinogenesis. Diets containing 3.7% STIC were fed for 4 wk, then diets containing either 5 or 20% corn oil were fed for 3 months. Pancreases were quantitatively evaluated for foci. All groups of azaserine-initiated rats had large numbers of atypical acinar cell foci per cm3 of pancreas. Of these, the group fed 3.7% STIC had pancreatic foci that occupied a significantly greater (P less than 0.01) percentage volume of pancreas than did groups fed 20% corn oil or control diets, which contained 5% corn oil and no added trypsin inhibitor. Very few or no foci were observed in all other groups of either experiment 1 or 2. STIC had a much greater effect on the growth of azaserine-induced lesions than did corn oil. STIC alone did not appear to initiate pancreatic lesions.

Animals↗
PubMed1997

Increased flux through the hexosamine biosynthesis pathway inhibits glucose transport acutely by activation of protein kinase C.

The hexosamine biosynthesis pathway and protein kinase C (PKC) activation mediate hyperglycaemia-induced impaired glucose transport, but the relative role of each pathway is unknown. Following a 2 h preincubation of rat adipocytes in the presence of either high glucose (30 mM) plus insulin (0.7 nM) or glucosamine (3 mM), both high glucose and glucosamine inhibited subsequent basal and insulin-stimulated glucose transport, measured at 5.0 mM glucose. Azaserine, an inhibitor of the enzyme glutamine:fructose-6-phosphate aminotransferase, abolished the effect of high glucose, but not that of glucosamine. Ro-31-8220, an inhibitor of PKC, reversed the effects of both high glucose and glucosamine, suggesting that flux through the hexosamine biosynthesis pathway impaired glucose transport acutely by activating PKC. Both high glucose and glucosamine caused a 3-fold increase in PKC activity; this effect of high glucose, but not that of glucosamine, was partially decreased by azaserine. Neither high glucose nor glucosamine altered basal or insulin-stimulated plasma membrane GLUT1 levels, whereas both treatments decreased basal, but not insulin-stimulated, GLUT4 levels. Azaserine abolished the effect of high glucose, but not that of glucosamine, on basal plasma membrane GLUT4 levels. Ro-31-8220, which returned glucose transport to control values, caused a further decrease in plasma membrane GLUT4 levels. It is concluded that, in rat adipocytes, an acute increase in flux through the hexosamine biosynthesis pathway inhibits glucose transport by activation of PKC.

Adipocytes↗
PubMed1976

Use of phytohaemagglutinin stimulated lymphocytes to study effects of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) deficiency on polynucleotide and protein synthesis in the Lesch-Nyhan syndrome.

The incorporation of [14C]thymidine and [14C]uridine into the nucleoprotein, and [14C]phenylalanine into the protein by phytohaemagglutinin (PHA) stimulated lymphocytes from a patient with the Lesch-Nyhan syndrome [hypoxanthine-guanine phosphoribosyl transferase (EC 2.4.2.8 HGPRT) deficiency] and controls, was studied over 72 hours of incubation, with and without azaserine to block de novo purine biosynthesis. No difference was observed between the values obtained for Lesch-Nyhan and control lymphocytes, when PHA-stimulated without added azaserine. The percentage reduction in the incorporation of precursors into nucleoprotein and protein after PHA stimulation in the presence of azaserine was more obvious in the lymphocytes of the patient with the Lesch-Nyhan syndrome than in the controls after the shorter incubation periods at the lower rates of synthesis. Blocking the de novo purine biosynthetic pathway, in control PHA stimulated lymphocytes, inhibited transformation, whereas loss of the purine salvage enzyme HGPRT did not have this effect. These results are compatible with the view that the brain and bone-marrow damage that occur in the Lesch-Nyhan syndrome are the result of lack of HGPRT in tissues with little de novo purine biosynthetic capability. Other tissues with both pruine biosynthetic and salvage pathways are less vulnerable to the enzyme defect. Some possible mechanisms by which HGPRT deficiency could act are discussed. We suggest that inability to increase the supply of guanylic acid (GMP) in response to a mitotic stimulus may mediate the effect of HGPRT deficiency.

DNA↗
PubMed1984

Incorporation of [35S]sulfate in normal and neoplastic rat pancreatic acinar cells in relationship to cytodifferentiation.

The rates of [35S]sulfate incorporation in highly differentiated acinar cells from normal pancreas, moderately differentiated cells of nafenopin-induced transplantable pancreatic carcinoma, and poorly differentiated cells from azaserine-induced transplantable pancreatic carcinoma were examined in an attempt to determine if sulfation is a property of acinar cells with well-developed secretory granules. The cells were dissociated, pulsed with [35S]sulfate (specific activity, approximately 1000 Ci/mmol) for 10 and 60 min, and chased with medium containing 100 X excess of cold inorganic sulfate for 0, 15, 60, and 120 min. The cells were then processed for determining their pool size and light and electron microscopic autoradiography. No significant differences among their pool sizes were observed. However, the light microscopic autoradiograms revealed the [35S]sulfate incorporation as follows: azaserine-induced transplantable pancreatic carcinoma greater than nafenopin-induced transplantable pancreatic carcinoma greater than normal pancreas. Electron microscopic autoradiograms revealed similar trends. The grain densities (concentration of radiation) were highest in the Golgi regions immediately postpulse (0 min) and gradually shifted toward the secretory granules over a 120-min period. In addition, the grain density values of the secretory granule-rich cells of nafenopin-induced transplantable pancreatic carcinoma were relatively similar to the cells of normal pancreas, whereas the grain density values of secretory granule-deficient cells from this tumor were similar to those of poorly differentiated neoplastic cells of azaserine-induced transplantable pancreatic carcinoma. These results show that poorly differentiated neoplastic cells incorporate more [35S]sulfate than do the well-differentiated cells, but the reasons for this unexpected differential incorporation are at present unknown.

Animals↗
PubMed1996

Effects of sandostatin, alone and in combination with surgical castration, on pancreatic carcinogenesis in rats and hamsters.

In a previous short-term study (4 months) we found that Sandostatin, when administered prophylactically, inhibited growth of putative pre-neoplastic ductular lesions induced in hamster pancreas by N-nitrosobis(2-oxopropyl)amine (BOP), but not of acinar lesions induced in rat pancreas by azaserine. The present long-term (12 months) study was carried out to investigate the effects of Sandostatin (3 microgram/day), alone and in combination with orchiectomy, on pancreatic carcinogenesis in azaserine-treated rats and BOP-treated hamsters. In order to mimic therapy in humans, treatment of the animals started 4 months after the last injection with carcinogen, when (pre)neoplastic lesions had already developed. After treatment with Sandostatin for 8 months, rats developed fewer pancreatic atypical acinar cell nodules and tumours than those not treated with Sandostatin. Moreover, multiplicity of (pre)neoplastic acinar lesions was also lower in orchiectomized rats than in intact rats. However, Sandostatin treatment did not enhance the inhibitory effect of surgical castration on pancreatic carcinogenesis in rats. In hamsters that were both orchiectomized and treated with Sandostatin, the development of borderline lesions was significantly inhibited, whereas such an effect was not present in hamsters that were either surgically castrated or treated with Sandostatin alone. In Sandostatin-treated hamsters a significantly lower number of microcarcinomas was found than in hamsters not treated with Sandostatin. The present findings suggest that Sandostatin, particularly in combination with surgical castration, might be of therapeutic value for treatment of ductular pancreatic tumours.

Animals↗
PubMed1992

Effects of voluntary exercise and/or food restriction on pancreatic tumorigenesis in male rats.

Studies were undertaken to evaluate the effects of caloric restriction on voluntary exercise in a rat model of pancreatic cancer. Suckling male Lewis rats were initiated with 3 doses (30 mg/kg body weight) of the pancreatic carcinogen azaserine. At 28 days of age they were weaned to one of four experimental protocols; namely, sedentary/ad libitum fed, voluntary exercise/ad libitum fed, sedentary/food restricted, and voluntary exercise/food restricted. Voluntary exercise was provided by free access to running wheels fitted with odometers. Food restriction was intended to be mild, at less than 10% reduction of ad libitum intake. Putative pre-neoplastic pancreatic foci were identified microscopically at 4 months post-azaserine treatment. As previously shown, food restriction led to increased wheel activity, but the increased activity could not be maintained beyond the first half of the post-initiation treatment phase. Additionally, the extensive wheel running occurred only when available food was restricted by greater than 10%. Exercise per se had a lesser effect compared to food restriction on pancreatic tumorigenesis.

Analysis of Variance↗
PubMed1992

The effect of fasting and cholecystokinin stimulation on normal and neoplastic tissue in the rat pancreas.

Pancreatic nodules were produced in rats by either feeding raw soya flour alone or by injection of azaserine plus raw soya flour feeding. The resulting nodules were studied to determine whether there was any functional difference between this tissue and the relatively normal internodular pancreas. Tissue DNA and trypsin content were significantly elevated in nodules compared to the adjacent tissue. With fasting, protein and enzyme content increased significantly and equally in both nodular and internodular tissues. RNA levels fell significantly and the decrease was more pronounced in nodular tissue. The responsiveness of the multinodular pancreas to cholecystokinin was examined by measuring pancreatic secretion basally and in response to cholecystokinin. Both the volume and protein content secreted by the multinodular pancreas were greatly elevated above control levels. When corrected for pancreatic weight, the difference remained significant and appeared to be due to increased basal secretion by the nodular pancreas. These studies demonstrate that azaserine-raw soya flour induced nodules are functionally efficient. Furthermore, the secretory response to cholecystokinin of these nodules is equal to or higher than that of normal tissue.

Amylases↗
PubMed1991

Characterization of HAT- and HAsT-resistant HPRT mutant clones of V79 Chinese hamster cells.

HPRT mutant clones of V79 Chinese hamster cells, isolated after 6-thioguanine (6TG) selection, normally exhibit sensitivity to growth in medium containing the folic acid inhibitor aminopterin or the glutamine analogue L-azaserine (e.g., HAT or HAsT medium). However, it has been shown that some HPRT- clones are resistant to both HAT and HAsT medium. The present study was undertaken to investigate whether any common structural gene alteration exists for such 6TGr-HATr-HAsTr clones. Four clones were studied, 1 of spontaneous origin, 2 induced by a low dose of MNU and 1 EMS-induced. In contrast to wild-type cells and a mutant clone carrying a complete deletion of the HPRT gene, these 4 investigated 6TGr-HATr-HAsTr clones all showed an enhanced incorporation of exogenous 3H-hypoxanthine in the presence of aminopterin and L-azaserine suggesting that these clones carry mutations in the structural part of the HPRT gene. Sequence analysis of PCR-amplified HPRT cDNA from these mutants showed that the spontaneous and the 2 MNU-induced mutant clones lacked exon 4, while the EMS-induced mutant had a GC to AT transition in exon 6. Southern blot analysis of genomic DNA after digestion with BglII, EcoRI and PstI showed no changes in fragment patterns as compared to the wild type. Further sequence analysis of PCR-amplified genomic DNA using exon 4-specific primers showed that all these 3 mutants had an AT to GC or GC to AT transition in exon 4, but had no alterations in the splice sites of exon 4. Based on their characteristics of hypoxanthine incorporation, the present mutant clones fit the model for the proposed functional domains of the HPRT protein.

Aminopterin↗
PubMed2002

Effect of hypergastrinemia on pancreatic carcinogenesis.

BACKGROUND: Previous studies in our laboratory demonstrated that pancreatic carcinomas in rodents express receptors for the peptide hormone gastrin that are not present in normal adult pancreas. In view of an abundant literature suggesting that gastrin may promote growth of various gastrointestinal tissues and tumors, the effect of hypergastrinemia on the process of pancreatic carcinogenesis was evaluated. METHODS: Rats received subcutaneous injections of the pancreatic carcinogen azaserine at 19 and 26 days of age. Starting at 12 months of age, animals were randomized to treatment with the proton pump inhibitor lansoprazole or vehicle by gavage for 6 months. At autopsy, pancreatic wet weight normalized to body weight was recorded, as well as the number of benign and malignant pancreatic lesions. RESULTS: Serum gastrin levels were determined by radioimmunoassay and showed a greater than two-fold increase in lansoprazole-treated animals. Pancreatic wet weight in hypergastrinemic rats was increased compared to controls (p <0.05). Premalignant lesions such as acidophilic atypical acinar cell foci, adenomas, heterogeneous phenotypic populations of nodules within nodules, and carcinoma-in-situ were not increased in the hypergastrinemic group. Likewise, there was no difference in the incidence of invasive carcinoma in hypergastrinemic animals (10%) compared to controls (5.7%). CONCLUSION: Hypergastrinemia stimulated an increase in pancreatic weight, but did not stimulate development of premalignant lesions or progression to cancer in the azaserine model of rat pancreatic acinar cell carcinoma.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1980

Regulation of purine biosynthesis in cultured Drosophila melanogaster cells: II/relationships between hypoxanthine-guanine-phosphoribosyl transferase and 5'-nucleotidase.

All in vitro cell lines from Drosophila melanogaster do not possess measurable hypoxanthine - guanine - phosphoribosyltransferase (HGPRT) and 5'-nucleotidase activities. Nevertheless these enzymatic activities could be detected by the modification of culture conditions or treatment of crude extracts from Drosophila cells (1). A Drosophila melanogaster hemocyte line enabled demonstration of a relationship between the activities of HGPRT and 5'-nucleotidase. Only the addition of azaserine to the culture medium allows detection of a measurable amount of HGPRT and 5'-nucleotidase in cells devoid of endogenous synthesis of purine nucleotides. This action of azaserine suggests that the simultaneous expression of both enzymes is first directed by the suppression of the 5'-nucleotidase inhibition by pyrimidine nucleotides, and later on by the 5'-nucleotidase activity hydrolyzing the mononucleotides which inhibited the HGPRT, resulting its expression. This regulation system is confirmed by the simultaneous recovery of HGPRT and 5'-nucleotidase activities after heating cell cultures or cell extracts. Under such experimental conditions, 5'-nucleotidase is desensitized towards its negative effectors, while HGPRT regulation remains unchanged.

5'-Nucleotidase↗
PubMed1989

Modulation of dietary fat-promoted pancreatic carcinogenesis in rats and hamsters by chronic coffee ingestion.

The effect of chronic coffee ingestion on dietary fat-promoted pancreatic carcinogenesis was investigated in rats and hamsters. Rats were given a single i.p. injection of 30 mg azaserine per kg body weight at 19 days of age. Hamsters were injected s.c. with 20 mg N-nitrosobis(2-oxopropyl)amine (BOP) per kg body weight at 6 and 7 weeks of age. The animals were fed a semi-purified diet high in unsaturated fat (25% corn oil) either in combination with coffee or not. Coffee was provided instead of drinking water. A separate group maintained on a diet low in unsaturated fat (5% corn oil) was included as extra controls. The rats and hamsters were given their diets and coffee after treatment with carcinogen. Terminal autopsy of rats was 15 months after azaserine treatment and of hamsters 12 months after the last injection with BOP. In rat pancreas, the numbers of adenomas and carcinomas were significantly lower in the group maintained on the combination of a high-fat diet and coffee than in the high-fat group without coffee, while in the latter group the number of adenomas and carcinomas had significantly increased as compared to the low-fat controls. In hamsters, the number of ductal/ductular adenocarcinomas had significantly increased in the high-fat group as compared to the low-fat controls. The inhibitory effect of coffee on dietary fat-promoted pancreatic carcinogenesis was also noticed in this species but was less pronounced than in rats. It was concluded that chronic coffee consumption has an inhibitory effect on dietary fat-promoted pancreatic carcinogenesis in rats and hamsters. More research is needed to elucidate the mechanism by which coffee (constituents) modulates carcinogenesis.

Adenocarcinoma↗
PubMed1997

Nitrosated peptides and polyamines as endogenous mutagens in O6-alkylguanine-DNA alkyltransferase deficient cells.

Mutants of Escherichia coli and Saccharomyces cerevisiae that lack O6-alkylguanine-DNA alkyltransferase activities have increased spontaneous mutation rates, indicating the presence of a cellular metabolite that can alkylate DNA. Bacterially catalysed nitrosation has been implicated previously in producing the endogenous alkylating agent(s). Here, nitrosated polyamines and azaserine, a model compound for nitrosated peptides, are shown to be mutagenic to E. coli ada ogt mutants deficient in O6-alkylguanine-DNA alkyltransferase activity. The mutagenicity of azaserine may be explained by its ability to methylate DNA, whereas nitrosated spermidine causes DNA damage that is susceptible to both nucleotide excision repair and O6-alkylguanine-DNA alkyltransferase activity, which indicates the generation of more bulky DNA adducts. Nitrosated peptides and polyamines are therefore potential endogenous mutagens that are harmful particularly in O6-alkylguanine-DNA alkyltransferase deficient cells.

Azaserine↗
PubMed1986

Modulation of putative preneoplastic foci in exocrine pancreas of rats and hamsters. I. Interaction of dietary fat and ethanol.

The effect of dietary fat and ethanol and their interactions on the development of putative, preneoplastic foci in exocrine pancreas was investigated in rats and hamsters. Rats were given a single i.p. injection of 30 mg azaserine per kg body wt at 19 days of age. Hamsters were injected s.c., with 20 mg N-nitrosobis(2-oxopropyl)amine (BOP)/kg body wt at 6 and 7 weeks of age. The animals were fed a low fat (LF) control diet (5% corn oil) or a high fat (HF) diet (25% corn oil). Ethanol was provided in drinking water at a 15% (w/v) concentration. The animals were given the respective diets and ethanol after the treatment with carcinogen. At 4 months post-initiation, the pancreata were quantitatively examined for the number and size of preneoplastic foci. In rats, acidophilic as well as basophilic foci were subject to modulation by HF and ethanol. The results point to a specific promoting effect of unsaturated fat on the growth potential of azaserine-induced acidophilic acinar cell foci in rat pancreas. There was no evidence of an interaction between HF and ethanol as far as acidophilic foci are concerned. Evaluation of the number and size of the basophilic foci demonstrated an enhancing effect of ethanol on the modulation of pancreatic carcinogenesis by fat, pointing to a possible interaction between these two lifestyle factors. This suggestion was supported by the finding that six out of 20 rats in the HF with ethanol group exhibited a carcinoma in situ, whereas in the HF and in the ethanol group such an advanced lesion was found in one animal only. Unlike in rats, ethanol had no modulating effect on number and growth of putative, preneoplastic lesions in hamsters, either in combination with LF or in combination with HF. A HF diet, however, caused a significant increase in number as well as an increase in percentage of pancreatic tissue occupied by early lesions induced in hamster pancreas by BOP.

Adenosine Triphosphatases↗