Role of cholecystokinin in dietary fat-promoted azaserine-induced pancreatic carcinogenesis in rats.

The role of cholecystokinin in dietary fat-promoted pancreatic carcinogenesis was investigated in azaserine-treated rats, using lorglumide, a highly specific cholecystokinin-receptor antagonist. The animals were killed 8 months after the start of treatment. Cholecystokinin, but not dietary unsaturated fat, increased pancreatic weight. Rats treated with cholecystokinin developed more acidophilic atypical acinar cell nodules, adenomas and adenocarcinomas than control animals. Rats maintained on the high-fat diet developed significantly more adenomas and adenocarcinomas than controls given a diet low in unsaturated fat. Lorglumide largely inhibited the enhancing effect of cholecystokinin, but not of dietary fat, on pancreatic carcinogenesis indicating that it is unlikely that the promoting effect of dietary unsaturated fat on pancreatic carcinogenesis is mediated via cholecystokinin

Effects of orchiectomy, alone or in combination with testosterone, and cyproterone acetate on exocrine pancreatic carcinogenesis in rats and hamsters

The results of a previous 4-mo study in azaserine-treated rats and BOP-treated hamsters indicated that orchiectomy inhibited pancreatic growth and development of putative preneoplastic lesions in the exocrine pancreas of rats but not hamsters. This 12-mo study was carried out to investigate the effects of orchiectomy, alone and in combination with testosterone, and of treatment with cyproterone acetate on pancreatic carcinogenesis in azaserine-treated rats and BOP-treated hamsters. Treatment started 4 mo after injection of the carcinogen. In orchiectomized rats, pancreatic wt was lower than in controls, whereas pancreatic wt of orchiectomized rats treated with testosterone was similar to that of controls. Both orchiectomy and cyproterone acetate caused a decrease in body wt gain and had an inhibitory effect on pancreatic carcinogenesis. Testosterone treatment did not influence the inhibitory effects of orchiectomy on body wt gain and on pancreatic carcinogenesis. In hamsters, neither orchiectomy, alone or in combination with testosterone, nor cyproterone acetate (CA) affected pancreatic growth or pancreatic carcinogenesis. This study indicates that testosterone plays a minor role in the development of pancreatic tumors induced in rats by azaserine but not in that of pancreatic tumors induced in hamsters by BOP

Effect of urinary pH on the progression of urinary bladder tumours

Systemic alkalosis has been postulated to enhance tumorigenesis, whereas systemic acidosis has been implicated to exert a favourable influence on tumour control and regression. In the present study the urinary pH was influenced by feeding acid-forming or base-forming diets, and the effect of alkaline or acid urine on the early and late progression phase of urinary bladder carcinogenicity was investigated in male Wistar rats. Bladder lesions were initiated by N-butyl-N-(4-hydroxybutyl) nitrosamine (0.05% BBN in the drinking water during 4 weeks) and promoted by sodium bicarbonate (3.4% NaHCO3 in the diet during 15 or 25 weeks). After short- (15 week) and more long-term (25 week) promotion with NaHCO3, groups of 20 rats were fed a diet containing the acidifying salt ammoniumchloride (2.1% NH4Cl) or the control diet. All surviving rats were killed after a total study duration of 52 weeks. Additional control groups were, after initiation, fed diets containing NaHCO3 and killed after 15 wk or 25 wk of promotion, or at the end of the study. In rats fed diets with added salts, water intake and the amount of urine produced were increased and the urinary density was decreased compared to rats fed control diet. During NaHCO3 feeding, urinary pH and sodium concentration were increased. During NH4Cl feeding, urinary pH was decreased and urinary chloride and calcium concentrations were increased. Initiation by BBN followed by treatment with NaHCO3 caused a high incidence of papillary/nodular hyperplasia, papillomas and carcinomas of the bladder epithelium. These lesions progressed with time or longer duration of NaHCO3 promotion. A tumour protective effect of urinary acidification by NH4Cl was not found. In fact, both acidification and prolonged alkalinization tended to aggravate the malignancy of bladder carcinomas. Copyright (C) 2000 Elsevier Science Ltd

Dietary fat and carcinogenesis

Epidemiologic investigations have suggested a relationship between dietary fat intake and various types of cancer incidences. Furthermore, epidemiologic studies as well as studies with animal models have demonstrated that not only the amount but also the type of fat consumed is important. At present, the mechanism by which dietary fat modulates carcinogenesis has not been elucidated. The effects of dietary fat on the development of tumours have been summarized in the present review with emphasis on colorectal, pancreas, breast and prostate cancer. It is concluded that influence on synthesis of prostaglandins and leukotrienes may be the universal mechanism by which dietary fats modulate carcinogenesis. Copyright (C) 1999 Elsevier Science B.V

Effects of sandostatin, alone and in combination with surgical castration, on pancreatic carcinigenesis in rats and hamsters

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 μg/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 Sandostitin 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. Chemicals/CAS: Anticarcinogenic Agents; Azaserine, 115-02-6; Carcinogens; Nitrosamines; nitrosobis(2-oxopropyl)amine, 60599-38-4; Octreotide, 83150-76-

Overexpression of transforming growth factor-α and epidermal growth factor receptor, but not epidermal growth factor, in exocrine pancreatic tumours in hamsters

Using immunohistochemistry, Northern blotting and a semi-quantitative PCR technique, epidermal growth factor (EGF), transforming growth factor-α (TGF-α) and epidermal growth factor receptor (EGFR) expression were studied in the pancreas of N-nitrosobis(2-oxopropyl)-amine (BOP)-treated hamsters. After initiation pancreatic carcinogenesis was modulated by a high fat diet or by injections with the cholecystokinin analogue caerulein. Autopsies were performed 6 and 12 months after the last injection with BOP. Immunohistochemistry revealed a weak expression of TGF-α in normal acinar cells and a stronger expression in ductular and centro-acinar cells. Overexpression of TGF-α was observed in advanced putative preneoplastic lesions (classified as borderline lesions) and in ductular adenocarcinomas. EGFR immunoreactivity was present only in ductular adenocarcinomas. EGF peptide expression was observed both in acinar and ductular normal and tumorous cells and the level of expression did not change significantly during carcinogenesis. Moreover, the post-initiation treatments did not cause differences in EGF, TGF-α or EGFR peptide or mRNA levels, except for a significantly lower expression of TGF-α mRNA in hamsters fed a high fat diet when compared with those fed a low fat diet. TGF-α mRNA levels increased, whereas EGF mRNA levels decreased significantly in total pancreatic homogenates of BOP-treated hamsters in comparison with untreated controls. Also, in ductular adenocarcinomas TGF-α and EGFR (but not EGF) mRNA levels were significantly higher than in normal pancreatic homogenates. In pancreatic homogenates obtained 6 months after the last BOP injection, these differences were less pronounced in comparison with those obtained after 12 months. The present results indicate that TGF-α (but not EGF) might act in a paracrine or autocrine manner in pancreatic tumours in BOP-treated hamsters via simultaneously expressed EGFR. However, TGF-α, EGF and EGFR do not seem to be involved in the modulating effects of a high fat diet or caerulein treatment on pancreatic carcinogenesis in BOP-treated hamsters