azaserine and Hyperplasia

The utility of gamma-glutamyltranspeptidase (gamma-GTP) as an enzyme marker during pancreatic acinar cell carcinogenesis in rats was assessed by measuring its enzyme-histochemical performance in pancreatic acinar cell lesions induced by 4-hydroxyaminoquinoline 1-oxide (4-HAQO) and/or azaserine in partially-pancreatectomized Fischer 344 and Wistar rats. Rats were given a single intravenous injection of 4-HAQO (10 or 7 mg/kg body weight) 3 days after partial pancreatectomy followed by intraperitoneal injections of azaserine (30 mg/kg) once a week for 10 weeks, or the same treatment without azaserine. The animals were sacrificed at 3, 6, 10, 12 and 18 months. 4-HAQO predominantly induced basophilic foci in Fischer rats, while in Wistar rats acidophilic foci and acidophilic hyperplastic nodules were predominant. A preferential enhancement of the induction of acidophilic foci and hyperplastic nodules was exhibited in Fischer rats following co-administration with azaserine. Normal acinar cells were positive for gamma-GTP. 90 to 100% of basophilic foci were either negative or slightly positive for gamma-GTP, whilst 68 to 98% of acidophilic foci were positive. The gamma-GTP activities of acidophilic hyperplastic nodules were more variable between nodules than within nodules, and either co-administration of azaserine or extension of experimental duration time appeared to increase the gamma-GTP positive nodules. Between the gamma-GTP positive and decreased nodules, no histological but some morphometrical differences were observed. As far as the nodules induced by 4-HAQO in Fischer rats were concerned, all of the gamma-GTP decreased nodules had thin fibrous capsules and exhibited ultrastructurally more atypia than the positive ones. Present study thus revealed that gamma-GTP is neither a useful nor invariable enzyme marker during pancreatic acinar cell carcinogenesis in rats.

Topics: 4-Hydroxyaminoquinoline-1-oxide; Animals; Azaserine; Body Weight; Cell Transformation, Neoplastic; gamma-Glutamyltransferase; Histocytochemistry; Hyperplasia; Male; Microscopy, Electron; Pancreas; Pancreatic Neoplasms; Precancerous Conditions; Rats; Rats, Inbred F344; 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

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

Rats were treated with raw soya flour to produce pancreatic hypertrophy and also received azaserine, a pancreatic carcinogen. The combined treatment resulted in the development of large numbers of hyperplastic nodules in the acinar tissue of the rat pancreas. We conclude that the pancreas of the rat stimulated to proliferate by raw soya flour provides a sensitive model for detecting and studying pancreatic carcinogens.

Topics: Animals; Azaserine; Cell Division; Glycine max; Hyperplasia; Male; Neoplasms, Experimental; Pancreatic Neoplasms; Precancerous Conditions; Rats

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