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PubMed1996

Inhibition by verapamil of cholecystokinin-enhancement of pancreatic carcinogenesis induced by azaserine in Wistar rats.

The effect of a calcium channel blocker, verapamil, on cholecystokinin (CCK)-enhancement of pancreatic carcinogenesis induced by azaserine was investigated in Wistar rats. During and after 25 weekly injections of azaserine, each rat received alternate-day injections of CCK-octapeptide (CCK-8) and/or verapamil. Carcinogen-induced pancreatic lesions staining for mu class glutathione S-transferase (GST-mu) were examined histochemically at week 62. Prolonged administration of CCK-8 significantly increased the number and area as a percentage of parenchyma of GST-mu-positive lesions. Concomitant administration of verapamil significantly attenuated the enhancing effect of CCK-8. These findings indicate that calcium may play an important role in CCK-enhancement of pancreatic carcinogenesis.

Animals↗
PubMed1996

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

The effects of prolonged administration of the diuretic amiloride on pancreatic carcinogenesis induced by azaserine and on the labeling index of carcinogen-induced pancreatic lesions were investigated in Wistar rats. Rats were given 25 weekly injections of 10 mg/kg body weight azaserine and also 5 mg/kg body weight amiloride every other day until the end of the experiment at week 62. Carcinogen-induced pancreatic lesions were examined by histochemical techniques and were classified as ATPase-positive or ATPase-negative. In week 62, quantitative histologic analysis showed that prolonged administration of amiloride significantly reduced the number and size (as percent of parenchyma) of ATPase-positive pancreatic lesions, which are closely correlated with the subsequent development of pancreatic cancer. Amiloride also significantly decreased the labeling index of carcinogen-induced pancreatic lesions, but not of the surrounding acinar cells. In contrast, amiloride has no significant influence on the number and size of ATPase-negative pancreatic lesions. These findings indicate that amiloride inhibits pancreatic carcinogenesis, and that this effect may be related to the reduction of ATPase-positive lesions and to amiloride's inhibition of cell proliferation in neoplastic lesions of the pancreas.

Adenosine Triphosphatases↗
PubMed1996

Dietary fish oil (MaxEPA) enhances pancreatic carcinogenesis in azaserine-treated rats.

In the present study the putative chemopreventive effect of dietary fish oil (MaxEPA) on azaserine-induced pancreatic carcinogenesis in rats was investigated. Groups of rats were maintained on a semipurified low-fat (LF; 5 wt%) diet or on semipurified high-fat (HF; 25 wt%) diets containing 5 wt% linoleic acid (LA) and including 0.0, 1.2, 2.4, 4.7, 7.1 or 9.4 wt% MaxEPA. Animals fed a HF diet developed significantly higher mean numbers of atypical acinar cell nodules (AACNs), adenomas and carcinomas than animals fed a LF diet. Dietary MaxEPA caused a significant (P < 0.01) dose-related increase in mean number of AACNs (0.5 < phi < 3.0 mm). The mean number of adenomas and carcinomas remained similar among the groups. Cell proliferation was significantly lower in AACNs from animals fed HF containing 9.4% MaxEPA in comparison with HF without MaxEPA and with LF. LA levels had increased and arachidonic acid (AA) levels had decreased in blood plasma and pancreas with increasing dietary MaxEPA. Feeding MaxEPA resulted in significant decreases in 6-keto-prostaglandin (PG) F1 alpha (P < 0.05) and PGF2 alpha (P < 0.01) in non-tumorous pancreas, whereas PGE2, PGF2 alpha and thromboxane B2 (TXB2) levels were significantly (P < 0.001) higher in pancreatic tumour tissue than in non-tumorous pancreatic tissue. It is concluded that (i) dietary MaxEPA enhances dose-relatively growth of putative preneoplastic AACNs in the pancreas of azaserine-treated rats; (ii) dietary MaxEPA inhibits the conversion of LA to AA, as well as the conversion of AA to TXB2 or PGF2 alpha in non-tumorous pancreatic tissue; (iii) the high levels of PGE2, PGF2 alpha and TXB2 in pancreatic adenocarcinomas indicate a possible role for these eicosanoids in modulation of tumour growth.

Animals↗
PubMed1989

Abnormal synthesis of cartilage-characteristic proteoglycan in azaserine-induced micromelial limbs.

Administration of azaserine (250 micrograms) to day-4 chick embryos in ovo was shown to induce micromelial limbs. In the present study, biosynthesis of cartilage-characteristic proteoglycan H (PG-H) as an index of limb chondrogenesis was examined in normal and micromelial hind limbs from day-7 chick embryos by biochemical and immunological methods. (1) Metabolic labelling of the micromelial limbs with [6-3H]-glucose and [35S]sulphate, followed by analysis of labelled proteoglycans by glycerol-density-gradient centrifugation under dissociative conditions, showed a marked reduction in PG-H synthesis. (2) PG-H synthesized by micromelial limbs differed from that synthesized by normal limbs in possessing a slower sedimenting velocity and much lower amounts of chondroitin sulphates. (3) The amount of PG-H core protein in micromelial limbs was significantly decreased to about 19% on a per limb basis and about 42% on a per DNA basis of that in normal limbs, as determined by e.l.i.s.a. (4) The transition from PG-M to PG-H during limb formation was retarded in micromelial limbs as judged by an indirect immunofluorescence technique using antibodies against PG-M and PG-H. (5) The deficiency of incorporation of labelled glucose into chondroitin sulphate chains of PG-H in micromelial limbs was partially restored by using [6-3H]-glucosamine as a precursor, suggesting that the synthesis of UDP-N-acetylhexosamine, required for chondroitin sulphate chain synthesis of PG-H in micromelial limbs, was decreased. These results suggest that the reduction in the synthesis of PG-H as well as the production of an abnormal form of PG-H during a critical period of limb morphogenesis may be important factors in explaining the micromelia induced by azaserine.

Abnormalities, Drug-Induced↗
PubMed1991

Glutathione S-transferase (mu class) as an early marker of azaserine-induced foci in the rat pancreas.

The alpha, mu and pi classes of glutathione S-transferase (GST) were evaluated as early immunocytochemical markers for the development of atypical foci within the pancreases of azaserine treated rats. Changes detected with haematoxylin and eosin (H&E) were compared with those detected by immunocytochemistry using antibodies raised against each class of GST. All foci detected with H&E staining were classified as acidophilic atypical acinar cell nodules (AACN), which have previously been reported in this model. All of these AACN overexpressed GST mu. However, 64% of foci detected with GST mu staining had not been identified as AACN during a prior examination with H&E. Re-evaluation of the H&E sections revealed that some of these foci showed subtle morphological changes which are indicative of AACN. In many cases, however, no morphological difference could be seen with H&E staining. We conclude that immunocytochemical staining for GST mu is a more reliable and sensitive method than H&E for detecting the early stages of azaserine-induced foci. Furthermore, we suggest that studies on the incidence and growth of these foci can be shortened considerably if GST mu staining is used in conjunction with H&E.

Animals↗
PubMed1992

Azaserine-induced pancreatic foci: detection, growth, labelling index and response to raw soya flour.

Atypical acinar cell foci were induced in the pancreases of rats by injection of azaserine. An incubation period of 6 weeks was sufficient for the detection of all glutathione S-transferase mu positive foci. In chow-fed rats, the labelling index of foci was 12-fold higher than normal pancreatic tissue. Feeding rats raw soya flour (RSF) for up to 20 weeks did not increase the number of foci per pancreas but did produce significant increases in labelling index and growth rate. In normal pancreatic tissue, the trophic response was complete after 4 weeks of RSF feeding. In foci, however, the trophic response to RSF was prolonged. Involution of normal pancreatic tissue was seen in rats fed RSF for 19 weeks and then switched to chow 1 week prior to death. No evidence for involution was seen in the foci of these animals, although a 40-fold reduction was seen in labelling index. The labelling index of these foci was reduced to the level seen in normal tissue of chow-fed rats. These results are consistent with increased cholecystokinin (CCK) responsiveness and CCK dependence in azaserine-induced pancreatic foci.

Animals↗
PubMed1999

Cellular autophagic capacity is highly increased in azaserine-induced premalignant atypical acinar nodule cells.

Although cellular autophagy is recognized as a major pathway of macromolecular catabolism, little data are available regarding its activity or regulation in tumor cells. We approach this problem by morphometrical investigation into the possible changes in autophagic activity during progression of rat pancreatic adenocarcinoma induced by azaserine and promoted by a raw soya flour-containing pancreatotrophic diet. In the present study, the autophagic capacity of the carcinogen-induced premalignant atypical acinar nodule cells was characterized and compared with controls (normal tissue of rats kept on standard laboratory or pancreatotrophic diet and host tissue of the premalignant nodules of the azaserine-treated rats). Given for 90 min, vinblastine, an enhancer of autophagic segregation (i.e. formation of autophagic vacuoles), caused a one to two orders of magnitude larger expansion of the autophagic compartment in atypical nodule cells than in the controls. Then a 20 min blockade of segregation by cycloheximide led to regression of the autophagic compartment, which was barely measurable or moderate in the controls but exceeded 50% in the premalignant cells. At the same time, the cytoplasmic volume fraction of early autophagic vacuoles regressed to a near zero value in each cell type. Expansion and regression rates of these nascent vacuoles showed that both segregation and degradation were 6-20 times faster in the nodule than in normal tissue cells. These results show that the autophagic capacity of the premalignant cells in our system is greatly increased, possibly making these cells unusually sensitive to up-regulation of their self-digesting activity in response to different extracellular signals or drugs.

Adenocarcinoma↗
PubMed1982

Effects of azaserine treatment on plasma glutamine concentration and uric acid production in chickens fed low and high protein diets.

Azaserine injected intravenously decreased uric acid in the blood and urine 1.6 and 2 times, respectively. It also resulted in 3 times larger increase in plasma glutamine concentration in chickens fed a 20% protein diet than in those fed a 5% protein diet, but it had no effect on liver glutamine synthetase activity in either dietary group. Thus the resultant concentration of plasma glutamine in the chickens fed the high protein diet was higher than in those fed the low protein diet, the reverse of the relationship observed before the injection. The infusion of ammonium acetate caused less of a rise in plasma glutamine concentration, but increased uric acid in the urine and blood, more with the high protein feeding than the low protein feeding. Pretreatment with azaserine further augmented the increase in plasma glutamine concentration caused by the infusion of ammonium acetate in the chickens fed the high protein diet but not in those fed the low protein diet, and concurrently removed the stimulatory effect of ammonia on uric acid in the blood and urine of both dietary groups. These data indicate that both glutamine in intact chickens and the increased glutamine in the ammonia-infused chickens are converted to uric acid more by high protein feeding than by low protein feeding, and this is a major reason for the low concentration of plasma glutamine in the chickens fed a high protein diet.

Acetates↗
PubMed1989

Effect of dietary omega-3 and omega-6 fatty acids on development of azaserine-induced preneoplastic lesions in rat pancreas.

We examined the effect of varying the ratio of dietary omega-3 (omega 3) to omega-6 (omega 6) on the development of pancreatic preneoplastic lesions in male Wistar rats given azaserine at 14 days of age. As the ratio of dietary omega 3 to omega 6 fatty acids increased in a diet totaling 20% by weight of fat, the development of preneoplastic atypical acinar cell nodules (AACNs) at 4 months after dosing with azaserine decreased significantly. In addition, serum levels of prostaglandin thromboxane B2, prostaglandin E2, and 6-keto-prostaglandin F1 alpha decreased significantly. The fatty acid composition of the rbc membrane was also significantly influenced by the ratio of dietary omega 3 to omega 6 fatty acids. In a second experiment, we examined the effect of dietary intervention with a different type of fat (corn oil or menhaden oil) 2 months into the 4-month postdosing period on AACN development at the end of the post-dosing period. Intervention of the omega 6 fatty acid-rich diet with the omega 3 fatty acid-rich diet significantly decreased focal development. The opposite was true when intervention involved substituting the omega 3 fatty acid-rich diet with the omega 6 fatty acid-rich diet.

Animals↗
PubMed2001

Changes in cellular autophagic capacity during azaserine-initiated pancreatic carcinogenesis.

Growth regulation is a crucial event in tumour progression. Surprisingly, relatively few papers have dealt with the catabolic side of regulation, and there are practically no data regarding the autophagic process during tumour development. We approach this problem by morphometrical investigation into the possible changes of autophagic activity during the progression of rat pancreatic adenocarcinoma induced by azaserine. In the present study, autophagic capacity of the azaserine-induced premalignant and malignant cells were characterised and compared to the respective host tissue cells of the rat pancreas and to the acinar cells in other stages of tumour development. Using vinblastine (VBL) as an enhancer, and cycloheximide (CHI) as an inhibitor of autophagic segregation we observed that autophagic capacity of premalignant cells (month 6 and 10 after initiation) is much higher than in the host tissue cells. We found a sharp decrease in self-digesting capacity in adenocarcinoma cells (month 20) where VBL induced a minimal accumulation of autophagic vacuoles which was, surprisingly, not inhibited by CHI, i.e. the CHI-sensitive regulatory step was lost. The changes in autophagic capacity are probably associated to specific steps of tumour progression in our system.

Adenocarcinoma↗
PubMed1979

Response of two rodents, Mastomys natalensis and Mystromys albicaudatus, to the pancreatic carcinogen azaserine.

The response of two rodents to azaserine carcinogenicity for the pancreas was evaluated. Mystromys albicaudatus was not responsive; however, Mastomys natalensis developed large numbers of atypical acinar cell nodules and several adenomas in a 6-month study. Mastomys is the most responsive of several animals in which azaserine has been studied as a pancreatic carcinogen.

Adenoma↗
PubMed1983

Divergent effects of retinoids on pancreatic and liver carcinogenesis in azaserine-treated rats.

Chemoprevention by synthetic retinoids of the progression of carcinomas of the pancreas induced in rats by azaserine was evaluated. Lewis rats were given five weekly injections of azaserine, 30 mg/kg, while being fed a chow diet. Two weeks after completion of carcinogen treatment, groups of rats were fed the chow diet supplemented with four different retinoids at the level of 0.5 to 2 mmol/kg of diet for 1 year. The incidence of pancreatic and other neoplasms was determined by autopsy and histological study. The incidence of localized pancreatic carcinoma among male and female non-retinoid-treated controls was 25 and 17%, respectively. No invasive or metastatic carcinomas were found in the control group. The combined incidence of localized and invasive pancreatic carcinomas among male and female rats treated with retinoids was: N-(4-pivaloyloxyphenyl)retinamide, 4 and 0%; N-(2-hydroxypropyl)retinamide, 14 and 6%; N-(3-hydroxypropyl)retinamide, 16 and 4%; and N-(2,3-dihydroxypropyl)retinamide, 12 and 6%. High- and low-dose groups are combined in this summary of data. Thus, there was a trend towards fewer pancreatic carcinomas among all retinoid-treated groups. The reduction in incidence was significant in both male and female rat groups given N-(4-pivaloyloxyphenyl)retinamide and N-(2,3-dihydroxypropyl)retinamide. The principal evidence of retinoid toxicity was growth failure, which was most severe in animals treated with N-(4-pivaloyloxyphenyl)retinamide, and testicular atrophy, which was most severe among male animals treated with N-(3-hydroxypropyl)retinamide. Among the females, groups treated with three of the four retinoids showed a dose-related increase in incidence of hepatocellular carcinomas. Since the retinoids were fed after the completion of exposure to the carcinogen, the effects on both pancreatic and liver carcinogenesis were exerted during the postinitiation phase of carcinogenesis.

Animals↗
PubMed1984

Modulation of azaserine-induced pancreatic foci by phenolic antioxidants in rats.

Effects of the dietary phenolic antioxidants butylated hydroxyanisole [(BHA) CAS: 25013-16-5; (1,1-dimethylethyl)-4-methoxyphenol] and butylated hydroxytoluene [(BHT) CAS: 128-37-0; 2,6-di-tert-butyl-p-cresol] on pancreatic tumorigenesis were examined. Male LEW inbred rats were given injections of 30 mg azaserine [CAS: 115-02-6; diazoacetate (ester) serine] per kg body weight once a week for 3 weeks and maintained on either a control diet or 0.45% BHA- or 0.45% BHT-supplemented control diet throughout the initiation and post-initiation phases of the experiment. At 4 months post initiation, pancreatic tissue sections were quantitatively examined for the number and size of preneoplastic foci. BHT and BHA treatments reduced the number of acidophilic foci per pancreas by 32 and 48%, respectively, but were without effect on focal size. By contrast, basophilic foci were not subject to modulation by these antioxidants. A constellation of enzyme activities involved in carcinogen inactivation and known to be perturbed by antioxidant treatment was examined in liver and pancreas. The hepatic activities of glucose-6-phosphate dehydrogenase, glutathione reductase, and glutathione-S-transferases were markedly elevated while catalase and superoxide dismutase activities were unchanged. Glutathione peroxidase activity was diminished. In the pancreas, only glutathione peroxidase activity was affected, and it was reduced in both the BHA and BHT treatment groups. Although the pancreas is refractory to the enzyme inductive effects of these antioxidants, morphometric analysis of foci demonstrated chemoprevention by BHA and BHT of azaserine-induced foci. Whether this reduction reflected inhibition of an initiation, postinitiation , or a combination of effects was not known.

Animals↗
PubMed1984

Inhibition by retinoids of the growth of azaserine-induced foci in the rat pancreas.

The usefulness of a short-term azaserine [CAS: 115-02-6; diazoacetate serine (ester)]-rat model for the screening of retinoids (known chemopreventive agents) and the effect of two retinoids on the growth of azaserine-induced, presumptive preneoplastic foci of acinar cells were examined. At 14 days of age, male Lewis rats were each given injections of a single dose of 30 mg azaserine/kg body weight. These rats were weaned to test diets to which retinoids were added. At 4 months post initiation, pancreata were examined by quantitative stereologic methods to determine number and mean size of foci. Two phenotypically different populations of foci were observed and characterized as acidophilic or basophilic. Retinylidene dimedone and N-2-hydroxyethylretinamide decreased the number and size of the acidophilic foci but not the basophilic foci. The inhibition of growth of the acidophilic foci correlates well with the known effects of these retinoids in long-term carcinogenicity studies.

Animals↗
PubMed1981

Promotion by unsaturated fat of azaserine-induced pancreatic carcinogenesis in the rat.

Diet has been shown to modulate the incidence of a wide variety of chemically induced cancers in animals. Various diets fed either during the initiation stage or the postinitiation (promotion) stage of carcinogenesis were evaluated for their ability to modulate the incidence of pancreatic cancer. Male Wistar/Lewis rats were treated with multiple injections of the pancreatic carcinogen, azaserine, during a 6- to 7-week-long initiation phase and were autopsied after a postinitiation phase of 34 or 44 weeks. The following diets were evaluated for their effects on the incidence of pancreatic neoplasms during each stage of carcinogenesis: high saturated fat; two high unsaturated fats (corn oil and safflower oil); low protein; and caloric restricted. A purified control diet was fed during that stage when the test diets were not fed. The incidence of pancreatic adenomas and adenocarcinomas was evaluated by light microscopy. Feeding of the caloric-restricted diet during the initiation phase suppressed the pancreatic neoplasm incidence. None of the ther diets tested had an effect on the incidence of pancreatic cancer during the initiation phase. During the postinitiation phase, both high-unsaturated-fat diets but not the high-saturated-fat diet significantly elevated the pancreatic neoplasm incidence. The low-protein and caloric-restricted diets had no effect on the neoplasm incidence when fed during the postinitiation phase. Thus, diets high in unsaturated fat appear to promote pancreatic carcinogenesis in the azaserine-treated rat while a diet high in saturated fat failed to show a similar degree of enhancement of pancreatic carcinogenesis.

Adenocarcinoma↗
PubMed1986

Effects of high levels of dietary fats on the growth of azaserine-induced foci in the rat pancreas.

Azaserine induced two phenotypically different populations of foci, namely, acidophilic and basophilic foci. The effects of dietary modification during the post-initiation phase of carcinogenesis were examined. A diet of 20% (w/w) unsaturated fat (unsat) compared to a 20% saturated fat (sat) diet or a control diet (5% unsaturated fat) increased the number of acidophilic foci, as well as the thymidine labeling index (LI) of their nuclei. While the basophilic foci are carcinogen-induced and at 2.5 mo post-initiation have a similarly high growth rate to the acidophilic foci, this rate is not sustained as indicated by examination of both the LI and mean size of foci at 4 mo post-initiation.

Animals↗
PubMed2003

Characterisation of the progression of azaserine-induced rat pancreatic adenocarcinoma by proliferative cell nuclear antigen, basement membrane laminin and trypsinogen immunohistochemistry.

The progression of azaserine-induced rat pancreatic adenocarcinoma (AC) was characterised using quantitative and semiquantitative immunohistochemistry for proliferating cell nuclear antigen (PCNA), basement membrane laminin (BML) and trypsinogen (TG). Samples were taken 5-20 months after initiation. High PCNA-labelling indices (PCNA LIs) were measured 5 months after the induction of atypical acinar cell nodules (AACNs), which decreased later and stagnated until a further decline in the month 10 adenomas. Then a second premalignant proliferative wave was observed (month 13) within the adenoma stage. Later, in month 20 differentiated ACs PCNA LIs fell to the host tissue level but were found highest in the month 20 anaplastic ACs indicating a switch to malignant proliferation. Month 20 invasive ACs showed a number of separate proliferative foci. In early AACNs, BML decreased and remained low till the local maximum in the month 13 adenoma. Invasive ACs did not express BML. Month 5 AACN and differentiated AC were TG deficient but anaplastic AC regained its TG expression. However invasive AC was again TG negative. These results are discussed in combination with our previous data on progressional changes of autophagic capacity and microvessel densities.

Adenocarcinoma↗
PubMed2002

Cellular autophagic capacity changes during azaserine-induced tumour progression in the rat pancreas. Up-regulation in all premalignant stages and down-regulation with loss of cycloheximide sensitivity of segregation along with malignant transformation.

The knowledge of alterations in regulation of autophagy during tumorigenesis may also help our understanding of its normal control. We established an experimental system and reported recently that autophagic capacity, measured as the cell's capability of increasing segregation (formation of autophagosomes) and subsequent degradation of cytoplasmic quanta were highly increased in premalignant nodule cells 6 months after initiation by azaserine in the rat pancreas in vivo. In the present study, we followed changes of these autophagic functions throughout the tumour progression. We carried out electron-microscopic morphometrical analysis of the expansion of autophagic vacuole compartment and subcompartments induced by vinblastine (an in vivo segregation enhancer), as well as their regression upon segregation-inhibitor cycloheximide post-treatment. Premalignant tumour samples were taken at month 5, month 8 (nodules), month 10 and month 15 (adenomas) after initiation. In all these stages, a highly increased and varying autophagic capacity was found compared with the host tissue. The basal (non-stimulated) autophagic compartment was measurable only at month 5 and month 15, and its regression upon cycloheximide was consistent with increased basal autophagic activity. Compared with the host tissue, autophagic capacity profoundly decreased in the differentiated and anaplastic adenocarcinomas at month 20, when, surprisingly, cycloheximide was unable to inhibit segregation. Our conclusion is that down-regulation of the cycloheximide sensitive segregation and a partly compensatory up-regulation of an alternative pathway of segregation might occur along with malignant transformation.

Adenocarcinoma↗