Effects of catechol and its analogs on pancreatic carcinogenesis initiated by N-nitrosobis(2-oxopropyl)amine in Syrian hamsters

The modifying effects of the phenolic antioxidant catechol (CC) and its analogs hydroquinone (HQ) and resorcinol (RN) on pancreatic carcinogenesis were evaluated in 146 female Syrian golden hamsters. Groups of animals received either saline or 70 mg/kg body wt N-nitrosobis(2-oxopropyl)amine (BOP) s.c. injections, twice with a 2 week interval, followed by basal diet or diet containing 1.5% of CC, HQ or RN, and 0.75% CC from week 4. All hamsters were killed at week 20 and histopathologically examined for development of pancreatic, liver and gall bladder lesions. The total numbers of pancreatic lesions comprising carcinomas, atypical ductal hyperplasias and ductal hyperplasias per hamster were significantly decreased in animals receiving BOP followed by CC, HQ and RN when compared to those in hamsters given BOP followed by basal diet. Incidence values for atypical ductal hyperplasias were also significantly decreased by the RN or 0.75% CC treatments. The results thus suggest that pancreatic carcinogenesis initiated by BOP in Syrian hamsters can be inhibited by treatments with phenolic antioxidants such as CC, HQ and RN for a relatively short experimental period.     

K-ras Gene Mutation in Early Ductal Lesions Induced in a Rapid Production Model for Pancreatic Carcinomas in Syrian Hamsters

The presence of K- ras gene mutation was examined in experimentally induced preneoplastic pancreatic ductal lesions. Syrian hamsters received 70 mg/kg of N -nitrosobis(2-oxopropyl)amine (BOP) followed by repeated exposure to an augmentation pressure regimen consisting of choline-deficient diet combined with dl -ethionine and l -methionine and administration of 20 mg/kg BOP. After two augmentation pressure cycles, pancreatic ductal cell hyperplasias appeared and after three cycles, atypical hyperplasias of pancreatic ductal cells and intraductal carcinomas developed. K- ras mutations were detected by single-strand conformation polymorphism analysis of polymerase chain reaction products and nucleotide sequencing. The results showed that K- ras mutation had occurred in one of 9 simple hyperplasias of pancreatic ductal epithelium, in 5 of 9 atypical hyperplasias, and in 4 of 8 intraductal carcinomas. The findings thus suggested that K- ras is activated in association with very early stage malignant transformation of pancreatic ductal cells in hamsters.     

Initiating Activity of Diethylnitrosamine in a Rapid Production Model for Pancreatic Carcinomas in Syrian Hamsters

The potential initiating activity of diethylnitrosamine (DEN) was studied in a rapid production model for pancreatic carcinogenesis in hamsters developed in our laboratory incorporating the principle of selection based on resistance to cytotoxicity, originally demonstrated for liver carcinogenesis in rats. Female Syrian golden hamsters were given DEN at a dose of 100 mg/kg body weight or N-nitrosobis-(2-oxopropyI)amine (BOP) at a dose of 70 mg/kg body weight as initiators followed by 3 cycles of augmentation pressure (choline-deficient diet combined with DL-ethionine, L-methionine upon return to basal diet and then administration of 20 mg/kg body weight BOP), and killed 10 weeks after the beginning of the experiment. DEN followed by the augmentation pressure induced a 65% incidence of total pancreatic lesions including 15% carcinomas, while BOP followed by the augmentation pressure induced 100% incidence of total pancreatic lesions and 84.2% for carcinomas. These yields were significantly greater than those observed for augmentation pressure alone. The results thus indicate that DEN possesses weak initiating activity for pancreatic carcinogenesis under the present experimental conditions.     

Initiating activity of diethylnitrosamine in a rapid production model for pancreatic carcinomas in Syrian hamsters.

The potential initiating activity of diethylnitrosamine (DEN) was studied in a rapid production model for pancreatic carcinogenesis in hamsters developed in our laboratory incorporating the principle of selection based on resistance of cytotoxicity, originally demonstrated for liver carcinogenesis in rats. Female Syrian golden hamsters were given DEN at a dose of 100 mg/kg body weight or N-nitrosobis-(2-oxopropyl)amine (BOP) at a dose of 70 mg/kg body weight as initiators followed by 3 cycles of augmentation pressure (choline-deficient diet combined with DL-ethionine, L-methionine upon return to basal diet and then administration of 20 mg/kg body weight BOP), and killed 10 weeks after the beginning of the experiment. DEN followed by the augmentation pressure induced a 65% incidence of total pancreatic lesions including 15% carcinomas, while BOP followed by the augmentation pressure induced 100% incidence of total pancreatic lesions and 84.2% for carcinomas. These yields were significantly greater than those observed for augmentation pressure alone. The results thus indicate that DEN possesses weak initiating activity for pancreatic carcinogenesis under the present experimental conditions.     

Promoting effects of both dietary cholesterol and cholestyramine on pancreatic carcinogenesis initiated by N-nitrosobis(2-oxopropyl)amine in Syrian golden hamsters.

The effects of dietary cholesterol and cholestyramine on pancreatic carcinogenesis initiated with N-nitrosobis(2-oxopropyl)amine (BOP) were investigated in 120 female Syrian golden hamsters. BOP (70 mg/kg body weight) was injected s.c. once at the beginning of the experiment. Starting 2 weeks later, the animals were then maintained on basal diet or diets containing either 0.5% cholesterol or 1% cholestyramine for a further 16 weeks. All surviving hamsters were killed at week 18, and the pancreas tissues examined histologically. The incidences of pancreatic carcinomas in hamsters fed cholesterol and the cholestyramine supplement were 40.0 and 30.0% respectively; in both cases significantly higher than the 6.9% incidence in the basal diet group. Cholesterol contents of the serum, pancreas and liver were significantly increased by cholesterol feeding and significantly decreased by the cholestyramine diet. The cholesterol diet also significantly increased pancreatic protein and DNA contents, and the concentration of total bile acids and the level of lithocholic acid in gallbladder bile. The cholestyramine diet significantly increased total pancreatic DNA and protein contents, and pancreatic weight. The results thus indicated that both dietary cholesterol and cholestyramine can enhance BOP-initiated pancreatic carcinogenesis in hamsters.     

Promoting effect of truncal vagotomy on pancreatic carcinogenesis initiated with N-nitrosobis(2-oxopropyl)amine in Syrian golden hamsters

The effect of truncal vagotomy (TV) on pancreatic carcinogenesis initiated with N-nitrosobis(2-oxopropyl)amine (BOP) was investigated in 81 female Syrian golden hamsters. The animals were divided into four groups according to the treatment, groups 1 and 2 serving as non-initiated controls receiving a single s.c. injection of 0.9% NaCl followed by either a sham operation or TV respectively, at week 2. Groups 3 and 4 were given a single s.c. injection of 70 mg/kg body wt of BOP before the sham operation or TV. All hamsters were killed at week 24, and the pancreas, liver and gall bladder tissues were examined histologically. While TV itself caused no significant change in pancreatic weight, the incidence of pancreatic carcinomas in hamsters from group 4 was 48.4%, significantly higher than the 16.7% evident in hamsters from group 3 (P less than 0.05). GLC analysis of the bile acid composition of gall bladder bile from hamsters not receiving carcinogen 1 and 4 months after TV revealed significantly decreased secondary bile acids. The results thus indicated that changes in bile acid composition may be involved in enhancement of BOP-initiated pancreatic carcinogenesis in hamsters by TV.     

Lack of influence of low blood cholesterol levels on pancreatic carcinogenesis after initiation with N-nitrosobis(2-oxopropyl)amine in Syrian golden hamsters

The effects of a cholesterol-free diet, a cholesterol-free dietsupplemented with sesamin, and a diet supplemented with sesaminon pancreatic carcinogenesis of N-nitrosobis(2-oxopropyl) amine(BOP) were investigated in 140 female Syrian golden hamsters.BOP (70 and 20 mg/kg body wt) was injected s.c. twice at aninterval of 2 weeks at the beginning of the experiment. Starting3 weeks thereafter, the animals were maintained on basal diet,cholesterol-free diet, basal diet plus sesamin, or cholesterol-freediet plus sesamin for a further 15 weeks. All surviving hamsterswere killed at week 18, and the pancreatic tissues examinedhistologically. The incidences of pancreatic neoplastic andpreneoplastic lesions in each group did not show any statisticallysignificant variation. The cholesterol-free diet significantlydecreased the cholesterol contents of the serum, pancreas andliver, and sesamin supplement significantly decreased the cholesterolcontents of the serum and liver. Both the cholesterol-free dietand sesamin decreased the serum lipoperoxide levels. The resultsthus indicated that low cholesterol per se and sesamin exertno significant influence on BOP-initiated pancreatic carcinogenesisin hamsters, at least within the 4 month period after carcinogentreatment.     

Carcinogenicity of heterocyclic amines for the pancreatic duct epithelium in hamsters.

Effects of eight heterocyclic amines (HCAs) on pancreatic duct carcinogenesis were investigated in a rapid production model in hamsters. N-Nitrosobis(2-oxopropyl)amine (BOP) was given to effect initiation, followed by augmentation pressure consisting of four daily i.p. injections of 500 mg/kg DL-ethionine, a choline-deficient (CD) diet, a single i.p. injection of 800 mg/kg L-methionine and a s.c. injection of 20 mg/kg BOP. After two cycles of augmentation pressure, the HCAs 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1), 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2), 2-amino-9H-pyrido[2,3-b]indole (AalphaC), 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeAalphaC) or 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline [4,8-DiMeIQx) were administered in the diet for 50 or 70 days. The numbers of pancreatic ductal hyperplasias (H) and a total lesions including, atypical hyperplasia (AH), carcinomas in situ (CIS) and invasive carcinomas, were increased in hamsters given the diet containing 0.02% Trp-P-1 for 50 days. This result was confirmed and extended by the finding of increased numbers of invasive carcinomas in hamsters given 0.02% Trp-P-1 for 70 days. The number and incidence of invasive carcinomas were also elevated in hamsters given the diet containing 0.06% 4,8-DiMeIQx for 50 days. These results suggest a possible involvement of Trp-P-1 and 4,8-DiMeIQx in pancreatic duct carcinogenesis.     

Cycles of repeated augmentation pressure in rapid production of pancreatic and cholangiocellular carcinomas in hamsters initiated with N-nitrosobis(2-oxopropyl)amine

We previously reported a rapid production model for pancreatic carcinoma development in Syrian hamsters incorporating the principle of selection by resistance to cytotoxicity. In the present experiment, the efficacy of repeated augmentation pressure with regard to generation of pancreatic lesions in hamsters initiated with N-nitrosobis(2-oxopropyl)amine (BOP) was investigated. Forty-eight female Syrian golden hamsters were divided into four groups according to the frequency of augmentation pressure. Group 1 received 70 mg/kg body weight of BOP and three injections of 20 mg/kg BOP. Groups 2-4 received 70 mg/kg BOP followed by one, two or three cycles of augmentation pressure consisting of dl-ethionine on sugar and salt diet, l-methionine and 20 mg/kg BOP. Hamsters were killed 10 weeks after the beginning of the experiment and the resultant incidences of pancreatic carcinomas from groups 1-4 were 0, 30, 50 and 46.2% respectively, the numbers of pancreatic carcinomas increasing with the frequency of augmentation pressure. A 46.2% yield of cholangiocarcinomas was also observed in group 4. The model should be useful for investigation of potential modulating factors since large numbers of lesions can be induced within a total experimental period of only 10 weeks.     

Dietary energy restriction does not inhibit pancreatic carcinogenesis by N-nitrosobis-2-(oxopropyl)amine in the Syrian hamster

Dietary energy restriction was previously shown to be effective in preventing a wide range of experimentally induced cancers. Studies were conducted to assess the influence on pancreatic carcinogenesis of dietary energy restrictions (reduced fat and carbohydrate) of 10%, 20% or 40% in comparison with control in Syrian hamsters treated with N- nitrosobis(2-oxopropyl)amine (BOP). Two carcinogenesis studies were conducted. One used a single treatment with 20 mg BOP/kg body weight and followed hamsters for 102 weeks following treatment, and the other used three weekly treatments of 20 mg BOP/kg body weight and followed hamsters for 45 weeks after treatment. Hamsters were fed control or energy restricted diet beginning the week following the last BOP treatment. Pancreatic carcinomas were induced in 9-18% of the hamsters in the first experiment and in 59-66% of the animals in the second. Dietary energy restriction did not influence carcinoma incidence in either study, and in the second experiment the multiplicity of tumors was higher in the 40% energy restriction (ER) group than in control hamsters. Plasma corticosterone was suppressed by BOP treatment, particularly in the 20% and 40% ER hamsters in the second experiment, and diet or BOP treatment did not significantly alter plasma cortisol. Pancreatic protein kinase Czeta measured by Western blot was highest in the cytosol and particulate fractions of the 40% ER hamsters in the first experiment. These results indicate that dietary energy restriction is not effective in the prevention of BOP induced pancreatic carcinogenesis in the Syrian hamster.      

Protective effects of benzyl isothiocyanate and sulforaphane but not resveratrol against initiation of pancreatic carcinogenesis in hamsters

Potential chemopreventive effects of naturally occurring agents were investigated using a new 16-week medium-term pancreatic carcinogenesis models in hamsters. Male 6-week-old Syrian hamsters were subcutaneously injected with 10mg/kg body weight N-nitrosobis(2-oxopropyl)amine (BOP) four times within a week, and fed a diet supplemented with 80ppm benzyl isothiocyanate (BITC), 80ppm sulforaphane (SFN) or 10ppm resveratrol (RES) during the initiation or post-initiation stages. For the initiation stage, each chemical was given for 3 weeks including 1 week before and after the BOP injections. With post-initiation exposure, the groups were changed from basal diet 1 week after the last BOP injection, and then fed each chemical for 14 weeks. All the animals were sacrificed after 16 weeks. The multiplicities of combined pancreatic lesions including atypical hyperplasias and adenocarcinomas were significantly decreased by BITC and SFN given in the initiation but not the post-initiation stage. On the other hand, RES, a naturally occurring inhibitor of cyclooxygenase-2 (COX-2) reported chemopreventive effects, failed to show significant effects on pancreatic carcinogenesis in either the initiation or post-initiation stages. Our data suggest that the naturally occurring isothiocyanates BITC and SFN can block BOP-initiation of hamster pancreatic carcinogenesis.     

Rapid production of pancreatic carcinoma by initiation with N-nitroso-bis(2-oxopropyl)amine and repeated augmentation pressure in hamsters

A rapid-production model incorporating the principle of selection by resistance to cytotoxicity demonstrated earlier for liver carcinogenesis in rats was established for pancreatic carcinoma development in Syrian hamsters. Adenocarcinomas were induced in 84% of treated animals by 10 weeks after initiation with 70 mg of N-nitroso-bis(2-oxopropyl)amine (BOP) per kg of body weight when augmentation pressure (choline-deficient diet combined with DL-ethionine and L-methionine and administration of 20 mg/kg BOP upon return to basal diet) was applied three times. A 52% yield of cholangiocellular tumors also resulted from this experimental protocol.     

Inhibitory effects of sulfation inhibitors on initiation of pancreatic ductal carcinogenesis by N-nitrosobis(2-oxopropyl)amine in hamsters

The effects of dehydroepiandrosterone sulfate (DHAS), a typicalhydroxysteroid sulfotransferase (HSTase) inhibitor, and of 3'-phosphoadenosine5'-phosphate (PAP), a nonspecific sulfation inhibitor on N-nitrosobis(2-oxopropyl)-amine(BOP)-induced initiation were examined in a rapid productionmodel for pancreatic carcinomas in hamsters in order to elucidatethe involvement of sulfotransferase in the metabolic activationof ß-oxypropylnitrosamines. While neither low norhigh doses of DHAS and PAP exerted any significant influenceon the incidence of ductal lesions including carcinomas, thehigh dose of DHAS (350 mg/kg body wt) and a both low (90 mg/kg)and high (180 mg/kg) doses of PAP reduced the mean numbers ofpancreatic ductal adenocarcinomas. The high dose of PAP alsoreduced the number of all ductal lesions combined. The resultsthus suggest that metabolic activation with STase is involvedin BOP-induced pancreatic ductal carcinogenesis in hamsters,and support the hypothesis that BOP is metabolized to ß-hydroxyalkylnitrosaminesfollowed by activation to proximate sulfuric acid esters byHSTase.     

Effects of 3-aminobenzamide on the post-initiation phase of N-nitrosobis(2-oxopropyl)amine induced pancreatic carcinogenesis in Syrian hamsters.

Effects of 3-aminobenzamide (ABA) on pancreatic carcinogenesis after initiation by N-nitrosobis(2-oxopropyl)amine (BOP) were investigated in Syrian hamsters. Animals were given BOP at a dose of 70 mg/kg body weight by subcutaneous injection and following a 2-week recovery period, were administered basal diet or basal diet containing 0.5, 0.75 and 1.5% ABA for 30 weeks. While the incidences of resultant pancreatic lesions, including hyperplasia, atypical hyperplasia and carcinoma, induced by BOP were not significantly influenced by ABA treatment, the mean numbers of those pancreatic lesions were significantly decreased in a dose-dependent way. The results therefore suggested the possible involvement of poly(ADP-ribosyl)ation in the post-initiation phase of pancreatic carcinogenesis in hamsters.     

Lack of inhibition by retinoids of bis(2-oxopropyl)nitrosamine-induced carcinogenesis in Syrian hamsters

Syrian hamsters were treated with either a low (10 mg/kg bodyweight) or high (40 mg/kg body weight) single dose of bis(2-oxopropyl)nitrosamine(BOP) and beginning 1 week later fed either low (0.2 mmol/kgdiet) or high (0.4–1.0 mmol/kg diet) levels of one offour retinoids [13 cis retinoic acid (13-cis-RA), N-ethylretinamide(ERA), N-(2-hydroxy- ethyl)retinamide (OHERA) or N-(phenyl)retinamide(PRA)] for periods of 40 or 50 weeks. The high retinoid levels(0.4–1.0 mmol/kg diet) fed following the highest BOP treatmentenhanced pancreatic carcinoma yields (average number/effectiveanimal) in males fed all four retinoids, and in females fedERA and 13-cis-RA. Enhanced adenoma yields were also seen inall groups when high retinoid levels were fed following 40 mgBOP/kg body weight. However, these retinoid levels caused anincreased adenoma yield in male hamsters only and did not modifycarcinoma yields when fed following 10 mg HOP/kg body weight.Similarly, tumor yields at extra-pancreatic sites were elevatedin refinoid-fed hamsters of both sexes after 40 mg BOP/kg bodyweight and in males fed ERA and 13-cis-RA after 10 mg BOP/kgbody weight when retinoids were given at the high levels (0.4–1.0mmol/kg diet). Increased incidences of bile duct and liver tumorsin particular were found in hamsters given 40 mg BOP/kg bodyweight. Consumption of retinoid levels of 0.4 mmol/kg diet andabove was also associated with a high incidence of liver cellnecrosis, ovarian cysts and ovarian hemorrhage. Retinoids (ERA,OHERA, and PRA) fed at the low level (0.2 mmol/kg diet) followingthe low BOP dose did not enhance carcinogenesis in the pan creasor at other sites and did not cause alterations in morphologicobservations.     

Usefulness of rapid production model for pancreatic carcinoma in male hamsters

The rapid production model of pancreatic duct adenocarcinoma established previously in female Syrian hamsters was applied to male hamsters to confirm the efficacy of the "augmentation pressure" procedure and to reveal sex difference in response to this procedure. Hamsters received 70 mg/kg N-nitrosobis (2-oxopropyl) amine (BOP) as an initiation and two cycles of "augmentation pressure" consisting of ethionine on a choline-deficient diet, methionine and BOP and an additional 20 mg/kg BOP and were killed 10 weeks after the beginning of the experiment. During the experimental period, 28% of the hamsters died and severe body weight loss was observed, however, incidence of pancreatic carcinomas reached 50% which is a significantly higher level than that in hamsters which received BOP without "augmentation pressure". A 66.7% yield of cholangiocellular tumors was also observed. The present result indicates that the "augmentation pressure" effected rapid production of pancreatic carcinoma in male hamsters in spite of sex difference in response.     

Modulation of dietary fat-promoted pancreatic carcinogenesis in rats and hamsters by chronic coffee ingestion

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.     

Effects of various prostaglandin synthesis inhibitors on pancreatic carcinogenesis in hamsters after initiation with N-nitrosobis(2-oxopropyl)amine

The effects of prostaglandin synthesis inhibitors on development of N-nitrosobis(2-oxopropyl)amine (BOP)-initiated pancreatic tumors were investigated. Female Syrian golden hamsters were given five weekly s.c. injections of BOP (10 mg/kg body weight) during the first 5 weeks and then given 20 p.p.m. indomethacin in the drinking water, 0.25% phenylbutazone in the diet, 1% aspirin in the diet, or no treatment (control group). The resultant incidence of pancreatic carcinoma at week 32 was significantly lower (P less than 0.05) in animals receiving phenylbutazone (36.8%) than in the controls (71.4%) and the numbers of carcinomas per hamster were significantly reduced by indomethacin (0.63) and phenylbutazone (0.58) treatment compared with the control group value (1.29). Aspirin also showed a tendency to decrease pancreatic tumor incidence, but this was not significant. Thus, prostaglandin synthesis inhibitors reduce the development of pancreatic cancer when administered during the post-initiation phase in this animal model.     

Effect of streptozotocin diabetes on development of nitrosamine-induced pancreatic carcinoma when diabetes induction occurs after nitrosamine exposure

Diabetes mellitus has been suggested as a possible risk factorfor the development of pancreatic cancer in humans. Previousstudies in our laboratory have shown, however, that streptozotocin(STZ) diabetes inhibits the development of cancer of the exocrinepancreas in hamsters when STZ is administered prior to treatmentwith the pancreatic carcinogen N-nitrosobis(2-oxopropyl)amine(BOP). It has been reported by others that the concurrent administrationof BOP and STZ enhances pancreatic carcinogenesis in hamsters.The purpose of the present study was to determine the effectof STZ diabetes on the development of BOP-induced pancreaticcarcinoma when STZ is given following exposure to BOP. Groupsof Syrian golden hamsters were treated with either BOP only(single s.c. injection, 40 mg/kg body wt at week 0), BOP (singles.c. injection, 40 mg/kg body wt at week 0) plus STZ (50 mg/kgbody wt x3 daily i.p. doses at weeks 10, 20 or 30), STZ only(50 mg/kg body wt x3 daily i.p. doses at weeks 10, 20 or 30),or neither BOP nor STZ. The experiment was terminated at 40weeks after BOP treatment. No significant difference was seenin the incidence of pancreatic cancer between those animalsreceiving BOP only at week 0 and those receiving BOP at week0 plus STZ at weeks 10, 20 or 30 of the study. The results wouldappear to indicate that STZ diabetes, established after BOPtumor initiation, plays no apparent role in the modulation ofpancreatic carcinogenesis.     

Inhibition by methionine of pancreatic carcinogenesis in hamsters after initiation with N-nitrosobis(2-oxopropyl) amine

The modifying effects of dietary L-methionine in the post-initiation phase of pancreatic carcinogenesis were investigated in hamsters treated with N-nitrosobis(2-oxopropyl)amine (BOP). Groups consisting of 20 and 30 animals, respectively, were given BOP subcutaneously, once a week five times at a dose of 10 mg/kg body wt. and then continuously fed diet supplemented with 2% (group 1) or 0% (group 2) methionine (weeks 5-32). After five subcutaneous injections of saline, group 3 animals were similarly fed diet supplemented with 2% methionine for the same period. The incidence of pancreatic ductal adenocarcinomas was significantly lower in group 1 (36.8%, P<0.05) than in group 2 (71.4%). Multiplicity of adenocarcinomas was also significantly lowered (0.52 and 1.28/hamster, P<0.05). Similarly, total numbers of combined adenocarcinomas and dysplastic lesions were significantly decreased in group 1 (2.05, P<0.05) as compared with group 2 (3.67). Methionine enhanced atrophic change of pancreatic acinar cells in hamsters given BOP, indicating that the inhibitory effects on the post-initiation stage of BOP-induced pancreatic carcinogenesis in hamsters could be generally linked to suppression of growth.