azaserine and Disease-Models--Animal

We investigated short (6 months) and long (12 months) term inhibitory effects of low (200 ppm) and high (400 ppm) dosages of acetylsalicylic acid (aspirin) on exocrine pancreatic carcinogenesis. It is known that exocrine pancreatic carcinogenesis can be detected by the presence of atypical acinar cell foci (AACF) in pancreas. We investigated possible inhibitory effects of acetylsalicylic acid in an azaserine-treated rat model. AACF were produced in rats by injection with azaserine according to previous studies. Our findings showed that the number, volume and diameter of pancreatic AACF were reduced after acetylsalicylic acid application. These observations suggest that acetylsalicylic acid may exert a protective effect against neoplastic development of pancreatic acinar cells in azaserine injected rats. Our findings corroborate reports in the literature concerning the effects of aspirin in reducing neoplastic development.

Topics: Acinar Cells; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Aspirin; Azaserine; Carcinogens; Colorectal Neoplasms; Disease Models, Animal; Humans; Male; Pancreas, Exocrine; Pancreatic Neoplasms; Rats; Rats, Wistar

Topics: 4-Hydroxyaminoquinoline-1-oxide; Aging; Animals; Azaserine; Cocarcinogenesis; Diet; Disease Models, Animal; Ethionine; Gonadal Steroid Hormones; Nitrosamines; Pancreatic Neoplasms; Precancerous Conditions; Vitamins

In order to understand the evolution, histogenesis, and biological behaviour of exocrine pancreatic carcinoma, some reproducible experimental models have been developed in certain rodent species. To date, more than 16 chemicals, many of them structurally unrelated, have been shown to induce pancreatic tumors. Although some of these chemicals appear species specific in their effect on the pancreas, others have been shown to be capable of inducing pancreatic tumors in more than one species. In hamsters, the administration of diisopropylnitrosamine or its oxidized metabolites leads to the development of ductal adenocarcinomas that histologically resemble human pancreatic carcinomas. The histogenesis of the ductal type of adenocarcinoma in hamsters is complex, and appears to involve both the duct cells and dedifferentiated acinar cells. All pancreatic tumors in rats develop from acinar cells showing variable degrees of differentiation, regardless of the type of carcinogen used. The type of pancreatic lesions that develop in mice are also of acinar cell origin. In guinea pigs the tumors are adenocarcinomas of the ductal type and are shown to be derived from dedifferentiated acinar cells that have undergone duct-like transformation. Irrespective of the type of tumor that develops in these experimental animals, all of these models can be successfully used to evaluate the various modifying (risk) factors and biological behaviour of these neoplasms.

Topics: 4-Hydroxyaminoquinoline-1-oxide; 9,10-Dimethyl-1,2-benzanthracene; Animals; Azaserine; Carcinogens; Corn Oil; Cricetinae; Disease Models, Animal; Guinea Pigs; Hypolipidemic Agents; Mice; Nitrosamines; Nitrosourea Compounds; Pancreatic Neoplasms; Rats

Topics: Animals; Azaserine; Carcinogens; Carcinoma; Cell Transformation, Neoplastic; Cells, Cultured; Diet; Disease Models, Animal; Female; Male; Microscopy, Electron; Pancreatic Neoplasms; Sex Factors; Time Factors

Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Asparaginase; Azaserine; Cell Division; Clinical Trials as Topic; Cyclophosphamide; Cytarabine; Disease Models, Animal; Drug Combinations; Humans; Kinetics; Leukemia L1210; Leukemia, Experimental; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Mercaptopurine; Methotrexate; Neoplasms; Prednisone; Remission, Spontaneous; RNA, Neoplasm; Vincristine

Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Asparaginase; Azaserine; Cell Division; Clinical Trials as Topic; Cyclophosphamide; Cytarabine; Disease Models, Animal; Drug Combinations; Humans; Kinetics; Leukemia L1210; Leukemia, Experimental; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Mercaptopurine; Methotrexate; Neoplasms; Prednisone; Remission, Spontaneous; RNA, Neoplasm; Vincristine

High-fat diet has been considered a risk factor for the development of pancreatic cancer. It is also shown to significantly impact composition and dysbiosis of gut microbiota in both humans and animals. However, there is little information on the effect of high-fat diet on the development of pancreatic cancer or upon the gut microbiota of patients with pancreatic cancer in humans or animal models.. In this study, the effect of high-fat diet on cancer pathology and the gut microbiota was investigated by a carcinogen-induced pancreatic cancer mouse model.. Compared with carcinogen alone, mice with high-fat diet and carcinogen showed more obvious pathological changes in pancreatic tissue; increased levels of proinflammatory cytokine tumor necrosis factor-α, interleukin-6, interleukin-10, and carbohydrate antigen 242; and increased expression of cancer-associated biomarkers mucin-4 and claudin-4 in pancreatic tissue. Moreover, there is a significant change in the gut microbiota between the carcinogen group and the carcinogen with high-fat diet group. We identified that Johnsonella ignava especially existed in the carcinogen with high-fat diet group, which may contribute to pancreatic cancer development.. Our results revealed that high-fat diet changed the composition of the gut microbiota and was involved in carcinogen-induced pancreatic cancer progression.

Topics: Animals; Azaserine; Bacteria; Carcinogens; Claudin-4; Cytokines; Diet, High-Fat; Disease Models, Animal; Drug Synergism; Feces; Female; Gastrointestinal Microbiome; Gastrointestinal Tract; Humans; Mice, Inbred C57BL; Mucin-4; Pancreatic Neoplasms; RNA, Ribosomal, 16S; Sequence Analysis, DNA

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

Artemisinin and its analogues (ARTs) are currently the most effective anti-malarial drugs, but the precise mechanism of action is still highly controversial. Effects of ARTs on

Topics: Animals; Antimalarials; Artemisinins; Azaserine; Disease Models, Animal; Dose-Response Relationship, Drug; Gene Expression; Glutamate Synthase (NADH); Glutamic Acid; Humans; Malaria; Mice, Inbred C57BL; Phytotherapy; Plasmodium falciparum

Through the hexosamine biosynthetic pathway (HBP) proteins are modified by O-linked-β-N-acetylglucosamine (O-GlcNAc), which acts as a stress sensor. Augmentation of O-GlcNAc confers cardioprotection against ischemia- reperfusion injury, but its role in ischemic preconditioning (IPC) is unknown. Azaserine and alloxan are unspecific blockers of the HBP and have been used to block the cardioprotective effects of O-GlcNAc. We hypothesized that IPC reduces infarct size and increases O-GlcNAc levels in hearts subjected to ischemia-reperfusion injury, and that these effects could be blocked by azaserine and alloxan.. Isolated rat hearts subjected to 40 min global ischemia and 120 min reperfusion were randomized to control, IPC, IPC + azaserine or alloxan, or control + azaserine or alloxan. The effects on infarct size, hemodynamic recovery, myocardial O-GlcNAc levels, and HBP enzyme activities were determined.. IPC reduced infarct size, increased O-GlcNAc levels, O-GlcNAc-transferase levels, and O-GlcNAc-transferase activity. Azaserine and alloxan did not block the effect of IPC on O-GlcNAc levels and O-GlcNAc-transferase activity.. IPC increased O-GlcNAc levels though increased O-GlcNAc-transferase expression and activity. Azaserine and alloxan failed to block these effects presumably due to poor specificity and sensitivity of the blockers, and IPC-mediated cardioprotection may therefore still be dependent on O-GlcNAc.

Topics: Acetylglucosamine; Alloxan; Animals; Azaserine; Disease Models, Animal; Glycosylation; Hemodynamics; Ischemic Preconditioning, Myocardial; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; N-Acetylglucosaminyltransferases; Rats; Rats, Wistar; Recovery of Function; Time Factors; Up-Regulation

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 majority of human pancreatic adenocarcinomas display a ductal phenotype; experimental studies indicate that tumors with this phenotype can arise from both acinar and ductal cells. In normal pancreas acinar cells, the pancreas transcription factor 1 transcriptional complex is required for gene expression. Pancreas transcription factor 1 is a heterooligomer of pancreas-specific (p48) and ubiquitous (p75/E2A and p64/HEB) basic helix-loop-helix proteins. We have examined the role of p48 in the phenotype of azaserine-induced rat DSL6 tumors and cancers of the human exocrine pancreas. Serially transplanted acinar DSL6 tumors express p48 whereas DSL6-derived cell lines, and the tumors induced by them, display a ductal phenotype and lack p48. In human pancreas cancer cell lines and tissues, p48 is present in acinar tumors but not in ductal tumors. Transfection of ductal pancreas cancers with p48 cDNA did not activate the expression of amylase nor a reporter gene under the control of the rat elastase promoter. In some cell lines, p48 was detected in the nucleus whereas in others it was cytoplasmic, as in one human acinar tumor. Together with prior work, our findings indicate that p48 is associated with the acinar phenotype of exocrine pancreas cancers and it is necessary, but not sufficient, for the expression of the acinar phenotype.

Topics: Adenocarcinoma; Amino Acid Sequence; Animals; Antimetabolites, Antineoplastic; Azaserine; Cell Differentiation; Disease Models, Animal; Helix-Loop-Helix Motifs; Humans; Molecular Sequence Data; Pancreas; Pancreatic Neoplasms; Phenotype; Rats; RNA, Messenger; Transcription Factors; Tumor Cells, Cultured

Studies were undertaken to evaluate the effects of exercise on the development of pancreatic cancer. Exercise is one life-style factor that has received little attention with regard to its role in the etiology of cancer. Male Lewis and female F344 rats were initiated with azaserine during the suckling period and weaned to the experimental protocols. Food and water were available ad libitum. A purified diet of 20% unsaturated fat was fed to both the sedentary and exercise groups. Rats of the exercise group had free access to voluntary exercise wheels. At approximately 2 and 4 months postinitiation, pancreases were evaluated for the number and size of azaserine-induced putative preneoplastic foci by quantitative stereology. Voluntary exercise activity peaked at approximately 2 months postinitiation with a gradual decline in activity there-after. Male Lewis rats averaged 0.95 +/- 0.13 km/day (SE) and female F344 rats averaged 2.73 +/- 0.26 km/day of voluntary wheel running. Compared with the sedentary groups, male Lewis and female F344 rats with access to the running wheels had significantly smaller foci at 4 months postinitiation. Azaserine-induced foci were evaluated in the male Lewis rats at both 2 and 4 months postinitiation. At 4 months postinitiation, the size and growth rate (as measured by [3H]thymidine autoradiography) of foci were less in the rats with access to the exercise wheels. No differences were observed at 2 months postinitiation. Access to voluntary exercise reduced the growth rate of azaserine-induced pancreatic foci. The effect occurred late in the postinitiation phase and was not directly related to the extent of running activity early in the postinitiation phase.

Topics: Animals; Azaserine; Disease Models, Animal; Female; Male; Pancreatic Neoplasms; Physical Conditioning, Animal; Rats; Rats, Inbred F344; Rats, Inbred Lew; Time Factors

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.

Topics: Animals; Azaserine; Benzyl Compounds; Corn Oil; Disease Models, Animal; Male; Pancreatic Neoplasms; Plant Oils; Rats; Rats, Inbred F344; Rats, Inbred Lew; Species Specificity

Foods containing soybean products have been shown to modify the biochemical and physiological status of the pancreas of several species of experimental animals. Recently, these products have been implicated as a factor in the causation of pancreatic neoplasms. Extensive experimental studies into the possible mechanisms need to be undertaken. Experimental details of a rat/azaserine model for the study of pancreatic carcinogenesis are reviewed. Emphasis is given to the quantitative components of this model and the adaptation of this model to the two-stage (initiation-promotion) concept of carcinogenesis. Particular attention is devoted to considerations of the experimental diets. Application of these concepts to the study of the postinitiational effects of raw and heated soybean protein isolate with and without the addition of high levels of unsaturated fat were undertaken. The results indicate that raw soybean isolate enhanced the growth of azaserine-induced pancreatic foci; whereas, a high level of unsaturated fat had a minimal effect. The effects of the soybean isolate were abolished by heat treatments, but the effects of the unsaturated fat would not be expected to be abolished by similar treatment with heat.

Topics: Animals; Azaserine; Carcinogens; Dietary Fats; Dietary Proteins; Disease Models, Animal; Nutritional Physiological Phenomena; Pancreatic Neoplasms; Plant Proteins, Dietary; Rats; Soybean Proteins

The effects of melphalan were studied in rats fed raw soya flour and injected with azaserine in order to determine the suitability of this experimental model for testing drugs potentially useful for the treatment of pancreatic cancer. While melphalan did not prevent or delay the development of pancreatic cancer in these rats, the drug significantly lessened the number and size of the premalignant proliferative lesions in the pancreas. It seems that the model is useful both for testing potentially useful therapeutic agents and for analysing some of the processes involved in the development of pancreatic cancer.

Topics: Animals; Azaserine; Body Weight; Disease Models, Animal; Male; Melphalan; Nucleic Acids; Organ Size; Pancreas; Pancreatic Neoplasms; Proteins; Rats; Rats, Inbred Strains

Topics: Animals; Azaserine; Carcinoma; Disease Models, Animal; Female; Humans; Male; Neoplasms, Experimental; Pancreatic Neoplasms; Rats; Rats, Inbred Lew

Subtoxic doses of azaserine induced atypical acinar cell nodules (AACN) in the pancreases of outbred Wistar rats, inbred W/LEW and F344 rats, and outbred Charles River CD-1 albino mice 4-6 months after initiation of treatment in the growing animal. These AACN apparently represented preneoplastic lesions, some of which have the potential to develop into adenomas or adenocarcinomas. Wistar and W/LEW rats were highly responsive to nodule induction; AACN developed in about 90% of the outbred Wistar rats and in all of the W/LEW rats tested. F344 rats were less susceptible and developed about 10% as many AACN as the Wistar rats. Female rats developed approximately half as many AACN as males. The mouse was intermediate in response between the F344 and the two Wistar rats. Syrian golden hamsters and strain 13 guinea pigs were relatively unresponsive. These studies of azaserine-induced AACN provided a basis for selection of carcinogenic azaserine regimens and suggested that the young male W/LEW rat was the most sensitive of the animals studied.

Topics: Animals; Azaserine; Cricetinae; Disease Models, Animal; Female; Guinea Pigs; Male; Mesocricetus; Mice; Neoplasms, Experimental; Pancreatic Neoplasms; Precancerous Conditions; Rats; Rats, Inbred F344; Rats, Inbred Lew; Sex Factors; Species Specificity

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: Acetates; Adenine; Adenine Nucleotides; Adenosine Triphosphate; Animals; Azaserine; Biotin; Carbon Isotopes; Cholesterol; Disease Models, Animal; Ethionine; Fatty Liver; Lipid Metabolism; Lipids; Nucleotides; Orotic Acid; Phospholipids; Pyrazoles; Pyrimidines; Rats; Triglycerides