azaserine and nitrosobis(2-oxopropyl)amine

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

In a previous short-term study (4 months) we found that Sandostatin, when administered prophylactically, inhibited growth of putative pre-neoplastic ductular lesions induced in hamster pancreas by N-nitrosobis(2-oxopropyl)amine (BOP), but not of acinar lesions induced in rat pancreas by azaserine. The present long-term (12 months) study was carried out to investigate the effects of Sandostatin (3 microgram/day), alone and in combination with orchiectomy, on pancreatic carcinogenesis in azaserine-treated rats and BOP-treated hamsters. In order to mimic therapy in humans, treatment of the animals started 4 months after the last injection with carcinogen, when (pre)neoplastic lesions had already developed. After treatment with Sandostatin for 8 months, rats developed fewer pancreatic atypical acinar cell nodules and tumours than those not treated with Sandostatin. Moreover, multiplicity of (pre)neoplastic acinar lesions was also lower in orchiectomized rats than in intact rats. However, Sandostatin treatment did not enhance the inhibitory effect of surgical castration on pancreatic carcinogenesis in rats. In hamsters that were both orchiectomized and treated with Sandostatin, the development of borderline lesions was significantly inhibited, whereas such an effect was not present in hamsters that were either surgically castrated or treated with Sandostatin alone. In Sandostatin-treated hamsters a significantly lower number of microcarcinomas was found than in hamsters not treated with Sandostatin. The present findings suggest that Sandostatin, particularly in combination with surgical castration, might be of therapeutic value for treatment of ductular pancreatic tumours.

Topics: Animals; Anticarcinogenic Agents; Azaserine; Body Weight; Carcinogens; Combined Modality Therapy; Cricetinae; Male; Mesocricetus; Microscopy; Nitrosamines; Octreotide; Orchiectomy; Organ Size; Pancreas; Pancreatic Neoplasms; Pituitary Gland; Rats; Rats, Wistar; Testis

It has been suggested that linoleic acid (LA) is responsible for the promoting effect of dietary polyunsaturated fat on pancreatic carcinogenesis via an accelerated prostaglandin synthesis, caused by metabolism of LA-derived arachidonic acid in (pre)neoplastic tissue. The purpose of the present study was to investigate whether dietary LA is the cause of pancreatic tumor promotion by a high fat diet. Five groups of 30 azaserine-treated rats and 5 groups of 30 N-nitrosobis(2-oxopropyl)amine-treated hamsters were maintained for 6 months (rats) and 12 months (hamsters) on high fat (25 weight %) AIN diets containing 2, 4, 6, 10, or 15 weight % LA. The results indicated that the strongest enhancing effect on the growth of pancreatic (pre)neoplastic lesions in rats and hamsters was obtained with 4 and 2 weight % of dietary LA, respectively. At higher LA levels the tumor response seemed to decrease rather than increase. In both rats and hamsters the fatty acid profiles of blood plasma and pancreas showed an accurate reflection of the dietary fatty acid profiles: a proportional increase in LA levels was observed in plasma and pancreas with increasing dietary LA. In both species plasma and pancreatic AA levels remained constant, except for arachidonic acid levels in rat plasma, which significantly increased with increasing dietary LA levels. Fatty acid profiles in hamster pancreatic tumors did not differ from fatty acid profiles in nontumorous pancreatic tissue from hamsters fed the same diet. Prostaglandin (PG) E2, 6-keto-PGF1 alpha, PGF2 alpha, and thromboxane B2-concentrations in nontumorous pancreatic tissue were similar among the diet groups. Ductular adenocarcinomas from hamster pancreas showed significantly higher levels of 6-keto-PGF1 alpha, PGF2 alpha, and thromboxane B2, but not of PGE2 in comparison with nontumorous pancreas. It is concluded that the strongest pancreatic tumor promotion by dietary LA is 4 weight % in rats and 2 weight % or less in hamsters, and that PGs may be involved in the development of ductular adenocarcinomas induced in hamster pancreas by N-nitrosobis(2-oxopropyl)amine.

Topics: Animals; Arachidonic Acid; Azaserine; Carcinogens; Cricetinae; Dietary Fats; Fatty Acids; Linoleic Acid; Linoleic Acids; Male; Mesocricetus; Microsomes; Nitrosamines; Pancreas; Pancreatic Neoplasms; Plant Oils; Precancerous Conditions; Rats; Rats, Wistar; Reference Values; Safflower Oil; Species Specificity; Sunflower Oil

The effects of treatment with the somatostatin analogue Sandostatin, separately and in combination with surgical castration, on the development of azaserine-induced lesions in rat pancreas and N-nitrosobis(2-oxopropyl)amine (BOP)-induced lesions in hamster pancreas were investigated. The animals were divided in 4 groups and treated as follows: (a) controls, injected s.c. with saline solution (0.9% NaCl); (b) orchiectomy directly after the last treatment with carcinogen; (c) Sandostatin (SMS 201-995) subcutaneously; (d) orchiectomy followed by treatment with Sandostatin. No significant suppressive effects on plasma EGF or IGF-I concentrations were noted after Sandostatin treatment, but plasma gastrin levels decreased slightly in the rats, not in the hamsters. In rats, Sandostatin treatment enhanced rather than inhibited growth of acidophilic atypical acinar cell nodules. In hamster pancreas, by contrast, Sandostatin inhibited the development of putative pre-neoplastic ductular lesions. There was no interaction between treatment with Sandostatin and surgical castration. It was concluded that Sandostatin, when administered prophylactically, has an inhibitory effect on the growth of putative pre-neoplastic ductular, but not acinar, lesions.

Topics: Animals; Azaserine; Carcinogens; Cricetinae; Drug Interactions; Eating; Growth Substances; Guinea Pigs; Hormones; Male; Mesocricetus; Nitrosamines; Octreotide; Orchiectomy; Organ Size; Pancreas; Pancreatic Neoplasms; Rats; Rats, Inbred Strains

We studied the effects of hormonal manipulation by orchiectomy, alone or in combination with the aromatase inhibitor aminoglutethimide (AGT), and by luteinizing hormone-releasing hormone agonist (LH-RH-A) (goserelin) treatment on the development of early putative (pre)neoplastic lesions induced in the pancreas of rats and hamsters by azaserine and N-nitrosobis(2-oxopropyl)amine respectively. Treatment of the animals started 1 week after the last injection with carcinogen and continued for 4 months. Orchiectomy caused a significant inhibition of growth of acidophilic atypical acinar cell nodules in the rat model, whereas surgical castration did not show an effect in the hamster model. In rats, but not in hamsters, orchiectomy resulted in a significant decrease in body weight and in absolute, but not relative pancreatic weight. Treatment of the animals with AGT or goserelin did not cause a significant effect on the development of either putative preneoplastic acinar lesions in rat pancreas or early ductular lesions in hamster pancreas. Hamsters showed clearly higher plasma epidermal growth factor (EGF) and insulin-like growth factor 1 (IGF-1) concentrations than rats, while plasma testosterone levels were significantly lower. Plasma EGF and IGF-1 levels decreased with increasing age in both control and treatment groups. Compared to controls there were no clear unequivocal effects of treatment on EGF, IGF-1 and gastrin levels. Plasma testosterone levels decreased by orchiectomy and LH-RH-A treatment. In rats hormone-induced effects on food intake and altered nutritional status might be important with respect to the development of carcinogen-induced preneoplastic pancreatic lesions.

Topics: Aminoglutethimide; Animals; Azaserine; Body Weight; Buserelin; Carcinogens; Cricetinae; Epidermal Growth Factor; Gastrins; Goserelin; Male; Mesocricetus; Nitrosamines; Orchiectomy; Organ Size; Pancreatic Neoplasms; Precancerous Conditions; Rats; Rats, Inbred Strains; Somatomedins; Testosterone

The cytotoxic and DNA-damaging effects of the pancreatic carcinogens azaserine, streptozotocin, and N-nitrosobis(2-oxyopropyl)amine (BOP) on propagable cultured normal rat pancreatic epithelial cells have been studied. All three chemicals in micromolar concentrations produced cytotoxicity to these cells. The concentrations that caused 50% reduction in colony formation (LD50) were approximately 0.3 mM for azaserine, 0.4 mM for BOP, and 2 mM for streptozotocin. Comparatively, the LD50 for N-methyl-N'-nitro-N-nitrosoguanidine was 3 microM. The toxicity of both azaserine and BOP did not require exogenously added S9 microsomal enzymes, indicating that the cells were capable of metabolic activation of these carcinogens. All three compounds induced unscheduled DNA synthesis, thus suggesting their mutagenic and carcinogenic potential in these cultured cells.

Topics: Animals; Azaserine; Carcinogens; Cell Line; DNA; DNA Replication; Epithelium; Male; Methylnitronitrosoguanidine; Nitrosamines; Pancreas; Rats; Rats, Inbred F344; Streptozocin

The effects of coffee and dietary fat (alone and in combination) on the development of preneoplastic lesions in exocrine pancreas were investigated in rats and hamsters, treated with azaserine or N-nitrosobis(2-oxopropyl)amine, respectively. The animals were given the respective diets (5% or 25% corn oil) and coffee (instead of drinking water) within one week after the treatment with carcinogen. At four months postinitiation, the pancreata were quantitatively examined for the number and size of preneoplastic foci. In rats, coffee alone inhibited growth of acidophilic foci and, moreover, slightly inhibited the positive modulating effect of fat on growth of these foci, pointing to a negative rather than a positive interaction between these two life-style factors. In hamsters, coffee alone enhanced growth of cystic foci, whereas fat alone enhanced growth of ductular foci. An interaction between fat and coffee on pancreatic carcinogenesis in hamsters could not be demonstrated.

Topics: Animals; Azaserine; Body Weight; Carcinogens; Coffee; Cricetinae; Dietary Fats; Drug Interactions; Male; Nitrosamines; Organ Size; Pancreas; Pancreatic Neoplasms; Precancerous Conditions; Rats; Rats, Inbred Strains; Specific Pathogen-Free Organisms; Time Factors; Weaning

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

Azaserine (CAS: 115-02-6), streptozocin (CAS: 18883-66-4; streptozotocin), and N-nitrosobis(2-oxopropyl)amine [(BOP) CAS: 60599-38-4] produce different types of pancreatic tumors in rodents. We have investigated the toxic effects of these compounds on pancreatic tissues from Wistar rats and Syrian hamsters. Inhibition of protein synthesis was used as a measure of toxicity. Pancreatic islets and acinar cells from rat and hamster were labeled with [3H]leucine for 60 minutes in vitro in the presence of the various carcinogens. Azaserine, which produces acinar cell tumors in the rat, inhibited synthesis by all tissues; rat acinar cells, however, were most sensitive. Glutamine, but not serine, provided some protection against azaserine toxicity. Streptozocin inhibited synthesis by islets of both species and acinar cells from hamster; islets were the most sensitive. BOP and N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine, which induce ductal tumors in the hamster, had no effect on any of the tissues examined. These results indicate that the specificities of the cellular toxicities of the pancreatic carcinogens parallel, to some degree, their tumorigenic effects.

Topics: Animals; Azaserine; Carcinogens; Cricetinae; Glutamine; Leucine; Male; Mesocricetus; Nitrosamines; Pancreatic Neoplasms; Protein Biosynthesis; Rats; Rats, Inbred Strains; Streptozocin; Tritium

The effect of dietary fat and ethanol and their interactions on the development of putative, preneoplastic foci in exocrine pancreas was investigated in rats and hamsters. Rats were given a single i.p. injection of 30 mg azaserine per kg body wt at 19 days of age. Hamsters were injected s.c., with 20 mg N-nitrosobis(2-oxopropyl)amine (BOP)/kg body wt at 6 and 7 weeks of age. The animals were fed a low fat (LF) control diet (5% corn oil) or a high fat (HF) diet (25% corn oil). Ethanol was provided in drinking water at a 15% (w/v) concentration. The animals were given the respective diets and ethanol after the treatment with carcinogen. At 4 months post-initiation, the pancreata were quantitatively examined for the number and size of preneoplastic foci. In rats, acidophilic as well as basophilic foci were subject to modulation by HF and ethanol. The results point to a specific promoting effect of unsaturated fat on the growth potential of azaserine-induced acidophilic acinar cell foci in rat pancreas. There was no evidence of an interaction between HF and ethanol as far as acidophilic foci are concerned. Evaluation of the number and size of the basophilic foci demonstrated an enhancing effect of ethanol on the modulation of pancreatic carcinogenesis by fat, pointing to a possible interaction between these two lifestyle factors. This suggestion was supported by the finding that six out of 20 rats in the HF with ethanol group exhibited a carcinoma in situ, whereas in the HF and in the ethanol group such an advanced lesion was found in one animal only. Unlike in rats, ethanol had no modulating effect on number and growth of putative, preneoplastic lesions in hamsters, either in combination with LF or in combination with HF. A HF diet, however, caused a significant increase in number as well as an increase in percentage of pancreatic tissue occupied by early lesions induced in hamster pancreas by BOP.

Topics: Adenosine Triphosphatases; Animals; Azaserine; Body Weight; Cricetinae; Dietary Fats; Eating; Ethanol; Male; Mesocricetus; Nitrosamines; Organ Size; Pancreas; Pancreatic Neoplasms; Precancerous Conditions; Rats; Rats, Inbred Strains

Focal proliferative changes in the acinar cells of the pancreas of rats have been induced by several systemically administered carcinogens including azaserine, N-nitrosobis(2-oxopropyl)amine, N-nitroso-(2-hydroxypropyl) (2-oxopropyl)amine, and N delta-(N-methyl-N-nitrosocarbamoyl)-L-ornithine (MNCO). Foci, nodules, and adenomas induced by these carcinogens are usually made up of atypical-appearing acinar cells that maintain a high degree of differentiation, but a minority of these lesions exhibit anaplastic cellular changes that suggest the development of malignant potential. Such anaplasia may occupy the whole of smaller lesions or may occur as a secondary focal change within larger nodules or adenomas. Many foci and nodules per pancreas have been induced by single or multiple exposures to these known genotoxic carcinogens, but relatively few of them develop into carcinomas. Azaserine and MNCO have induced acinar cell carcinomas in rats. Those induced by azaserine have exhibited a broad spectrum of histologic variants, including ductlike cystic, and undifferentiated patterns. Higher doses of MNCO have induced a second pattern of change in the pancreatic lobules of rats, which includes cystic and tubular ductlike structures that have been called cystic and tubular ductal complexes. MNCO has also induced focal acinar cell lesions, cystic and tubular ductal complexes, and adenocarcinomas in the pancreas of Syrain golden hamsters. In this species, ductal complexes are much more numerous than are proliferative lesions of acinar cells, and the histologic appearance of the carcinomas is ductlike. Hyperplasia and atypical changes were also seen in the epithelium of the intralobular ducts of hamsters.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Azaserine; Carcinogens; Cell Transformation, Neoplastic; Cricetinae; Nitrosamines; Nitrosourea Compounds; Pancreatic Neoplasms; Rats; Rats, Inbred Lew