Effect of rofecoxib on colon chemical carcinogenesis at colonic anastomotic area in the rat.

AIM: To investigate the effect of the selective cyclooxygenase-2 (COX-2) inhibitor rofecoxib on the incidence of perianastomotic colonic tumors in a model of chemical carcinogenesis in the rat. EXPERIMENTAL DESIGN: Experimental study with 45 male Sprague-Dawley rats randomly assigned to one of three groups: control (n = 15) with colocolic anastomosis and chemical carcinogenesis with 1-2 dimethylhydrazine (1-2 DMH); rofecoxib 0.0027% (n = 15) with colonic anastomosis, chemical carcinogenesis and the addition of dietary rofecoxib at doses of 27 parts per million (ppm), and rofecoxib 0.0058% (n = 15) with colonic anastomosis, chemical carcinogenesis and the addition of dietary rofecoxib at doses of 58 ppm. Carcinogenic induction was performed with 1-2 DMH at a weekly dose of 25 mg/kg of weight for 18 weeks, and colonic tumors induced were analyzed in postoperative week 20. The main parameter evaluated was the percentage of colonic neoplastic tissue, which relates tumor surface area to the colon's surface area. RESULTS: Rofecoxib at doses of 2.5 mg/kg or 0.0058 ppm significantly reduced chemical colon carcinogenesis in rats, both in the perianastomotic area and the rest of the colon (p < 0.01). In the extra-anastomotic area, rofecoxib at doses of 2.5 mg/kg has significantly greater inhibitory effect than rofecoxib in doses of 1.2 mg/kg or 0.0027 ppm (p < 0.005). CONCLUSIONS: Rofecoxib causes a reduction in chemical colon carcinogenesis in rats. This effect is sustained in the perianastomotic area, and the investigation of its role in operated colorectal cancer with risk of locoregional recurrence may therefore be of interest.     

Influence of the surgical manipulation of the colon in colonic induced carcinogenesis in rats.

AIM: to investigate the influence of different experimental manipulations in a model of colonic experimental carcinogenesis with pharmacological induction in the rat. EXPERIMENTAL DESIGN: a total of 90 Sprague-Dawley male rats, divided into three groups, were used: non-surgical (n = 30); surgical with colonic trauma (n = 20), and surgical with colo-colonic anastomosis (n = 40). Carcinogenic induction was carried out with 1-2 dimethylhydrazine dihydrochloride. Colonic adenocarcinomas were identified and the number of tumors, as well as tumoral surface and percentage of tumoral surface was established. One-way ANOVA and Chi-square were employed for the statistical analysis. RESULTS: the number of tumors was greater in the surgical group than in the control group, and tumors preferentially developed around the manipulated colon. Surface and tumoral percentage were greater in the surgical group than in the control group, being also greater in the anastomosis group than in the group with colonic trauma. Within anastomosis groups, a greater tumor surface and percentage was found in the group with titanium than in the group with reabsorbable material. CONCLUSIONS: the experimental manipulation of the colon in rats enhances drug-induced colon carcingenesis. The creation of an anastomosis further increases the carcinogenic process compared with simulated anastomosis. This process is also enhanced by the quantity of suture material included in the anastomosis, and by the non-reabsorbable nature of the materials used in the anastomotic line.     

Methane excretion and experimental colonic carcinogenesis

To examine the association between methane (CH4) excretion and experimental colonic carcinogenesis, we measured CH4 excretion in rats treated with the colonic carcinogen azoxymethane (AOM, 7 mg/kg weekly for 10 weeks) and paired controls. CH4 excretion was not initially detected in either experimental or control groups, but all animals acquired positive CH4 excretion status by time of sacrifice (week 26). There was no difference between groups or among AOM-treated animals with and without tumors in the median time to onset of detectable CH4 excretion or in the amount of CH4 excreted. Our results fail to provide support for a link between CH4 excretion and experimental colonic dysplasia or adenocarcinoma.     

Proliferative instability and experimental carcinogenesis at colonic anastomoses.

The possibility that proliferative instability around a healing anastomosis promotes carcinogenesis was tested in 234 male Sprague-Dawley rats. Animals received the first of five weekly injections of azoxymethane (total dose 50 mg/kg) either immediately after transection of the descending colon or at 2, 4, 8, and 12 weeks later; controls received handling of the bowel alone. Crypt cell proliferation was assessed by autoradiography following 3HTdR injection. An overall increase in tumour yields in all transection groups was due solely to the frequent presence of anastomotic tumours. Changes in crypt morphometry and labelling index were most marked in crypt positions 1-10 away from the anastomosis. Crypts at this site increased in height at 2, 4, and 8 weeks (p less than 0.001) but returned to normal values by 12 weeks. Likewise, labelling index was increased at 2, 4, and 8 weeks (p less than 0.001) and remained higher at 12 weeks (p less than 0.05). Increased crypt cell proliferation in the immediate vicinity of an apparently 'healed' colonic anastomosis may explain its persisting susceptibility to carcinogenesis.     

Dietary lipids and experimental colonic carcinogenesis. Critical review of the literature

Colon cancer is one of the most common tumours observed in the western population for which the relationship between epidemiological and laboratory findings and an overall assessment of the influence of diet on carcinogenesis is not straightforward. The aim of this review is to evaluate critically the experimental data which suggest a positive modulating effect of dietary lipids. Although a great number of data are available on the relation between the nature of fat in diet and colon cancer, no clear conclusions can be drawn from their analysis. The lack of consistent findings is due to the discrepancy of the results which may have arisen from methodological differences between the studies. Concerning the influence of the amount of dietary fat on colon cancer, it has been demonstrated that a high fat diet could increase the incidence and the number of colonic tumours in rats. Nevertheless, this positive modulating effect could be seen provided the fat amount in the diet was at least 20% (w/w). This observation is of first importance for colon cancer prevention and must be confirmed for fat of various nature. Systematic dose-effect studies are necessary. The question whether the effect of dietary fat on carcinogenesis is due to the specific action of fat or to an associated caloric effect has been raised several times. Although the previous studies concerned the role of caloric intake versus fat intake in carcinogenesis, the observed effects might have been due to a change in body weight or to changes in other dietary components such as non nutritive fibre, protein and micronutrients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Enhanced colonic carcinogenesis with azoxymethane in rats after pancreaticobiliary diversion to mid small bowel.

Since biliary excretion of metabolites might determine the pattern of intestinal neoplasms induced by azoxymethane, the number and distribution of tumors were studied in rats after pancreaticobiliary diversion to the mid small bowel. Pancreaticobiliary diversion was performed either immediately before the first of 16 weekly injections of azoxymethane or 10 days after the last. Seven months after pancreaticobiliary diversion, persistent ileal hyperplasia was manifested by higher levels of mucosal RNA and DNA compared with controls (34--102%: P less than 0.001), while there was little residual adaptation in the colon. Qualitative and quantitative analysis of fecal bile acids 6--26 wk after pancreaticobiliary diversion showed few differences. Pancreaticobiliary diversion doubled the incidence of colonic tumors, whether operation preceded (P less than 0.005) or followed (P less than 0.02) the course of azoxymethane. Suture-line tumors were common in the small bowel, particularly in the transposed duodenal stump. Despite intense ileal hyperplasia as a consequence of pancreaticobiliary diversion, the ileum remained resistant to chemical carcinogenesis. The potentiation of colonic neoplasms by pancreaticobiliary diversion probably depends on the stimulation of colonic mucosal proliferation.     

Effect of hypercholesterolemia on experimental colonic anastomotic wound healing in rats

AIM: To evaluate the mechanical and biochemical parameters of colonic anastomotic healing in hypercholesterolemic rats. METHODS: Sixty rats were divided into two groups of 30 each according to their dietary regimens. The test group was fed with a high cholesterol-containing diet for two months while the control group had standard diet. These two groups were further divided into three subgroups consisting of ten rats each. After hypercholesterolemia was established, left colon resection and anastomosis were performed in both groups and samples from liver and abdominal aorta were taken to evaluate the systemic effects of hypercholesterolemia. Anastomotic wound healing, blow-out pressures and tissue hydroxyproline levels were evaluated. RESULTS: The test group had a significant weight gain in two months. Microscopic examination of the abdominal aorta revealed no atherosclerotic change in none of the groups, but liver tissue specimens showed significant steatosis in the test group. Tissue hydroxyproline levels and anastomotic blow-out pressures were significantly lower in the test group than in the controls. CONCLUSION: Hypercholesterolemia not only increases hydroxyproline levels and blow-out pressures but also worsens anastomotic wound healing.     

Elevated plasma enteroglucagon alone fails to alter distal colonic carcinogenesis in rats

The effect of physiologic increases of plasma enteroglucagon, induced by massive bypass or resection of small bowel, on large bowel cell turnover and carcinogenesis was studied in rats in which the distal colon was isolated as a mucous fistula. After injections of azoxymethane, either 85% end-to-side jejunoileal bypass, 85% jejunoileal resection, or sham bypass was performed. Controls underwent colonic transection and resuture, azoxymethane treatment, and then sham bypass. Thirty weeks later the plasma enteroglucagon level had almost trebled after jejunoileal bypass (p less than 0.001) and almost doubled after jejunoileal resection (p less than 0.002) when compared with sham bypass; sham values did not differ from controls. The median number of tumors per rat in the distal (defunctioned) colon fell from 2 to 0 (p less than 0.05). Segmental weight fell by 45% (p less than 0.001) and crypt cell production rate by 75% (p less than 0.001). Neither tumor yield nor adaptation was affected by jejunoileal bypass or jejunoileal resection. Plasma enteroglucagon has no effect on colonic cell turnover or carcinogenesis in the absence of luminal content.     

Endoscopic study on the effect of dietary fiber against 1,2-dimethylhydrazine-induced colonic carcinogenesis in rats

The effect of dietary fiber on colonic carcinogenesis was studied endoscopically in rats administered 1,2-dimethylhydrazine. Colonic tumors appeared about six weeks later in rats fed 15% cellulose diet or 40% wheat bran diet than in those fed basal diet. Furthermore, the incidence of colonic tumor was significantly lower from 23th week to 26th week in the cellulose diet group (p less than 0.01) and at 26th week in the wheat bran diet group (p less than 0.05) than in the basal diet group. However, the incidence of colonic tumors and the mean number of tumors per rat at sacrifice (30th week) were not significantly different between these two high-fiber diet groups and the basal diet group. These two diets significantly increased feces 3 to 4 times in weight and 5 times in volume over the base diet. However, 15% pectin diet could neither inhibit colonic carcinogenesis nor increase the fecal weight. These results suggested that cellulose and some dietary fibers of wheat bran were effective to retard colonic carcinogenesis, and that the increased fecal weight and volume by fibers may be involved in the inhibitory effect.     

Histochemical study of colonic cancer in experimental colitis of rats

A reliable test for premalignant lesions in the development of colonic cancer in chronic ulcerative colitis has been needed. Thus, we designed this cytochemical study, using a model of experimental colitis and colonic tumors induced in Wistar male rats by the feeding of dextran sulfate sodium. The colitis had histologic similarities to ulcerative colitis in man. The percent frequency of polypoid lesions (dysplasia or dysplasia with carcinomain situ) in the cecum and ascending colon was about 25% at three months and 90% at six months of dextran sulfate feeding. The cytochemical findings by high-iron diamine-Alcian blue staining andUlex europeus agglutinin binding were chronologically paralledled by histological changes in the colonic mucosa, and the binding pattern of peanut agglutinin was not different between normal and dextran-treated animals. Moreover, some cytochemical changes that occurred during the inflammatory responses were not present in dysplastic or malignant lesions. Thus, the histochemical tests were not useful for detecting of premalignant lesions earlier than by conventional histology. Nevertheless, the dextran sulfate model of colitis in the rat appears suitable for study of cancer development in ulcerative colitis.     

Influence of proximal end diverting colostomy on the healing of left-sided colonic anastomosis: an experimental study in rats

The purpose of this study was to evaluate the healing of an experimental left-sided colonic anastomosis in rats protected by an end diverting proximal colostomy. The anastomoses were studied by radiological and biochemical examination and breaking strength was estimated. The results were compared with a non-operated group and with a group of rats having a non-defunctional anastomosis constructed in the same manner. In animals with an end diverting colostomy, anastomotic protein levels and enzymic activity were lower than in those with a colostomy, and the development of anastomotic strength was delayed compared with those not defunctioned.

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Résumé Le but de cette étude est d'évaluer la guérsion d'une anastomose colique gauche expérimentale réalisée chez le rat sous le couvert d'une colostomie proximale terminale. Les anastomoses ont fait l'objet d'études radiologique, biolochimique et mécanique. Les résultats ont été comparés avec un groupe non opéré et avec un groupe de rats chez lesquels une colostomie non excluante avait été réalisée de la même manière. Chez les animaux avec une colostomie terminale excluante, la concentration de protéines au niveau de l'anastomose et l'activité enzymatique était inférieure à celle observée chez ceux qui avaient une colostomie non excluante; la résistance mécanique de l'anastomose était retardée en comparaison avec ceux qui avaient une colostomie non excluate.

     

Influence of pulsed electromagnetic fields on healing of experimental colonic anastomosis

PURPOSE: The study investigated the influence of pulsed electromagnetic fields (PEMFs) on the mechanical strength and collagen content of uncomplicated colonic anastomosis in rats. METHODS: A standardized left colonic resection was performed 3 cm above the peritoneal reflection, and end-to-end anastomosis was constructed with eight interrupted inverting sutures. Beginning immediately after surgery, randomly assigned groups were exposed to one of the following: 1) 100 Hz (frequency), 1 mT (intensity) PEMFs with 16-hour on/8-hour off cycles (n=8); 2) 100 Hz, 2 mT PEMFs with 16-hour on/8-hour off cycles (n=8); 3) 100 Hz, 1 mT PEMFs with 6-hour on/6-hour off cycles (n=6), whereas the control group (n=10) received no PEMFs. Relaparatomy was performed at 72 hours postoperatively, and the bursting pressure of the anastomotic segment was recorded in situ.The hydroxyproline contents of the anastomotic and adjacent perianastomotic segments of equal lengths were determined. RESULTS: Mean bursting pressure values of the groups that received 100 Hz, 1 or 2 mT PEMFs with 16-hour on/8-hour off cycles (90.88±19.13 and 83.88±7.08 mmHg, respectively) were significantly higher than those of the control group (61.66±10.6 mmHg) and the group with 6-hour on/6-hour off cycles (64.83±7.36 mmHg;P <0.05 for all comparisons). Hydroxyproline contents of the anastomotic and perianastomotic segments were consistently higher in the 16-hour on/8-hour off PEMF groups, compared with those of the corresponding segments of the control group. CONCLUSIONS: PEMFs applied externally to unrestrained rats within a window of PEMF parameters provided a significant gain in the mechanical strength of the colonic anastomosis, at least 72 hours postoperatively. Associated relative increases in the hydroxyproline contents of the (peri)anastomotic colonic segments suggest that an altered collagen metabolism might contribute to this enhancement of the anastomotic repair. Further investigations based on these preliminary data and the definition of the exact measures regarding the effects of PEMFs on biologic systems, in general, may lead to an efficient and new adjunctive modality in colorectal surgery.Suture materials were supplied by Ethicon Limited, Birmingham, United Kingdom.Read at the Third International Congress on New Technology and Advanced Techniques in Surgery, Luxembourg, June 13 to 17, 1995.     

The influence of chronic pancreatitis on carcinogenesis: an experimental study in rats

BACKGROUND: The literature contains many controversial or unclearly defined opinions about the risk of development of carcinoma of the exocrine part of the pancreas in patients with chronic pancreatitis. This and our own clinical observations based on analysis of patients with chronic pancreatitis treated surgically (anastomotic and resectional procedures) formed the background to an experimental study to define the risk of carcinogenesis in the course of chronic pancreatitis in rats. EXPERIMENTAL FINDINGS: In Wistar rats with chronic pancreatitis induced by etionine and then exposed to carcinogenic action of azaserine, proliferation, adenomas and acinic cell carcinomas of the exocrine part of the pancreas were diagnosed; the carcinomas were transplantable. In rats treated with azaserine only, benign proliferative lesions and adenomas were found. The presence of the p53 mutation protein was observed in carcinomatous pancreatic cells in malignant lesions of the pancreas in primary and transplantable cancers, but was not detected in benign proliferative lesions and adenomas. Chronic pancreatitis in Wistar rats predisposes the exocrine part of pancreas to malignant transformation. Growth of cancers of the exocrine part of the pancreas in male rats, but not in female rats, suggests hormonal determination of experimental pancreatic cancer. CONCLUSIONS: Results demonstrate that chronic pancreatitis in rats predisposes to malignant proliferative lesions, including acinic cell carcinoma. Expression of the protein product of p53 gene mutations correlated with neoplastic transformation of pancreas preceded by chronic pancreatitis, and was also detected in transplantable tumours.     

Influence of surgically induced gastric and gastroduodenal content reflux on esophageal carcinogenesis – experimental model in Wistar female rats

Studies in human beings and animals have shown that esophageal exposure to duodenal and gastric contents may be important for the development of Barrett's esophagus and its complications, including adenocarcinoma and epidermoid carcinoma. Diethylnitrosamine (DEN) is a carcinogen that stimulates the development of epidermoid carcinoma in the esophagus of mice. The aim of this study was to evaluate the effect of gastroduodenal and gastric content reflux on induction of esophageal carcinogenesis. Gastroesophageal reflux (GER) and gastroduodenoesophageal reflux (GDER) were produced by cardioplasty and esophagoduodenostomy. The chosen carcinogen was DEN, diluted in drinking water, given 3 days a week for 20 consecutive weeks. One hundred Wistar female rats were divided into six groups, as follows: group 1 (18 rats), cardioplasty without DEN; group 2 (18 rats), cardioplasty with DEN; group 3 (10 rats), only water; group 4 (17 rats), cardioplasty with DEN; group 5 (17 rats), esophagoduodenostomy with DEN; group 6 (20 rats), only DEN. GER in isolation induced papillomatosis or ulceration in 22.2% of rats and, when associated with DEN, induced papillomatosis in 61.1% of rats. GDER in isolation induced marked esophagitis in 61.1% of rats, Barrett's esophagus in 16.7% and esophageal adenocarcinoma in 16.7%; when associated with DEN, 23.5% of rats presented marked esophagitis, papillomatosis or ulceration, whereas 76.5% had esophageal carcinoma, with 70.6% epidermoid carcinoma and 5.9% adenocarcinoma. Rats treated with water alone did not show histologic abnormalities of the esophageal mucosa. Rats treated with DEN alone developed papillomas in 50.0% of the cases and remained histologically unchanged in 50.0%. There was no development of low- or high-grade dysplasia in any group. The conclusions are that (1) GDER is significantly more deleterious to esophageal mucosa than GER; (2) in this study, GER did not present carcinogenic potential in relation to the esophagus; (3) GDER in isolation is an esophageal carcinogen, producing Barrett's esophagus and esophageal adenocarcinoma; (4) esophageal oncogenesis caused by GDER is potentiated by DEN, inducing esophageal epidermoid carcinoma; (5) in this study, DEN in isolation did not generate tumors in the esophagus of rats.     

Colonic carcinogenesis in vagotomyzed rats.

INTRODUCTION: An increased incidence of colorectal cancer (CRC) has been reported in patients with peptic ulcer disease treated with truncal vagotomy. Inhibition of gastric acid output and its hormonal consequence, hypergastrinemia, have been considered risk factors for the development of CRC. The aim of the present study was to determine whether truncal vagotomy increases, in the short (7 days) and long term (120 days), the incidence of CRC in a model of carcinogenesis. MATERIAL AND METHOD: We used 86 Wistar rats distributed in 7 groups to which DMH (1,2-dimethylhydrazine dihydrochloride) was administered for the induction of colon tumors, at doses of 5 and 20 mg/kg of weight. The first three groups were used as control groups; the rats of the four other groups underwent a truncal vagotomy with pyloroplasty and Heller myotomy prior to the administration of DMH. Finally, we compared the incidence of colonic tumors in vagotomized vs non-vagotomized groups receiving the same dose of DMH. RESULTS: In the non-vagotomized rats that received low doses of DMH (5 mg/kg of weight), mortality was 0% and 0% developed cancer as compared to 40% and 0%, respectively, of rats vagotomized 7 days before the administration of DMH and 20% and 0%, respectively, of rats vagotomized 120 days before the administration of DMH. After the administration of high doses of DMH, mortality was 50% and 80% developed cancer as compared to 100% and 0%, respectively, of rats vagotomized 7 days before the administration of DMH and 61.11% and 42.8%, respectively, of rats vagotomized 120 days before the administration of DMH. CONCLUSION: Truncal vagotomy does not increase the incidence of CRC induced by DMH in the rat.