No abstract

The role of cholecystokinin (CCK) has been explored in pancreatic carcinogenesis following pancreatobiliary diversion (PBD), using the specific CCK receptor antagonist CR-1409. Male Wistar rats (n = 80) weighing 70-100 g were given weekly i.p. injections of azaserine (30 mg kg-1 week-1) for 3 consecutive weeks. One week later animals were randomised to receive either PBD or sham PBD and thereafter to receive s.c. injections of either saline or CR-1409 (10 mg kg-1 day-1, 5 days a week). Six months after operation surviving rats were killed as follows: sham + saline 20, PBD + saline 19, sham + CR-1409 14, PBD + CR-1409 11. Cardiac blood was taken for CCK assay and the pancreas was excised for wet weight measurement and quantitative estimation of atypical acinar cell foci (AACF), the precursor of carcinoma. PBD reduced median body weight (3-20% less than shams) but trebled the absolute and relative pancreatic weights (P < 0.001). CR-1409 blunted this adaptive response to PBD, reducing absolute pancreatic weight by 35% (P < 0.005). PBD quadrupled circulating CCK concentrations, regardless of the antagonist treatment. Acidophilic AACF occurred only in rats with PBD. CR-1409 markedly reduced the number of observed acidophilic AACF by 90% (P < 0.001) and the number of foci per pancreas by 93% (P < 0.001). Moreover, CR-1409 reduced the mean focal diameter of each lesion by 18% (P < 0.005), the mean focal volume by 58% (P < 0.05) and the percentage of pancreas occupied by acidophilic foci by 95% (P < 0.001). PBD enhances pancreatic carcinogenesis by causing hypercholecystokininaemia, and CR-1409 largely inhibits this enhancement.

Groups of male and female IF strain mice were fed a diet containing either 0.5% or 1.0% paracetamol for up to 18 months. Among male mice fed the higher dose, the total liver cell tumour incidence was 87%, 21.7% developing hepatocellular carcinomas: both yields were statistically significant. The corresponding incidence in high dose females was 19.2% and 4.3%, respectively, only the former being significant. Foci of cellular alteration were also present in the livers of high dose mice of both sexes and also in those of the low dose males.

No abstract

Male Syrian golden hamsters were given weekly s.c. injections of 250 mg/kg body weight of N-nitroso-bis(2-hydroxypropyl)amine (BHP) for up to 15 weeks. Electron microscope studies were carried out on early changes in the exocrine pancreas of these hamsters for 2 weeks to 15 weeks. The majority of observed alterations occurred in the acinar cells and included the appearance of "dark" and "light" cells, the former showing nuclear shrinkage and irregularity but maintaining a normal rough endoplasmic reticulum (ER) and zymogen content. The "light" cells exhibited a variety of early fine structural alterations including conformational changes in their rough ER, together with a reduction in zymogen granules, increased autophagic vacuoles and Golgi hypertrophy. Ducts and ductules were relatively unaffected. The observations indicate that the acinar cells were most affected, morphologically, by BHP and are consistent with the view that these cells are the primary target for BHP.