azaserine and Adenoma

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

Topics: Adenoma; Animals; Antimetabolites, Antineoplastic; Azaserine; Bromodeoxyuridine; Carcinogens; Carcinoma, Acinar Cell; Cell Proliferation; Coloring Agents; Homeodomain Proteins; Homozygote; Immunohistochemistry; Inflammation; Lymphocytes; Mice; Mice, Transgenic; Pancreatic Neoplasms; Phenotype; Precancerous Conditions; Receptor, Cholecystokinin B; Receptors, G-Protein-Coupled; Risk; Time Factors; Trans-Activators; Transgenes

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.

Topics: Adenocarcinoma; Adenoma; Animals; Azaserine; Biomarkers, Tumor; Carcinogenicity Tests; Cell Count; Disease Progression; Fluorescent Antibody Technique, Indirect; Laminin; Male; Pancreatic Neoplasms; Proliferating Cell Nuclear Antigen; Rats; Rats, Wistar; Trypsinogen

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.

Topics: Adenocarcinoma; Adenoma; Animals; Autophagy; Azaserine; Cell Cycle; Cell Division; Disease Progression; Male; Pancreas; Pancreatic Neoplasms; Precancerous Conditions; Rats; Rats, Wistar; Time Factors; Vinblastine

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.. 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.. 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%).. 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.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Adenoma; Animals; Anti-Ulcer Agents; Azaserine; Carcinoma in Situ; Carcinoma, Acinar Cell; Disease Models, Animal; Gastrins; Lansoprazole; Male; Omeprazole; Organ Size; Pancreas; Pancreatic Neoplasms; Precancerous Conditions; Rats; Rats, Inbred Lew

The ubiquitin (Ub)-proteasome proteolytic system is highly selective, and the specific proteins involved in cell division, growth, activation, signaling and transcription are degraded at different rate depending on the physio-pathological state of the cell. Ubiquitination serves first of all as a signal for protein degradation of short-lived and abnormal proteins under several stressful conditions. The immunocytochemical localization of Ub in some malignant tumours has recently been presented and differences in Ub expression has been observed during malignant transformation. Change in the level of Ub and Ub-conjugated proteins might reflect a higher metabolic-catabolic ratio in neoplastic cells. Most studies have been focused on the malignant stage of tumour progression, and only a few papers have dealt with the change in Ub and Ub-protein conjugates level during the whole progression. To address this problem, we applied an azaserine-induced pancreatic carcinogenesis model, in which premalignant and malignant stages were investigated throughout the progression. The level of Ub immunoreactivity was measured in nucleus and cytoplasm by electron microscopic immunocytochemical and morphometrical methods. We found a significant increase of Ub level in the nucleus and the cytoplasmic area in premalignant atypical acinar cell nodule (AACN) cells and in malignant adenocarcinoma in situ (CIS) cells at month 20 after initiation.

Topics: Adenocarcinoma; Adenoma; Animals; Azaserine; Carcinoma in Situ; Cell Nucleus; Cysteine Endopeptidases; Cytoplasm; Immunohistochemistry; Male; Multienzyme Complexes; Neoplasm Proteins; Pancreatic Neoplasms; Precancerous Conditions; Proteasome Endopeptidase Complex; Rats; Rats, Wistar; Ubiquitin

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.

Topics: Adenocarcinoma; Adenoma; Animals; Autophagy; Azaserine; Carcinoma in Situ; Cycloheximide; Male; Pancreatic Neoplasms; Rats; Rats, Wistar; Time Factors; Vinblastine

This study investigates digestive and lysosomal enzyme secretion of azaserine-induced pancreatic acinar carcinomas in response to cholecystokinin in rats. After 15-20 months of treatment, 95% of the animals developed pancreatic acinar carcinomas encompassing more than 90% of the tissue. In anesthetized rats basal trypsin output was significantly elevated in the tumor group despite diminished fluid secretion. There was a linear correlation between tumor size and basal amylase and trypsin secretion. Intravenous infusion of cholecystokinin (25 IDU.kg-1.h-1) induced a significantly lower secretion of fluid per gram pancreas, as well as decreased amylase and trypsin output, in the tumor group compared with the control group. Plasma amylase and lipase levels were significantly elevated in the tumor group under both basal and stimulated conditions. The output of the lysosomal enzymes beta-D-glucuronidase and alpha-D-glucosidase was significantly increased in the tumor group under background secretin infusion. Additional cholecystokinin infusion caused a sharp increase in glucuronidase output in this group with only minimal increase in controls. Glucosidase output increased similarly in both groups. Amylase, lipase, and trypsin tumor tissue concentrations were markedly reduced by 85%, 90%, and 87%, respectively. It was concluded that the decreased secretory response of digestive enzymes may result from decreased synthesis, lowered storage capabilities, and/or a decreased/increased responsiveness to cholecystokinin. Increased glucuronidase secretion may reflect an augmented cell turnover of malignant tissue.

Topics: Adenoma; alpha-Glucosidases; Amylases; Animals; Azaserine; Carcinoma; Cholecystokinin; Food, Formulated; Glucuronidase; Lipase; Lysosomes; Male; Pancreatic Neoplasms; Rats; Rats, Inbred Lew; Secretin; Trypsin

Benzyl acetate was found to induce liver tumours and gastric squamous neoplasms in mice in a chronic bioassay conducted through the National Toxicology Program. An increased incidence of acinar cell adenomas of the pancreas of F344 rats was noted in the bioassay, but the significance of these lesions was confounded because the benzyl acetate was given by gavage in corn oil. The use of corn oil as a vehicle has been shown to enhance the growth of such lesions in the rat pancreas. The current studies were undertaken to evaluate benzyl acetate alone as an initiator and promoter of carcinogenesis in the pancreas. Alkaline elution analysis of acinar cell DNA showed no evidence of damage 1 hr after administration of benzyl acetate. Significant stimulation of growth of azaserine-induced foci was observed in a 6-month study, and a low but significant incidence of carcinoma in situ was observed in rats fed benzyl acetate in the diet for 2 yr. These experiments suggest that benzyl acetate is a weak promoter of the growth of carcinogen-induced and spontaneous pre-neoplastic foci in the pancreas.

Topics: Adenoma; Animals; Azaserine; Benzyl Compounds; Chi-Square Distribution; Corn Oil; DNA; Kidney; Kidney Failure, Chronic; Male; Pancreas; Pancreatic Neoplasms; Rats; Rats, Inbred F344

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.

Topics: Adenoma; Animals; Azaserine; Blotting, Northern; Carcinoma; Cell Cycle; Esters; Gabexate; Gene Expression; Guanidines; Mitotic Index; Pancreas; Pancreatic Neoplasms; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-myc; Proto-Oncogene Proteins c-raf; Proto-Oncogene Proteins p21(ras); Proto-Oncogenes; Rats; Rats, Inbred Lew; Regeneration; RNA, Neoplasm

We have previously shown that rats fed raw soya flour (RSF) for more than four months develop hyperplastic foci of pancreatic acinar cells, which undergo malignant change if feeding RSF is continued throughout the life of the animals. The tendency to undergo malignant change is augmented by the additional use of a genotoxic carcinogen such as azaserine. The present study has sought to examine the reversibility of the focal neoplastic change in the pancreas. Rats fed RSF for 24 weeks and then given a diet not containing soya flour (NSC) had a normal pancreas when killed after 60 weeks of study. When RSF was fed for only 36 weeks, however, some of the rats developed pancreatic cancer even though the diet had been switched to NSC. Similarly, while azaserine in the dose used in the present study does not produce pancreatic cancer in our strain of Wistar rats, coincident administration of RSF for 12 weeks (but not for six weeks) resulted in progression to pancreatic adenoma. Although change from RSF to NSC after 30 weeks resulted in rapid reduction in pancreatic weight and content of RNA, neoplastic foci persisted and became frankly malignant. We conclude that phenotypic reversion to normal of the RSF diet- and azaserine-treated rat pancreas is only possible if RSF alone is fed continuously for not more than about 24 weeks or six weeks if the rats have been exposed to a pancreatic initiating carcinogen.

Topics: Adenoma; Animals; Azaserine; Diet; Flour; Glycine max; Male; Organ Size; Pancreas; Pancreatic Neoplasms; Rats; Rats, Inbred Strains

Continuous administration of a diet consisting of raw soya flour produces pancreatic cancer in rats and sensitises the rat pancreas to the action of genotoxic carcinogens. We have therefore studied the effects of continuous feeding of diets containing lesser amounts of raw soya flour (5%, 25% and 50%) and feeding raw soya flour intermittently (2 days each week). The study has shown that a diet containing as little as 5% raw soya flour stimulates focal proliferation of the pancreatic acinar cells and sensitises to the action of azaserine. Similarly, intermittent feeding of raw soya flour induced focal proliferation of the acinar pancreas and, when 100% raw soya flour diet was fed for 2 days each week, resulted in the development of pancreatic cancer in some of the rats. We conclude that raw soya flour must be excluded from the diets of rats used in toxicological and carcinogenicity studies.

Topics: Adenoma; Animals; Azaserine; Diet; Flour; Glycine max; Male; Pancreatic Neoplasms; Rats; Rats, Inbred Strains

Pancreatic acinar cell hyperplastic lesions and neoplasms in rats and humans were studied for their nuclear DNA content by microspectrophotometry. Atypical hyperplastic acinar cell lesions induced in rats by azaserine displayed a wide range of DNA contents, 1.5-8C for those composed of acidophilic-type cells and 1.5-9C for those of basophilic-type cells compared with the euploid pattern of 1.5-5C in acinar cells in normal pancreas. The modal DNA values of rat acinar cell adenomas were distributed over an even wider range of 2-11C. In human pancreas, hyperplastic acinar cell lesions composed of eosinophilic-type cells displayed a slightly wider range of DNA content (1.5-8C) than that in surrounding normal acinar cells (1.5-5C). The DNA histograms of basophilic acinar cell lesions were of an aneuploid pattern (2-12C) similar to that of an acinar cell carcinoma (2-15C). These findings demonstrate that acinar cell hyperplastic lesions in rats and humans have an altered genetic complement and suggest that they probably are precursor lesions for acinar cell neoplasms.

Topics: Adenoma; Animals; Azaserine; DNA; DNA, Neoplasm; Humans; Hyperplasia; Male; Pancreas; Pancreatic Neoplasms; Ploidies; Precancerous Conditions; Rats; Rats, Inbred ACI; Spectrophotometry

Rat acinar cells in the azaserine-induced hyperplastic nodules or adenomas in the siderotic pancreas produced by repeated iron injections were found to be resistant to iron accumulation. These iron-resistant acinar cell lesions coincided rather well with the lesions having markedly decreased activity of gamma-glutamyl transpeptidase. These properties of the acinar cells could be useful for the identification of early lesions in pancreatic carcinogenesis.

Topics: Adenoma; Animals; Azaserine; Ferric Compounds; gamma-Glutamyltransferase; Histocytochemistry; Hyperplasia; Iron; Male; Nitrilotriacetic Acid; Pancreas; Pancreatic Neoplasms; Precancerous Conditions; Rats; Rats, Inbred ACI

Because diet has been shown to modulate the incidence of a wide variety of chemically induced cancers in experimental animals, various dietary constituents were evaluated for their ability to modulate the incidence of pancreatic exocrine cancer in male Wistar/Lewis rats given injections of the pancreatic carcinogen, azaserine. Ten different diet regimens were fed. The incidence of pancreatic cancers in rats fed a control diet was compared to that in groups fed diets formulated to evaluate the effect of caloric restriction, high protein, low protein, low fat, cyclopropenoid fatty acids, lipotrope deficiency, high unsaturated fat, and high saturated fat. The incidence of pancreatic adenomas and carcinomas was evaluated by light microscopy. The number of pancreatic neoplasms was reduced in carcinogen-treated groups which were underfed the control diet or fed the diet high in protein. Pancreatic carcinogenesis appeared to be enhanced in two groups which were fed diets containing 20% corn oil, i.e., high in unsaturated fat; whereas, the group fed a diet high in saturated fat had the same incidence of neoplasms as did the group fed the control diet. The pancreatic neoplasms from groups in which the incidence was enhanced by diet showed less evidence of acinar cell differentiation and displayed diverse histological types. In the lipotrope-deficient group, there was a significantly increased incidence of hepatocellular carcinoma; however, a low incidence of liver tumors was encountered in all other dietary groups.

Topics: Adenocarcinoma; Adenoma; Animals; Azaserine; Cocarcinogenesis; Diet; Dietary Fats; Energy Intake; Fatty Acids, Unsaturated; Male; Neoplasms, Experimental; Pancreatic Neoplasms; Rats

Pancreatic tumorigenesis of azaserine by a single intraperitoneal (i.p.) injection after partial pancreatectomy in male Wistar rats was studied. Pancreatic lesions developed in all rats 52 weeks after the administration of azaserine at doses of 50 mg (Group 1) or 100 mg/kg body wt (Group 2). Histologically, there were hyperplastic nodules in 4 of 12 rats and 4 of 7 rats, in Groups 1 and 2, respectively, adenomas 100% in both groups, and adenocarcinomas 2 of 7 rats of Group 2. It appears that pancreatic regeneration induced by partial pancreatectomy enhances the azaserine tumorigenesis.

Topics: 4-Hydroxyaminoquinoline-1-oxide; Adenocarcinoma; Adenoma; Animals; Azaserine; Carcinogens; Hyperplasia; Injections, Intraperitoneal; Male; Pancreas; Pancreatectomy; Pancreatic Neoplasms; Rats; Regeneration; Time Factors

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.

Topics: Adenocarcinoma; Adenoma; Animals; Azaserine; Carcinogens; DNA; Liver; Liver Neoplasms; Lung Neoplasms; Mice; Neoplasms, Experimental; Pancreas; Pancreatic Neoplasms; Rats; Rats, Inbred Strains

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.

Topics: Adenoma; Animals; Azaserine; Neoplasms, Experimental; Pancreatic Neoplasms; Precancerous Conditions; Rodentia

Topics: Adenocarcinoma; Adenoma; Animals; Azaserine; Ethionine; Male; Pancreas; Pancreatectomy; Pancreatic Neoplasms; Rats; Regeneration

Development of a model of carcinoma of the pancreas in rats was approached by attempting to identify chemicals that (a) behave as mutagens and (b) localize in the pancreas following systemic administration; and then to study the effects of long-term administration. Azaserine was selected because it behaves as a direct-acting mutagen in two bacterial test systems and because tissue distribution studies showed concentration especially in kidney and pancreas. Groups of rats have been given i.p. injections once or twice weekly for 6 months, and rats have been autopsied after 6 to 18 months. During the first year pancreases developed (a) nodules of atypical exocrine cells which seem to represent hyperplastic foci and (b) encapsulated adenomas. After 1 year most pancreases from treated rats are diffusely abnormal and contain many hyperplastic nodules and adenomas, while more than one-quarter have had pancreatic adenocarcimona. Metastases have been observed in lymph nodes, liver, and lung. No carcinomas or adenomas have been observed in control rats. No other organ shows as high an incidence of involvement as pancreas, but renal neoplasms were frequent. Studies with another chemical O-(N-methyl-N-nitroso-beta-alanyl)-L-serine, are at an earlier stage. The tissue distribution of radioactivity following injection of a 14C-labeled sample is similar to that of azaserine; however, this compound is not a direct-acting bacterial mutagen. Rats treated for 6 months twice weekly i.p. have a higher incidence of nodules of atypical acinar cells than did controls, although the number of nodules per rat is few. No adenomas or carcinomas have been found during 13 months of the study. We conclude that azaserine is a carcinogen in rats and causes major abnormalities of growth and differentiation of the exocrine pancreas, including adenocarcinoma in some rats. O-(N-Methyl-N-mitroso-beta-alanyl)-L-serine had less effect than azaserine on pancreatic growth and differentiation.

Topics: Adenocarcinoma; Adenoma; Animals; Azaserine; Dipeptides; Disease Models, Animal; Hyperplasia; Injections, Intraperitoneal; Kidney Neoplasms; Mutagens; Neoplasm Metastasis; Neoplasms, Experimental; Nitrosamines; Pancreas; Pancreatic Neoplasms; Rats; Salmonella typhimurium; Serine

Topics: Adenoma; Animals; Azaserine; Carcinogens; Hyperplasia; Injections, Intraperitoneal; Neoplasms, Experimental; Pancreas; Pancreatic Neoplasms; Rats