azaserine and Carcinoma

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

Using receptor binding assays, we have previously demonstrated the overexpression of the high-affinity cholecystokinin (CCK) receptor and the novel expression of the gastrin (CCK-B) receptor in the azaserine-induced rat pancreatic carcinoma DSL-6. Since cDNA of both the CCK-A receptor (classical pancreatic CCK receptor) coding region and the CCK-B receptor coding region have recently been cloned and sequenced, we investigated the expression of messenger RNA of these receptors in DSL-6 pancreatic carcinoma. Our results showed that the 32P-labelled cDNA probe of the CCK-A receptor coding region hybridized with an approximately 2.7 kb mRNA from both DSL-6 pancreatic carcinoma and normal rat pancreas. However, the relative expression of the CCK-A receptor mRNA in DSL-6 pancreatic carcinoma was approximately 8-fold of that in normal rat pancreas. The 32P-labelled cDNA probe of the CCK-B receptor coding region hybridized with an approximately 2.7 kb mRNA from DSL-6 pancreatic carcinoma; no hybridizing mRNA could be identified from normal rat pancreas. In summary, the CCK-A receptor mRNA is overexpressed approximately 8-fold and the gastrin (CCK-B) receptor mRNA is novelly expressed in DSL-6 pancreatic carcinoma as compared to normal rat pancreas. These results further confirm our previous findings based on receptor binding assays. The gene overexpression of the CCK-A receptor and the novel gene expression of the gastrin (CCK-B) receptor may be generated by alterations in gene regulation during carcinogenesis, and may play an important role in promoting tumor growth.

Topics: Animals; Azaserine; Blotting, Northern; Carcinoma; Male; Pancreatic Neoplasms; Rats; Rats, Inbred Lew; Receptors, Cholecystokinin; RNA, Messenger

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

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

The incidence of carcinoma of the pancreas is higher among men than women. It is also higher among male than female carcinogen-treated rats. The role of testosterone in this preferential induction of pancreatic cancer was evaluated in a rat model of pancreatic carcinogenesis. Two-week-old Lewis rats were treated with a single injection of azaserine. At weaning (3 weeks), rats were divided into five groups as follows: females; intact males; sham-operated males; orchiectomized males; and orchiectomized males plus testosterone. Four months after administration of azaserine, quantitative histologic analysis of atypical acinar cell foci and nodules of the pancreas showed that in female and orchiectomized male rats, foci and nodules were smaller and less numerous than in intact males. Testosterone treatment partly reversed the effect of orchiectomy. This suggests that the susceptibility of male rats to induction of pancreatic carcinomas by azaserine is at least partially mediated by testosterone. Estrogen and testosterone receptors were assayed, but high-affinity receptors characteristic of gonadal tissues were not detected in normal pancreas or in a transplantable azaserine-induced acinar cell carcinoma. Thus, the effect of testosterone in the pancreas may depend on steroid-binding proteins of another type, or may be indirectly mediated.

Topics: Animals; Azaserine; Body Weight; Carcinoma; Female; Male; Neoplasm Transplantation; Orchiectomy; Organ Size; Pancreas; Pancreatic Neoplasms; Rats; Rats, Inbred Lew; Receptors, Androgen; Receptors, Estrogen; Testosterone

Studies were undertaken to characterize the growth of the azaserine-induced putative preneoplastic lesions in rats and to determine if a single dose of azaserine would be carcinogenic. Male Lewis rats were given a single i.p. injection of 30 mg L-azaserine/kg body weight at 7 weeks of age. A purified diet was fed throughout the study. Rats (10-12 per group) were autopsied at 6, 9, 12, 15 and 18 months post-initiation, and pancreases were quantitatively evaluated to characterize the growth of acidophilic and basophilic foci and nodules (henceforth called foci), and the incidence of neoplasms. All azaserine-treated rats had foci, and at all times approximately equal numbers of acidophilic and basophilic foci were present in the pancreas. The number of basophilic foci increased with time, and while their size also increased, the change was small compared with the increase in size of the acidophilic foci. Conversely, all acidophilic foci appeared to be present by 6-9 months, and their size greatly increased with time. The data suggest that virtually all foci persist rather than regress or remodel. At 9 months the incidence of carcinoma in situ was 30% and by 18 months there was a 100% incidence of pancreatic cancers (58% carcinoma in situ and 42% carcinoma).

Topics: Animals; Azaserine; Carcinoma; Carcinoma in Situ; Male; Pancreas; Pancreatic Neoplasms; Precancerous Conditions; Rats; Rats, Inbred Lew

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

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

Glycoproteins and lipids of rat pancreatic acinar cell carcinomas maintained in nude mice and in cell culture, were analyzed. The tumor contained significantly elevated levels of glycoproteins when compared with their normal counterparts. SDS-PAGE of tumor glycoproteins revealed that there were increased amounts of small molecular weight glycoproteins and the tumor also contained a 51,000 dalton glycoprotein which was not detected in the pancreas, liver or the sera of the control animals. The tumor in nude mice and cancer cells in culture had decreased lecithins and triglycerides, and increased amounts of free fatty acids, and both free and esterified cholesterols. The results indicate that altered glycoprotein and lipid compositions represent some of the characteristic features of the acinar cell carcinoma.

Topics: Animals; Azaserine; Carcinoma; Cells, Cultured; Cholesterol; Glycoproteins; Lipids; Molecular Weight; Pancreatic Neoplasms; Rats

The effect of azaserine on the pancreatic tumorigenesis of 4-hydroxyaminoquinoline 1-oxide (4-HAQO) after partial pancreatectomy in rats was studied. Pancreatic acinar cell carcinomas were produced in 7 out of 10 rats (70%), which received 7 mg/kg body wt. 4-HAQO 3 days after partial pancreatectomy, followed by 10 weekly injections of 30 mg/kg body wt. azaserine. Partial pancreatectomy enhanced the carcinogenesis of 4-HAQO, which was further promoted by azaserine.

Topics: 4-Hydroxyaminoquinoline-1-oxide; Aminoquinolines; Animals; Azaserine; Carcinoma; Drug Synergism; Male; Neoplasms, Experimental; Pancreas; Pancreatectomy; Pancreatic Neoplasms; Rats; Regeneration

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

Topics: Amino Acids; Anti-Bacterial Agents; Asparagine; Aspartic Acid; Azaserine; Azo Compounds; Carcinoma; Cell Line; Culture Techniques; Glutamine; Humans; Ligases; Mouth Neoplasms; Puromycin

Topics: Animals; Azaserine; Carcinoma; Cesium; Cyclophosphamide; Fluorouracil; In Vitro Techniques; Mammary Neoplasms, Experimental; Mice; Potassium; Sarcoma; Sarcoma, Experimental; Sodium

Topics: Adenine Nucleotides; Animals; Ascites; Azaserine; Carcinoma; Carcinoma, Ehrlich Tumor; Chromatography; Histocytochemistry; Mercaptopurine; Metabolism; Mice; Neoplasms, Experimental; Nucleotides; Pharmacology; Phosphoric Monoester Hydrolases; Research

Topics: Animals; Antineoplastic Agents; Ascites; Azaserine; Carcinoma; Neoplasms, Experimental; Serine

Topics: Antineoplastic Agents; Ascites; Azaserine; Biological Transport, Active; Carcinoma; Diazooxonorleucine; Leucine; Neoplasms; Serine