azaserine and lorglumide

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.

Topics: Animals; Azaserine; Biliopancreatic Diversion; Body Weight; Cholecystokinin; Cocarcinogenesis; Male; Organ Size; Pancreas; Pancreatic Neoplasms; Precancerous Conditions; Proglumide; Rats; Rats, Wistar

Cholecystokinin and bombesin have been shown to promote pancreatic growth and development of azaserine-induced acidophilic atypical acinar cell nodules in rat pancreas after treatment for 16 weeks. Lorglumide, a specific cholecystokinin receptor antagonist, inhibited the stimulating effect of cholecystokinin, but not of bombesin. The present study was carried out to determine effects of cholecystokinin and bombesin, alone and in combination with lorglumide, on pancreatic growth and carcinogenesis after chronic treatment. The animals were killed 8 months after the start of treatment. Growth of the pancreas and the development of acidophilic atypical acinar cell nodules in exocrine pancreas was enhanced significantly by both cholecystokinin and bombesin, but the number of carcinomas was increased only by bombesin. Lorglumide inhibited the effects of cholecystokinin on both pancreatic growth and on the development of acidophilic nodules. The effects of bombesin on pancreatic growth and development of pancreatic lesions, except for adenomas, were not inhibited by lorglumide.

Topics: Animals; Azaserine; Bombesin; Carcinogens; Cholecystokinin; Drug Synergism; Male; Pancreatic Neoplasms; Proglumide; Rats; Rats, Wistar; Receptors, Cholecystokinin

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.

Topics: Animals; Azaserine; Body Weight; Cholecystokinin; Dietary Fats; Liver; Male; Organ Size; Pancreas; Pancreatic Neoplasms; Proglumide; Rats; Rats, Inbred Strains; Receptors, Cholecystokinin

Feeding of raw soya flour or other trypsin inhibitors such as camostate is a well-established method for promoting growth of (pre)neoplastic foci induced in the exocrine pancreas of rats by azaserine. The effect of trypsin inhibitors is thought to be mediated through an increased release of cholecystokinin. Using the specific cholecystokinin receptor antagonist lorglumide (CR-1409), we performed a 16-wk study to investigate the potential of this drug in inhibiting growth of putative preneoplastic foci and to determine whether and to what extent cholecystokinin is responsible for the effect of trypsin inhibitors on pancreatic growth. After initiation with 30 mg/kg of azaserine at 19 days of age, six groups of 15 rats each received one of the following treatments: camostate, cholecystokinin-8, or gelatin control, either or not in combination with CR-1409, once daily, 3 days wk for 16 wk. Plasma cholecystokinin levels, measured 30 min after the stimulus, were similar after camostate and cholecystokinin octapeptide administration. After 16 wk the pancreata were removed, weighted, and quantitatively analyzed for the number and size of putative preneoplastic foci by light microscopy. Both camostate and cholecystokinin octapeptide stimulated pancreatic growth and development of acidophilic putative preneoplastic foci, whereas growth of basophilic putative preneoplastic foci was inhibited by camostate but stimulated by cholecystokinin. CR-1409 almost completely abolished the effect of cholecystokinin and was found to cause a significant decrease in the effects of camostate. It is concluded that (a) cholecystokinin plays a significant role in camostate-stimulated growth of acidophilic putative preneoplastic foci in rat pancreas and (b) CR-1409 inhibits growth of putative preneoplastic foci induced in rat pancreas by azaserine and hence may be of potential value for the treatment of pancreatic cancer in humans.

Topics: Animals; Azaserine; Cholecystokinin; Esters; Gabexate; Glutamine; Guanidines; Male; Pancreatic Neoplasms; Precancerous Conditions; Proglumide; Rats; Rats, Inbred Strains; Receptors, Cholecystokinin; Sincalide; Trypsin Inhibitors

Both cholecystokinin and bombesin have been shown to promote pancreatic carcinogenesis in the azaserine-rat model. The present study was undertaken to discriminate between the effects of cholecystokinin and bombesin and to establish the modulating properties of the specific cholecystokinin receptor antagonist CR-1409 on pancreatic carcinogenesis. After initiation with 30 mg/kg of azaserine, six groups of 15 Wistar rats were treated for 16 wk with cholecystokinin, bombesin, or gelatin (control), some in combination with CR-1409. Doses of cholecystokinin (2.5 micrograms/kg) and bombesin (10 micrograms/kg) were chosen that rendered approximately equal plasma cholecystokinin levels. Both cholecystokinin and bombesin were found to stimulate pancreatic growth, whereas CR-1409 only inhibited the growth-promoting effect of cholecystokinin significantly. Furthermore, both peptides stimulated the development of putative preneoplastic lesions, whereas CR-1409 only inhibited the effect of cholecystokinin significantly. It is concluded that (a) CR-1409 inhibits the promoting effect of cholecystokinin on pancreatic growth and azaserine-induced early pancreatic lesions and (b) the effects of bombesin cannot be fully ascribed to stimulation of the secretion of endogenous cholecystokinin.

Topics: Animals; Azaserine; Bombesin; Cholecystokinin; Glutamine; Male; Pancreas; Proglumide; Rats; Rats, Inbred Strains