BOP Injection Research Articles

Effects of cigarette smoke on N-nitrosobis(2-oxopropyl)amine-induced pancreatic and respiratory tumorigenesis in hamsters.

Influences of cigarette smoke on N‐nitrosobis(2‐oxopropyl)amine (BOP)‐induced pancreatic duct and respiratory tract tumorigenesis were investigated using a hamster two‐stage carcinogenesis model. Male 5‐week‐old hamsters were divided into 5 groups. Group 1 was s.c. injected with BOP at a dose of 10 mgAg once a week for 3 weeks as an initiation treatment together with cigarette smoke exposure over the same 4‐week period. Group 2 was exposed to cigarette smoke for 26 weeks after the BOP‐initiation. Groups 3 and 4 were respectively given the BOP‐initiation alone and the 26‐week cigarette smoke exposure without initiation. Group 5 served as a sham‐smoked negative control. The experiment was terminated 30 weeks after the first BOP injection. The incidence of pancreatic adenocarcinomas was significantly decreased in Group 1 as compared to the Group 3 value (P < 0.01) while the Group 2 value did not show any change. In contrast, the incidence of laryngeal and tracheal proliferative lesions (hyperplasias and papillomas) was significantly increased in Group 2 over Group 3 (P<0.01). The incidence of pulmonary hyperplasias was also increased in Group 2 over Group 3 (P<0.05), although that of pulmonary adenomas or adenocarcinomas was decreased in Group 2 as compared to the Group 3 value (P<0.01). Cigarette smoke exposure in the BOP‐initiation phase (Group 1) did not affect the development of respiratory proliferative lesions. No animals in Groups 4 and 5 developed any tumors in the pancreas or respiratory tract. Our results thus indicate that cigarette smoke exposure inhibits pancreatic carcinogenesis when given in the initiation phase, whereas it modulates (enhances or suppresses) the development of proliferative lesions in the respiratory tract if applied during the promotion stage to hamsters pretreated with BOP.

Analysis of proliferative activity in renal lesions induced by N-nitrosobis(2-oxopropyl)amine (BOP) in male Syrian golden hamsters

Binding of a specific antibody to proliferating cell nuclear antigen (PCNA) and staining of argyrophilic proteins associated with nucleolar organizer regions (AgNORs) were investigated in proliferative lesions induced by N-nitrosobis(2-oxopropyl)amine (BOP) in the hamster kidney. Thirty male Syrian golden hamsters were given three weekly s.c. injections of BOP (10 mg/kg body wt.) and sacrificed for characterization of proliferative changes 30 weeks after the first BOP treatment. Morphologically, lesions of the tubular epithelia were classified either as tubular adenoma or dysplasia, the latter being further classified into small cluster, acidophilic cell, clear cell and cystic types. Immunohistochemistry for PCNA revealed significant increases of cell proliferation activity in adenomas and acidophilic cell types of dysplasia, along with significantly elevated mean numbers of AgNORs per nucleus. The results thus indicate that the acidophilic cell type of dysplasia may be of prime significance as the preneoplastic renal lesion induced by BOP.

Promoting effects of ethinyl estradiol on development of renal proliferative lesions induced by N-nitrosobis (2-oxopropyl)amine in female Syrian golden hamsters.

The modulating effects of female sex hormones, ethinylestradiol and levonorgestrel, on the development of renal proliferative lesions after initiation with N-nitrosobis(2-oxopropyl)amine (BOP) were investigated. Three groups of female Syrian golden hamsters, each comprising 30 animals, were given four weekly s.c. injections of BOP (10 mg/kg body weight) and then fed diet containing 1 ppm ethinylestradiol (group 1: BOP/EE), diet containing 10 ppm levonorgestrel (group 2) or basal diet (group 3) for the next 27 weeks. As hormone controls, two groups of 20 female hamsters each received diet containing 1 ppm ethynylestradiol (group 4) and 10 ppm levonorgestrel (group 5) from week 3 for 27 weeks without the prior initiation treatment. The severity of diffuse anisokarya, characterized by varied nuclear size and the incidence of dysplasias of the proximal tubular epithelia induced by BOP, were significantly increased in the BOP/EE group, indicating the promoting effects of the hormone. In the renal dysplastic lesions (small-cluster, cystic, clear-cell and acidophilic cell types), adenomas and nephroblastomas, increases in the numbers of argyrophilic proteins associated with nucleolar organizer regions (NOR) in the nucleus, suggesting a high proliferative activity, were seen in dysplasia of acidophilic cell types and adenomas. In addition, the number of bizarre NOR per nucleus was significantly higher in adenomas than in dysplasias and highest in nephroblastomas. This morphological change in NOR should therefore be a useful parameter for the diagnosis of malignancy of renal tumors.

Blocking Effects of Synthetic Trypsin Inhibitor (Camostat) on Pancreatic Carcinogenesis in Hamsters Initiated with N-Nitrosobis(2-oxopropyl)amine

The effects of concomitant administration of a synthetic trypsin inhibitor (camostat) on pancreatic carcinogenesis in hamsters treated with N-nitrosobis(2-oxopropyl)amine (BOP) were investigated. Thirty-two female Syrian golden hamsters were given weekly 10 mg/kg s.c. injections of BOP for 5 weeks while simultaneously receiving a 500 ppm camostat diet (BOP + camostat group). Additional groups of 30 animals received either the s.c. injections of BOP (BOP group), or the 500 ppm camostat diet (camostat group) during the same 5-week period. Thirty weeks after the first BOP administration, the incidence of pancreatic adenocarcinomas in the BOP + camostat group was significantly lower than in the group administered BOP only (p < 0.05). Similarly, the total numbers of pancreatic adenocarcinomas or dysplastic lesions were significantly decreased in the BOP + camostat group as compared with the BOP group (p < 0.01). None of the animals receiving camostat alone developed any adenocarcinomas or dysplastic lesions of the pancreas. The results of the present experiments clearly show that camostat can inhibit induction of hamster pancreatic ductal neoplasms when administered simultaneously with BOP.

Effects of caffeine, nicotine, ethanol and sodium selenite on pancreatic carcinogenesis in hamsters after initiation with N-nitrosobis(2-oxopropyl)amine.

The modulating effects of caffeine, nicotine, ethanol and sodium selenite on development of N-nitrosobis(2-oxopropyl)-amine (BOP)-initiated pancreatic tumors were investigated. Female Syrian golden hamsters were given s.c. injections of BOP (10 mg/kg body weight) or saline alone once a week for 3 weeks and then administered 2000 p.p.m. caffeine, 25 p.p.m. nicotine, 20% ethanol or 4 p.p.m. sodium selenite in their drinking water for the next 37 weeks. Control animals were given tap water alone after BOP initiation. Only the BOP-treated groups developed pancreatic adenocarcinomas and dysplasias. The multiplicity of pancreatic carcinomas was significantly higher (P less than 0.05) in animals receiving caffeine than in the controls. In addition, caffeine treatment slightly increased the incidence of carcinomas. Nicotine and ethanol also showed tendencies to enhance pancreatic carcinogenesis, although there were statistically no significant differences regarding lesion development. In contrast, sodium selenite administration was associated with a tendency for a decrease in the number of carcinomas and dysplasias. Thus, among these chemicals of obvious significance to human life-style, caffeine enhanced the development of pancreatic tumors when administered during the post-initiation phase in this hamster model.

Inhibitory effects of crude soybean trypsin inhibitor on pancreatic ductal carcinogenesis in hamsters after initiation with N-nitrosobis(2-oxopropyl)amine.

The effects of soybean trypsin inhibitor (SBTI) administration during the promotion phase of pancreatic carcinogenesis were investigated. Female Syrian golden hamsters were given three weekly s.c. injections of N-nitrosobis(2-oxopropyl)amine (BOP) each at a dose of 10 mg/kg and then administered 5% SBTI diet for the following 37 weeks. Additional groups of animals received the BOP injection alone or the 5% SBTI diet alone as controls. At week 40 of the experiment, all surviving animals were killed and development of pancreatic lesions was assessed histopathologically. The results showed that the incidence of dysplastic lesions in hamsters of the BOP/SBTI group was significantly decreased as compared to that of the BOP group (P < 0.01). A similar but not significant tendency was also found for pancreatic adenocarcinomas. In addition, the number of dysplastic lesions in the pancreas head portion in the BOP/SBTI group were significantly decreased as compared to the BOP group value (P < 0.05). Furthermore, atrophic changes of the pancreatic exocrine tissue were more severe in the BOP group than in the BOP/SBTI group (P < 0.01), indicating that SBTI treatment gave effective protection against the replacement process of acinar cell induced by BOP. Thus, the present experiment demonstrated that SBTI can inhibit hamster pancreatic ductal carcinogenesis when given in the promotion phase, in clear contrast to the enhancing effects reported for preneoplastic acinar lesion development in rats.

Inhibitory effects of soybean trypsin inhibitor on induction of pancreatic neoplastic lesions in hamsters by N-nitrosobis(2-oxopropyl)amine

The effects of simultaneous soybean trypsin inhibitor (SBTI) treatment on initiation of pancreatic carcinogenesis by N-nitrosobis(2-oxopropyl)amine (BOP) were investigated. Female Syrian golden hamsters were given five weekly s.c. injections of BOP at a dose of 10 mg/kg while being administered a diet containing 5% SBTI for 5 weeks (BOP + SBTI group). Two other groups of 30 animals each received the s.c. injections of BOP or the 5% SBTI diet for the same period, alone (BOP and SBTI groups respectively). Total numbers of pancreatic dysplastic lesions in hamsters of the BOP+SBTI group were significantly decreased as compared to the BOP group values, though the incidences of pancreatic adenocarcinomas were not significantly different. Atrophic changes were, however, more severe in the BOP group than in the BOP+SBTI group pancreatic exocrine tissue, showing that treatment with SBTI was effective for protection of acinar cells from carcinogen toxicity.

Inhibition by selenium of intrahepatic cholangiocarcinoma induction in Syrian golden hamsters by N'-nitrosobis(2-oxopropyl)amine.

The effects of selenium supplementation on induction of cholangiocarcinomas and related precancerous lesions in female Syrian Golden hamsters by N'-nitrosobis(2-oxopropyl)amine (BOP) were investigated. Four-week-old animals were divided into two groups according to the selenium level contained in the drinking water (0.1 ppm or 4.0 ppm) and fed a purified diet containing less than 0.05 ppm of the trace element. Starting at Week 4 of the experiment, hamsters were administered 10 weekly injections of BOP (10 mg/kg body wt) and then killed 18 weeks after the last carcinogen administration. Animals receiving physiological saline alone served as controls. Cholangiocellular carcinomas tended to be reduced, and putative preneoplastic lesions of cholangiofibrosis were significantly decreased in the high-as opposed to the low-selenium groups in terms of both incidence rate and number per effective animal. The respective high and low selenium values for incidence and number were 24/38% and 0.34/0.66, respectively, for cholangiocarcinomas and 50/89% and 1.21/8.44, respectively, for cholangiofibroses. Proliferation of intrahepatic bile ducts was also significantly inhibited in the high-selenium group along with cyst formation. Biochemical investigation revealed both selenium level and glutathione peroxidase activity to be significantly greater in the high-than in the low-selenium group livers. The results thus suggest that selenium may inhibit BOP-induction of bile duct lesions, possibly via glutathione peroxidase-mediated alteration of carcinogenesis.

Evaluation of combination effects of three carcinogens at low dose: Initiation of pancreatic ductal carcinogenesis in a Syrian hamster rapid production model.

Combination effects of low doses of three carcinogens, N-nitrosobis (2-oxopropyl) amine (BOP), N-methyl-N-nitrosourea (MNU), and diethylnitrosamine (DEN) on initiation of pancreatic ductal carcinogenesis were examined using a rapid production model in female Syrian hamsters. Groups of animals received intraperitoneal injections of BOP, MNU, and DEN at doses of 20, 10, and 20mg/kg body weight, respectively, either alone or in combination as initiators, followed by three cycles of augmentation pressure, established earlier to cause selective growth of initiated cell populations. All hamsters were sacrificed 10 weeks after the commencement and pancreatic duct lesions were histopath-ologically diagnosed. The low single dose of 20mg/kg body weight of BOP still retained relatively strong initiating activity resulting in substantial induction of ductal adenocarcinomas 67%, while neither MNU nor DEN alone exerted significant initiating activity under the present experimental conditions. Combined administration of these three carcinogens either simultaneously or serially at intervals of one day exhibited no significant synergism, with the incidences and mean numbers of ductal lesions being almost the same as those of the BOP alone group. Thus, under the present experimental conditions, BOP, MNU, and DEN exerted no synergism regarding initiation of pancreatic ductal carcinogenesis in hamsters.

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.

Experimental pancreatic cancer in the Syrian hamster: effect of cholecystectomy.

Because cholecystectomy stimulates hypertrophy and hyperplasia in the hamster pancreas, its effect on experimental pancreatic carcinogenesis was studied in this animal model. Forty female Syrian hamsters underwent cholecystectomy, while 40 others underwent sham operations. Two weeks later, 30 hamsters undergoing cholecystectomy and 30 hamsters undergoing sham operations received 4 weekly subcutaneous injections of N-nitroso-bis (2-oxopropyl) amine (BOP) (10 mg/kg). Remaining hamsters (n = 20) received equal volumes of 0.9% saline solution. A further 10 hamsters (controls) underwent no surgery and received no injections. Thirty weeks after the first BOP or saline injection the pancreas of hamsters that had undergone cholecystectomy was only 3% heavier than that of sham-operated animals, and there was no difference in the incidence of pancreatic cancer between BOP-treated hamsters that had undergone cholecystectomy and those that had undergone sham operations. In this study, cholecystectomy had no influence on BOP-induced pancreatic carcinogenesis in the Syrian hamster.

Effects of the Interaction of Dietary Fat and Protein on &lt;italic&gt;N&lt;/italic&gt;-Nitrosobis(2-oxopropyl)amine-Induced Carcinogenesis and Spontaneous Lesions in Syrian Golden Hamsters&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;

Syrian golden hamsters were fed four diets in experiments designed to evaluate the effects of the interaction of dietary fat and protein on carcinogenesis induced by N-nitrosobis(2-oxopropyl)amine [(BOP) CAS: 60599-38-4]. The diets consisted of two levels of dietary fat [4.5 g (low fat, LF) or 18 g (high fat, HF) of corn oil/385 kilocalories (kcal)]. These levels were fed with each of two levels of dietary protein [9 g low-protein (LP) and 36 g high-protein (HP) casein/385 kcal]. The four diets were fed to two separate groups of hamsters at two different periods in their life-span. For testing of the effects of diet on tumor initiation, one group received the diets from 3 to 7 weeks of age. At 8 weeks, they were given injections sc of 10 mg BOP/kg body weight and placed on a control diet [9 g corn oil (medium fat) and 18 g casein (medium protein)/385 kcal]. The other group received control diet until 8 weeks of age, at which time they were given injections of BOP and placed on the four diets. This group was designed to test the effects of the diets on tumor development. BOP-induced lesions in the lungs, liver, common bile duct, gallbladder, and kidneys are described; results in the pancreas were reported separately. In hamsters fed the four diets after BOP treatment, the LF-LP groups had the fewest tumors, the LF-HP-fed and HF-LP-fed groups had intermediate yields of tumors, and the hamsters given HF-HP diet exhibited the largest numbers of neoplasms. Several specific tumor types showed a similar pattern. For example, the pulmonary adenoma incidence, which was low in the non-BOP-treated hamsters, was higher in the HF-HP group than in those fed LF-HP diet after BOP, but it was not influenced by fat at the LP level. In addition, renal adenomas were observed at a low incidence in non-BOP-treated hamsters and in hamsters fed LF-LP levels before or after BOP treatment (0.5% incidence) but were present at an 8% incidence in all other BOP-treated groups. The incidence of biliary cystic adenomas was highest in male hamsters that received HF diets, irrespective of BOP treatment, and BOP treatment resulted in increased yields of this lesion in females only in groups given HF-LP diet.(ABSTRACT TRUNCATED AT 400 WORDS)

Effect of dibutyltin dichloride on incidence of pancreatic adenocarcinoma induced in hamsters by a single dose of N-nitrosobis(2-oxopropyl)amine

The effects of timing of a single intragastric application of dibutyltin dichloride, at a dosage of 30 mg/kg body wt, on N-nitrosobis(2-oxopropyl)amine (BOP)-induced pancreatic carcinomas have been studied in female Syrian golden hamsters. Dibutyltin dichloride, which has been shown to produce selected bile duct injury, was administered either 1 week before or 1 week after a single injection of BOP (20 mg/kg body wt). Control hamsters were injected with BOP alone or were given dibutyltin dichloride alone. The incidence of ductal adenocarcinomas strikingly decreased in hamsters when dibutyltin dichloride was ingested after BOP treatment, but remained unaffected when dibutyltin dichloride was given before carcinogen treatment. Two cases of sarcoma were observed in the group treated with dibutyltin dichloride before BOP injection. The incidence of insulomas, which were considered as spontaneous tumors, was not influenced by dibutyltin dichloride. These results showed that intragastric application of dibutyltin dichloride after BOP treatment significantly reduced the induction of pancreatic cancer. These findings do not support speculations based on epidemiologic studies as to a promoting effect of cholestasis.

Modification of Pancreatic Carcinogenesis in the Hamster Model. IX. Effect of Pancreatitis&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;

The effect of acute and recurrent pancreatitis was investigated in pancreatic cancer induction by N-nitrosobis(2-oxopropyl)amine (BOP) in Syrian golden hamsters. For the correlation of the cellular alteration with carcinogenesis, BOP (20 mg/kg body wt) was injected once sc into hamsters at day 3 (group 2), week 1 (group 3), and week 8 (group 4), corresponding to cellular degeneration, regeneration, and healing, respectively. Additional groups received BOP 30 minutes before common duct ligation for 48 hours (group 1) or before repeated induction of pancreatitis at 4 weekly intervals for 4 weeks (group 5). Group 6 was a pancreatitis control. Two groups of hamsters received BOP only, at the age of 8 weeks (group 7, which served as a BOP control for groups 1-3 and 5) or at the age of 16 weeks (group 8, the control for group 4). Hamsters were killed 46 weeks after BOP injection (with the exception of group 1 animals, which were killed 52 wk after BOP) to guarantee the same postcarcinogen exposure time in each group. The results showed that BOP, when given during cellular degeneration (group 2) and healing (group 4), induced significantly fewer carcinomas than in the control groups, whereas the tumor pattern was not affected when BOP was given before pancreatitis induction (group 1) or at the time of cellular regeneration (group 3). Recurrent pancreatitis (group 5), however, resulted in carcinomas significantly larger in number and size than those in control group 8. A significantly higher incidence of carcinomas occurred in group 8 controls (treated with BOP at the age of 16 wk) compared to the incidence in group 7 controls (treated with BOP at the age of 8 wk).

Interaction of Dietary Fat and Protein on Pancreatic Carcinogenesis in Syrian Golden Hamsters&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;

The role of interactions between dietary fat and protein in experimental pancreatic cancer was determined in Syrian golden hamsters treated with N-nitrosobis(2-oxopropyl)amine (BOP). Two levels of corn oil [4.5 and 18 g/385 kilocalorie (kcal)] were fed with each of two levels of casein (9 g/385 kcal and 36 g/385 kcal), either before or after a single sc injection of BOP (10 mg/kg body wt) at 8 weeks of age. Control diet was fed at other times (9 g corn oil and 18 g casein/385 kcal). The pancreatic ductular carcinoma incidence and multiplicity (average No. of tumors/tumor-bearing animals) increased as dietary fat and protein levels rose in hamsters fed the four diets after carcinogen treatment. Enhanced carcinogenesis by high-fat (HF) diets occurred only in hamsters fed the high-protein (HP) level, and protein effects were seen only with the HF diets. The low-fat-low-protein (LF-LP) diet inhibited pancreatic carcinogenesis among the hamsters given the four diets before BOP treatment. Pancreatic adenoma yields were elevated in hamsters given either HF or HP diets following BOP treatment, by comparison with the low levels. However, when diets were fed before BOP treatment, an increased yield occurred with the rise in protein, but the yield was reduced in males with the increase in fat. Acinar cell nodules were observed primarily in hamsters fed LP levels after BOP, and their multiplicity was highest in those given the HF diet. The interaction between dietary fat and protein demonstrated the interdependence of the effects of these two nutrients on pancreatic carcinogenesis in hamsters.

Modifying Factors in Pancreatic Carcinogenesis in the Hamster Model. IV. Effects of Dietary Protein&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;

The possible effects of dietary protein on pancreatic cancer induced in outbred Syrian golden hamsters by N-nitrosobis(2-oxopropyl)amine (BOP) were studied. Three levels of casein as protein at low [LP = 9 g/385 kilocalories (kcal)], medium (MP = 18 g/385 kcal), or high levels (HP = 36 g/385 kcal) were fed in two sequences to 4 groups of hamsters. The effects of protein level on the initiation phase of BOP carcinogenesis were examined in hamsters fed LP or HP from 3 through 7 weeks of age, followed by MP for the remainder of their lives. The role of protein level on the promotional (developmental) phase of carcinogenesis was evaluated in hamsters fed (from 3 through 7 wk of age) MP, followed by LP or HP for the rest of their lives. One-half of the hamsters from each of the 4 groups received a single sc BOP injection (10 mg/kg body wt) at 8 weeks of age. Changes in diet from one type to the other occurred 2 days after BOP treatment. An MP diet fed before and after BOP served as the experimental control diet. The results demonstrated that the LP diet inhibited the developmental phase of carcinogenesis only in females, whereas the MP and HP diets did not affect initiation or promotion of cancer in either sex. The inhibitory effect of the LP diet in pancreatic carcinogenicity only in females calls for further studies.

Modification of pancreatic carcinogenesis in the hamster model. 5. Effect of partial pancreatico-colostomy.

Studies were conducted to evaluate the possibility of a bile reflux mechanism in the etiology of induced pancreatic cancer. N-Nitrosobis(2-oxopropyl)amine (BOP) was administered to Syrian hamsters after partial pancreatico-colostomy. Either the gastric or the splenic lobe of the pancreas was anastomosed to the transverse colon in groups 1 and 2, respectively. Group 3 were sham-operated controls and group 4 were controls without surgery. Shortly after surgery all 4 groups received a single subcutaneous BOP injection (20 mg/kg body weight) and survivors were sacrificed 46 weeks after BOP treatment. BOP-induced pancreatic tumor patterns were not altered by pancreatico-colostomy when compared with those in sham-operated controls. In all BOP-treated hamsters the number and distribution of benign and malignant lesions were similar in each individual pancreatic segment, including the anastomosed lobe (A-lobe); some hamsters developed tumors only in the A-lobe. As in other pancreatic regions, the initial hyperplasia in the A-lobe primarily affected peri- and intra-insular ductules and less frequently involved the ducts. These findings support the theory that the carcinogen is bloodborne and indicate that BOP-responsive pancreatic cells are distributed on a volume basis in distinct proportions within the pancreatic segments. As in previous experiments a higher incidence of pancreatic neoplasms was found in BOP-treated controls (those not operated upon) than in partially pancreatico-colostomized hamsters, including those with sham operations. Hyperplastic and dyplastic development of colonic mucosa around the anastomosis could be related to a local effect of carcinogen or of its metabolites, which are known to be excreted via pancreatic secretions.