gastrins and nitrosobis(2-oxopropyl)amine

In order to examine the effect of cholecystokinin on spontaneous and induced pancreatic carcinogenesis in the hamster, two sets of experiments were carried out, one involving long-term hypercholecystokininemia and one involving cancer induction during hypercholecystokininemia. The effect of hypercholecystokininemia, induced by pancreaticobiliary diversion (PBD), was studied for 8 months. Neither PBD animals nor sham-operated controls developed premalignant or malignant pancreatic lesions. However, in the PBD group the mean pancreatic weight, total protein content and DNA content were increased by 30, 29 and 27% respectively. No such increases were found in PBD animals receiving a cholecystokinin-A receptor antagonist during the last 24 days of the experiment. In the cancer induction study, the effect of PBD on N-nitrosobis(2-oxopropyl)amine-induced pancreatic carcinogenesis was studied for 3 months. Putative premalignant pancreatic lesions were diagnosed in all PBD hamsters and in four of 15 sham-operated controls. Pancreatic ductular carcinoma in situ was only found in PBD animals. The [3H]thymidine labeling index of the pancreatic lesions was significantly higher in the PBD group than in the controls. No such increase was observed in PBD animals receiving a cholecystokinin-A receptor antagonist during the last 5 days of the experiment. It is concluded that chronic endogenous hypercholecystokininemia promotes early phase pancreatic carcinogenesis, but does not per se cause development of premalignant or malignant pancreatic lesions in the hamster.

Topics: Animals; Carcinogens; Cholecystokinin; Cricetinae; Duodenum; Gastrins; Male; Mesocricetus; Nitrosamines; Organ Size; Pancreas; Pancreatic Ducts; Pancreatic Neoplasms

To examine the effect of gastrin on spontaneous and induced pancreatic carcinogenesis in the hamster.. Two sets of experiments were carried out, one involving long term hypergastrinaemia and one involving cancer induction during hypergastrinaemia. The effect of hypergastrinaemia accomplished by gastric fundectomy was studied for eight months. Neither fundectomised hamsters nor sham operated controls developed premalignant or malignant pancreatic lesions. In the fundectomy group, the mean pancreatic weight, total protein content, and DNA content was increased by 28%, 25%, and 25% respectively. No such increases were found in fundectomised animals receiving a cholecystokinin-B receptor antagonist during the last 24 days of the experiment. In the cancer induction study, the effect of fundectomy on N-nitrosobis(2-oxopropyl) amine induced pancreatic carcinogenesis was studied for three months. There were no significant differences in the incidence or [3H]-thymidine labelling index of focal pancreatic lesions between fundectomised and sham operated control animals.. Fundectomy with chronic hypergastrinaemia induces pancreatic hypertrophy, but does not enhance N-nitrosobis (2-oxopropyl)amine induced pancreatic carcinogenesis in the hamster. The increases in growth were inhibited by a cholecystokinin-B receptor antagonist, indicating that the trophic effect of fundectomy is mediated by gastrin.

Topics: Animals; Benzodiazepinones; Carcinogens; Cholecystokinin; Cricetinae; Disease Models, Animal; Gastric Fundus; Gastrins; Hypertrophy; Male; Mesocricetus; Neoplasms, Experimental; Nitrosamines; Pancreas; Pancreatic Neoplasms; Phenylurea Compounds; Receptors, Cholecystokinin

Female Syrian golden hamsters with N-nitrosobis(2-oxopropyl)amine-induced pancreatic cancers were treated for 2 months with new pseudononapeptide bombesin receptor antagonist [D-Tpi6,Leu13 psi (CH2NH)-Leu14]bombesin(6-14)(RC-3095), administered s.c. with implanted osmotic minipumps releasing 20 micrograms/day of the analogue. The results were compared to those obtained by treatment with somatostatin analogue RC-160 (35 micrograms/day and 150 micrograms/day) or [D-Trp6]luteinizing hormone-releasing hormone (25 micrograms/day), which inhibited the growth of pancreatic cancers in our previous studies. A new acetylated somatostatin analogue [formula: see text] (30 micrograms/day) also was used for comparison of therapeutic response. All peptide analogues induced tumor inhibition by at least one of the measured parameters. Bombesin antagonist RC-3095 and high dose of RC-160 (150 micrograms/day) had the greatest inhibitory effect on pancreatic cancers: A significant decrease in the number of animals with tumors, reduced pancreatic weight, 87-89% inhibition of tumorous pancreas weight, and a significant diminution in the number of tumor nodules and argyrophilic nucleolar organizer region count in tumor cell nuclei were observed in the groups treated with these regimens. We were able to detect receptors for bombesin in membranes of N-nitrosobis(2-oxopropyl)amine-induced pancreatic tumors and these receptors were not down-regulated after treatment with the bombesin antagonist. In hamsters treated with bombesin antagonists, tumor inhibition might be explained by a significant decrease in the binding capacity of epidermal growth factor receptors in pancreatic cancers. The acetylated somatostatin analogue RC-160-II had a similar inhibitory effect on the tumors as the original analogue RC-160. Our results suggest that the increase in the dose of RC-160 improves the therapeutic response, and this finding should be taken into account in clinical use of this somatostatin analogue. In view of its strong inhibitory effect on experimental pancreatic tumors, the bombesin antagonist RC-3095 might be considered as a possible new agent for the therapy of human exocrine pancreatic cancer.

Topics: Adenocarcinoma; Amino Acid Sequence; Animals; Antineoplastic Agents; Bombesin; Carcinogens; Cell Membrane; Cricetinae; ErbB Receptors; Female; Gastrins; Mesocricetus; Molecular Sequence Data; Nitrosamines; Organ Size; Pancreatic Neoplasms; Peptide Fragments; Receptors, Bombesin; Receptors, Neurotransmitter; Somatostatin

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