azaserine and Adenocarcinoma

Topics: 4-Hydroxyaminoquinoline-1-oxide; Adenocarcinoma; Aminoquinolines; Animals; Azaserine; Carcinoma; Cricetinae; Neoplasms, Experimental; Nitrosamines; Pancreatic Neoplasms

Topics: Adenocarcinoma; Amino Sugars; Animals; Antibiotics, Antineoplastic; Azaserine; Benzazepines; Bleomycin; Carcinoma, Ehrlich Tumor; Carcinoma, Hepatocellular; Cricetinae; Dactinomycin; Daunorubicin; DNA; Dogs; Glycosides; Haplorhini; Humans; Leukemia L1210; Liver Neoplasms; Lymphoma; Mice; Mitomycins; Naphthacenes; Plicamycin; Pyrroles; Rats; RNA; Sarcoma 180; Streptonigrin; Streptozocin

We investigated whether the acrylamide formed during cooking carbohydrate-rich foods at high temperatures causes neoplastic changes in rat pancreas. Azaserine, which is an amino acid derivative that has the ability to initiate neoplastic changes in rat pancreas, was injected into 14-day-old male rats once a week for three weeks. Acrylamide was given to both azaserine-injected and non-injected rats at doses of 5 and 10 mg/kg/day in drinking water for 16 weeks after which tissue slides were prepared from the pancreata. Pancreas weights and body weights of rats treated with azaserine and acrylamide together increased significantly compared to the other groups. Moreover, the size, average diameter and volume of atypical acinar cell foci that developed in the pancreata of rats treated with azaserine and acrylamide together increased significantly compared to rats treated with either azaserine or acrylamide alone and control groups. Atypical acinar cell adenoma or adenocarcinoma was not observed in the pancreata of rats in any group.

Topics: Acrylamide; Adenocarcinoma; Animals; Azaserine; Body Weight; Carcinogenicity Tests; Male; Organ Size; Pancreas, Exocrine; Pancreatic Neoplasms; Rats; Rats, Wistar

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

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

Although angiogenesis is considered to be indispensable for continuous tumour growth, only very few studies have been published performing microvessel quantification during tumour progression. We measured the tumour vascularity in different stages of rat pancreatic carcinogenesis induced by azaserine and promoted by raw soya flour-containing pancreatotrophic diet. Besides the tumour samples taken at 6 (atypical acinar cell nodules), 15 (adenomas) and 20 (localised adenocarcinomas) months after carcinogen initiation, we also investigated 3 control groups: tumour-bearing host tissue of azaserine-treated rats and normal tissue of untreated rats kept on standard or pancreatotrophic diet. In contrast with the usual microvessel counting on hot spots, we determined microvascular surface density (Sv) and volume density (Vv) by electron microscopic morphometry. There was no significant difference in these respect between the control groups. At month 6 after the azaserine induction Sv and Vv showed slight, nonsignificant decrease as compared to the host control. Both values remained unchanged until the 15th month and increased significantly by the 20th month. These results may indicate comparable growth rate of tumour and new microvessels in the premalignant stages of carcinogenesis while a more intense angiogenesis than tumour growth afterwards.

Topics: Adenocarcinoma; Animals; Azaserine; Male; Microcirculation; Neovascularization, Pathologic; Pancreatic Neoplasms; Rats; Rats, Wistar; Time Factors

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

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.

Topics: Adenocarcinoma; Animals; Autophagy; Azaserine; Male; Pancreatic Neoplasms; Precancerous Conditions; Rats; Rats, Wistar

The purpose of this study was to describe the inoculation technique and patterns of growth as well as to characterize typical histological features of Lewis rat subcutaneous and intrapancreatic tumors, induced by inoculation of cultured pancreatic cancer cells (DSL-6A/C1). Subcutaneous inoculation of cultured cells produced a solid tumor that was a locally invasive, well- to moderately differentiated ductal adenocarcinoma. Tumor take was 100% in animals 5 weeks of age; tumor growth was consistent and predictable and a tumor volume of approximately 1 cm3 was reached in 8 weeks. After intrapancreatic transplantation the tumors showed the same histological features as subcutaneous tumors. During inoculation carcinoma cells easily spread around the injected area, and after 2 weeks both pancreatic tumors and superficially infiltrating carcinomas were found in the liver and spleen and around the peritoneum. Tumor take was 60% and tumor growth was somewhat indefinite and unpredictable in the pancreas. However, by reducing the injected carcinoma cell volume and solving the technical problems, 100% tumor take was achieved. The tumor volume reached 2 mm3 during 2 weeks and larger tumors showed a tendency for invasion. According to our results, subcutaneous as well as intrapancreatic tumor induction with cultured cells offers a model for pancreatic cancer studies.

Topics: Adenocarcinoma; Animals; Azaserine; Lymphocytes, Tumor-Infiltrating; Male; Neoplasm Invasiveness; Neoplasm Transplantation; Pancreatic Neoplasms; Plasma Cells; Rats; Rats, Inbred Lew; Skin; Tumor Cells, Cultured

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.

Topics: Adenocarcinoma; Animals; Azaserine; Cocarcinogenesis; Coffee; Cricetinae; Dietary Fats; Male; Mesocricetus; Nitrosamines; Pancreatic Neoplasms; Rats; Rats, Inbred Strains

The intratumoral content of 5-phosphoribosyl 1-pyrophosphate (PRPP) and the activity of the enzymes anabolizing and catabolizing the sugar phosphate were determined following i.p. administration of an LD10 dose of an L-glutamine antagonist or saline to tumor-bearing animals. Elevation of PRPP pool size following administration of L-[alpha S,5S]-alpha-amino-3-chloro-4,5-dihydro-5-isopazoleacetic acid (NSC-163501) (AT-125) was maximal at 8 hr and returned to pretreatment levels by 24 hr. In P388 leukemia, dose for dose, at 4 hr, 6-diazo-5-oxo-L-norleucine (NSC-7365) (DON) was the most potent of the L-glutamine antagonists in elevating basal PRPP pool size (50% above control) followed by AT-125 and azaserine, 300 and 100% above control respectively. Moreover, such augmentation in PRPP pool size preferentially affected P388 tumor rather than the small intestine. Following i.p. administration of LD10 doses of AT-125, DON and azaserine, the specific activities of PRPP anabolizing and catabolizing enzymes were determined. A significant inhibition of PRPP amidotransferase was demonstrated with DON and AT-125 (P less than 0.05), and no inhibition with azaserine. A similar modulation of PRPP pool size demonstrated in vivo following administration of 250 mg/kg of ART-125 in mice bearing colonic adenocarcinoma lines. It was suggested that a significant increase of PRPP pool size might cause the possible synergism of a selected L-glutamine antagonist and 5-fluorouracil as reported after the appropriately scheduled administration of methotrexate and 5-fluorouracil.

Topics: Adenocarcinoma; Animals; Azaserine; Colonic Neoplasms; Diazooxonorleucine; Glutamine; Intestine, Small; Isoxazoles; Leukemia P388; Leukemia, Experimental; Mice; Neoplasms, Experimental; Pentosephosphates; Phosphoribosyl Pyrophosphate

Forty-seven substances were tested for antitumor activity against the McCall rat colon adenocarcinoma. The most effective compounds were mitomycin C, 1,1', 1"-phosphinothiolylidynetrisaziridine and adriamycin. Others less active were azaserine, N-(4-chlorophenyl)-N'-(1-methylethyl)-imidodicarbonimidic diamide and 3,6-bis(5-chloro-2-piperidinyl)-2,5-piperazinedione. A number of standard anticancer drugs, 5-fluorouracil, arabinosylcytosine, methotrexate, bleomycin, daunomycin, 6-mercaptopurine, cis-dichlorodiammine platinum(II), cyclophosphamide and actinomycin D, were not effective under the test conditions and evaluation procedure used. Lentinan, though causing no initial inhibition of growth, did cause some regression. Significant synergism in terms of regression was seen in combination therapy with mitomycin C and azaserine.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Azaserine; Colonic Neoplasms; Drug Therapy, Combination; Male; Mitomycin; Mitomycins; Neoplasms, Experimental; Rats; Rats, Inbred Strains

Pancreatic carcinomas have been induced in Wistar and W/LEW rats by administration of total azaserine doses of 150-520 mg/kg by injection or oral routes over periods of 5-52 weeks. The latent period for development of invasive carcinomas was 1-2 years, but focal abnormalities in acinar cells appear earlier. The incidence of carcinomas varied with total dose, route, and schedule of azaserine administration. The spectrum of histologic patterns of the carcinomas included well and poorly differentiated acinar cell, ductlike, and undifferentiated carcinomas. Rats fed a purified diet developed more pancreatic neoplasms than rats fed a commercial laboratory chow. Selective feeding of these diets during the administration of carcinogen and following completion of carcinogen treatment indicated that the inhibitory effect of chow on pancreatic carcinogenesis was exerted during the postinitiation phas. Supplementation of diet with 0.025% retinyl acetate during the postinitiation phase also inhibited the progression of azaserine-induced lesions in the pancreas.

Topics: Adenocarcinoma; Animals; Azaserine; Carcinoma; Cell Transformation, Neoplastic; Cytoplasmic Granules; Diet; Diterpenes; Enzyme Precursors; Male; Neoplasms, Experimental; Pancreatic Neoplasms; Rats; Rats, Inbred Lew; Rats, Inbred Strains; Retinyl Esters; Vitamin A

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.

Topics: Adenocarcinoma; Animals; Azaserine; Cocarcinogenesis; Dietary Fats; Fats, Unsaturated; Male; Neoplasms, Experimental; Pancreatic Neoplasms; Rats; Rats, Inbred Strains

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

Two pancreatic adenocarcinomas which had been induced in Wistar/Lewis rats by azaserine treatment were transplanted into rats of the same strain by subcutaneous and intraperitoneal injection of minced tumor. Subsequently, we have serially transplanted into non-radiated recipients. Transplanted tumors have maintained evidence of acinar cell differentiation including the presence of zymogen granules in tumors studied by electron microscopy, and of lipase, amylase and trypsin activity in the supernatant of tumor homogenates. Histologically, the tumors vary from poorly differentiated solid carcinomas to well differentiated variants which form acini. Transplanted tumors are locally invasive and have metastasized to lung and liver in some recipients.

Topics: Adenocarcinoma; Animals; Azaserine; Neoplasm Transplantation; Neoplasms, Experimental; Pancreatic Neoplasms; Rats; Transplantation, Homologous

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: Adenocarcinoma; Amides; Azaserine; Carcinoma; Cell Line; Culture Techniques; Escherichia coli; Glycine; Guanine; Humans; Imidazoles; Laryngeal Neoplasms; Ligases; Neoplasms, Experimental; Nucleosides

Topics: Adenine; Adenocarcinoma; Animals; Azaserine; Carbon Isotopes; Cell Line; Feedback; Hypoxanthines; Mercaptopurine; Methotrexate; Neoplasms, Experimental; Nucleotides; Phosphotransferases; Purines; Sarcoma 180; Thioguanine

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Azaserine; Carcinoma 256, Walker; Carcinoma, Ehrlich Tumor; Diet; Drug Synergism; Female; Leukemia, Experimental; Lymphoma, Non-Hodgkin; Mice; Neoplasms, Experimental; Osteosarcoma; Sarcoma 180; Sarcoma, Experimental; Thiosemicarbazones; Vitamin B 6 Deficiency

Topics: Adenocarcinoma; Antineoplastic Agents; Aspergillus; Azaserine; Carcinoma, Bronchogenic; Chick Embryo; Glycine; Mercaptopurine; Neoplasms; Neoplasms, Experimental; Puromycin; Pyrroles; Research; Saccharomyces; Tissue Culture Techniques; Triethylenemelamine

Topics: Adenocarcinoma; Alopecia; Antineoplastic Agents; Azaserine; Carcinoma, Squamous Cell; Diarrhea; Drug Eruptions; Drug Therapy; Geriatrics; Guanine; Leukopenia; Nausea; Neoplasms; Stomatitis; Thioguanine; Thrombocytopenia; Toxicology

Topics: Adenocarcinoma; Antineoplastic Agents; Azaserine; Humans; In Vitro Techniques; Infrared Rays; Magnetic Resonance Spectroscopy; Mercaptopurine; Mitosporic Fungi; Spectrum Analysis; Ultraviolet Rays