Influence of diets containing high and low risk factors for colon cancer on early stages of carcinogenesis in human flora-associated (HFA) rats

Germ-free rats colonised with a human intestinal flora were fed diets containing high risk (HR) or low risk (LR) factors for colorectal cancer, and putative biomarkers were evaluated in the colonic mucosa; (i) proliferation, (ii) 1,2-dimethylhydrazine (DMH)-induced aberrant crypt foci and (iii) DMH-induced DNA damage. The HR diet was high in fat (45% of calories) and low in calcium and fibre, reflecting levels characteristic of typical western diets. The LR diet was low in fat (<5% of calories), and high in calcium and fibre. The nutrient/energy ratio of the two diets were similar. Mucosal crypt cell proliferation, assessed after microdissection, was higher on the LR diet (mean number of mitoses per crypt was 2.65 on the LR diet, and 1.62 on the HR diet; P < 0.05). Aberrant crypt foci (ACF) were assessed in the mucosa 12 weeks after DMH treatment. On the HR diet there were significantly more small ACF with 1 and 2 crypts per focus, but fewer ACF with 3, 5 and 7 or more crypts per focus. There was no significant difference in total ACF or the total number of crypts. The effect of diet on DNA damage in the colon was assessed in vivo by the comet assay. Animals were fed a HR or LR diet for 12 weeks before treatment with DMH or saline. For carcinogen-treated animals, DNA damage was significantly higher in colon cells from animals on the HR diet. On the LR diet both DNA damage and the induction of small ACF were reduced despite an increase in cell proliferation. The increase in large ACF on the LR diet may be attributable to elevated crypt cell proliferation possibly increasing crypt fission rates.     

Inhibition of development of N,N'-dimethylhydrazine-induced rat colonic aberrant crypt foci by pre, post and simultaneous treatments with 24R,25-dihydroxyvitamin D3

It has recently been reported that new vitamin D3 derivatives can exert inhibitory effects on colon carcinogenesis in rats. In the present study the chemopreventive potential of 24R,25-dihydroxyvitamin D3 (24R,25(OH)2vitamin D3) was assessed in a murine model of colon carcinogenesis. In experiment 1, male 6-week-old F344 rats were administered N,N'-dimethylhydrazine (DMH) 20 mg/kg s.c. once a week 4 times. The rats were fed 24R,25(OH)2vitamin D3 at 10 ppm in the diet prior to (pre), together with (simultaneous) or after (post) DMH treatment. Modifying effects were assessed using aberrant crypt foci (ACF), putative preneoplastic lesions, as the end point markers in this model of colon carcinogenesis. After 8 weeks, pre and more markedly simultaneous administration of 24R,25(OH)2vitamin D3 was found to have reduced the total numbers of ACF and significantly inhibited the development of foci. After 16 weeks, numbers of foci with > or = 4 crypts, which are more likely to progress to tumors, were significantly reduced. The most pronounced inhibition of ACF development was noted in rats fed the 24R,25(OH)2vitamin D3 after DMH administration. The reduction was particularly marked in the proximal colon. Blood levels of calcium were not significantly increased over the control levels in groups administered DMH and the vitamin. Immunohistochemical staining showed numbers of proliferating cell nuclear antigen-positive cells to be lower in the colonic epithelia of rats fed the vitamin D3 metabolite than in the controls. In experiment 2, the effect of 24R,25(OH)2vitamin D3 on the alterations in c-fos, c-myc and c-jun oncogene expression in response to DMH administration was examined by northern blot analysis. The early increase in expression of ornithine decarboxylase (ODC) activity was not altered by 24R,25(OH)2vitamin D3. The results suggest that 24R,25(OH)2vitamin D3 is a cancer chemopreventive agent which may suppresses DMH induction of lesions and their subsequent development via an antiproliferative action.     

Melatonin and colon carcinogenesis: I. Inhibitory effect of melatonin on development of intestinal tumors induced by 1,2-dimethylhydrazine in rats

The effect of pineal indole hormone melatonin on colon carcinogenesis was firstly studied in rats. Two-month-old outbred female LIO rats were weekly exposed to 15 (experiment 1, groups 1 and 2) or to five (experiment 2, groups 1 and 2) s.c. injections of 1,2-dimethylhydrazine (DMH) at a single dose of 21 mg/kg of body weight. From the day of the first injection of the carcinogen DMH, the rats from groups 2 (experiments 1 and 2) were given melatonin five days a week during the night-time (from 18:00 h to 8:00 h), dissolved in tap water at 20 mg/l. The experiment was finalized in 6 months after the first injection of DMH. In both experiments the majority of tumors were localized in the descending colon. Tumors of the small intestines developed only in rats from experiment 1. Total incidence of colon tumors as well as tumors in different parts of the colon and the mean number of tumors per rat were much higher in rats from both groups in experiment 1 than that in rats from experiment 2. In experiment 1 melatonin failed to influence the total incidence of colon tumors. However, incidence of carcinomas in the ascending colon was significantly reduced (P < 0.01). The multiplicity of total colon tumors per rat, as well as the mean number of tumors, ascending and descending colon per rat, was also decreased under the influence of melatonin (group 2 vs group 1, P < 0.01). In the same experiment, melatonin slightly decreased the depth of tumor invasion and increased number of highly differentiated colon carcinomas induced by DMH. The percentage of small tumours in the descending colon among rats from group 2 was higher than that of group 1. Treatment with melatonin was also followed by a decrease in the multiplicity of DMH-induced tumors of the duodenum (group 2 vs group 1, P < 0.05) and by a decrease in the incidence of jejunum and ileum tumors (group 2 vs group 1, P < 0.05). In experiment 2, the inhibitory effect of melatonin on DMH-induced colon carcinogenesis was much more expressed than that in experiment 1. Thus, in group 1 the incidence of total colon tumors, ascending and descending colon tumors, was significantly decreased in comparison with group 2; also melatonin reduced the number of tumors per rat in the ascending and descending colon. The number of colon tumors that invaded only mucosa was significantly higher in group 2 than in group 1, P < 0.05. The ratio of highly differentiated tumors was increased (P < 0.05) and the ratio of low-differentiated tumors was decreased (P < 0.05) in rats exposed to melatonin (group 4) as compared with group 3. The number of large size tumors in the ascending and descending colon was decreased whereas the number of small size tumors (<10 mm2) was increased in those parts of the colon that were under the influence of melatonin in experiment 2. Thus, our results demonstrate the inhibitory effect of melatonin on intestinal carcinogenesis induced by DMH in rats.     

Chemoprevention of colon cancer by organoselenium compounds and impact of high- or low-fat diets

BACKGROUND: Observational and experimental studies have suggested that dietary supplementation with selenium can inhibit the development of colon cancer. However, many forms of selenium are toxic. Consequently, the development of efficacious compounds with low toxicity has been pursued. PURPOSE: Two synthetic organoselenium compounds, p-methoxy-benzyl selenocyanate (p-methoxy-BSC) and 1,4-phenylenebis(methylene)selenocyanate (p-XSC), were tested for their ability to inhibit colon carcinogenesis in rats that were treated with the carcinogen azoxymethane and fed low- or high-fat diets. METHODS: Groups of 5-week-old male F344 rats (42 animals/ group) were fed either a high-fat diet or a low-fat diet with or without added p-methoxy-BSC (10 or 20 parts per million [ppm]) or p-XSC (20 ppm). Two weeks later, 30 animals in each group received a subcutaneous injection of azoxymethane (15 mg/kg body weight); 1 week later, they received a second injection. The remaining 12 rats in each group received two injections of saline. Three days after the second injection of carcinogen or saline, animals being fed diets with p-methoxy-BSC or p-XSC were switched to corresponding organoselenium-free low- or high-fat diets for the remainder of the study to determine the effects of the selenium compounds on the initiation phase of colon carcinogenesis. At that time, groups of animals that had been maintained on organoselenium-free low- or high-fat diets were switched to diets containing p-methoxy-BSC or p-XSC until the end of the study to determine the effects of these compounds on the postinitiation phase of colon carcinogenesis. All animals were killed during the 38th week after azoxymethane or saline treatment, and histopathologic analysis of the colon tumors was performed. Colon tumor incidence and multiplicity were analyzed statistically. RESULTS: No obvious toxic effects were observed following dietary administration of 10 or 20 ppmp-methoxy-BSC or 20 ppm p-XSC. Administration of 20 ppm p-methoxy-BSC in a high-fat diet during the initiation and postinitiation phases of colon carcinogenesis significantly (statistically) reduced colon tumor incidence; 10 ppmp-methoxy-BSC in a high-fat diet significantly reduced colon tumor incidence but only when it was given during the postinitiation phase. Colon tumor incidence was also significantly reduced when 20 ppm p-XSC was given in a high-fat diet during the initiation phase of colon carcinogenesis. When 20 ppm p-XSC was administered in either a high-fat diet or a low-fat diet during the postinitiation phase, both colon tumor incidence and multiplicity were significantly reduced; the greatest reductions were in animals fed a low-fat diet. CONCLUSIONS: In this model system, p-methoxy-BSC and p-XSC are effective agents for the chemoprevention of colon cancer. The effects of p-XSC were enhanced in animals fed a low-fat diet.     

The nonfermentable dietary fiber lignin alters putative colon cancer risk factors but does not protect against DMH-induced colon cancer in rats

The effect of supplementation of the diet with autohydrolyzed lignin on 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis was studied using 112 male Sprague-Dawley rats. Rats received eight weekly injections of DMH (9.5 mg/kg s.c.) or the saline vehicle solution and then were maintained on a basal AIN-76 fiber-free diet or the basal fiber-free diet plus 5% or 10% (wt/wt) lignin for 24 weeks. Rats were killed 32 weeks after the start of the experiment. Colon tumor incidence, location, and multiplicity were determined. Body weight, caloric intake, fecal dry weight, gut transit time, pH of cecal contents, and total fecal bile acid excretion were measured. Supplementation of the diet with 5% or 10% lignin resulted in increased fecal dry weight and total fecal bile acid excretion and in decreased gut transit time, colon pH, and fecal bile acid concentration. Dietary lignin did not significantly affect colon tumor incidence or multiplicity compared with the fiber-free diet. Thus dietary supplementation with autohydrolyzed lignin, a food fiber with good bulking characteristics, had a significant effect on several factors that have previously been linked to reduction of colon cancer risk, but the consumption of high levels of lignin did not decrease the risk for colon cancer.     

Positive association between dietary fat intake and risk of gastric stump carcinoma in rats

Effect of high- and low-fat diets on gastric stump carcinogenesis was experimentally investigated. A total of 130 Wistar male rats weighing 250-300 g received either sham operation or Billroth II partial gastrectomy, the resection of the distal two-thirds glandular stomach and reconstruction of gastro-jejunostomy. After surgery, each group of rats was switched from a standard diet (CRF-1) to a special diet containing either 15% soybean oil (high-fat) or 0.5% soybean (low-fat), fed ad libitum and tap water, and were killed 50 weeks after surgery. Gastric tumours were observed only in the animals that underwent gastrectomy while no tumours were detected in the animals following the sham operation. Tumours located invariably at the gastrojejunostoma, were carcinomas or adenomas in histology. Carcinomas developed in 12 of 29 gastrectomy animals (41%) fed the high-fat diet and 4 of 27 gastrectomy animals (15%) fed the low-fat diet. The difference was significant (P < 0.05). The incidence of adenoma was also significantly higher in the gastrectomy animals fed the high-fat diet (38%) than that in those fed the low-fat diet (15%) (P < 0.05). A daily faecal output of bile acids was significantly greater in the gastrectomy animals fed the high-fat diet (19.0 +/- 16.4 micromol/day) than that in those fed the low-fat diet (11.2 +/- 6.2 [micromol/day; P < 0.05). This study suggests that increased fat intake is associated with a high risk of gastric stump carcinoma.     

Chemoprevention of azoxymethane-induced intestinal carcinogenesis by a novel synthesized retinoidal butenolide, 5-hydroxy-4-(2-phenyl-(E)-ethenyl)-2(5H)-furanone, in rats

The present study was designed to investigate the modifying effects of dietary 5-hydroxy-4-(2-phenyl-(E)-ethenyl)-2(5H)-furanone (KYN-54), a new synthetic retinoidal butenolide, during the post-initiation phase on azoxymethane (AOM)-induced rat intestinal carcinogenesis. The number of aberrant crypt foci (ACF) in rat colon, colonic ornithine decarboxylase (ODC) activity and bromodeoxy-uridine (BrdUrd) labeling index in rat colonic epithelium were also assessed. At 7 weeks of age, male F344 rats (except the KYN-54 alone and control groups) were given weekly s.c. injections of AOM at 15 mg/kg body wt for 3 weeks. Starting 1 week after the last injection of AOM, rats (except the control group) were fed a diet containing KYN-54 at concentrations of 100 or 200 p.p.m. throughout the experiment. All animals were necropsied at 32 weeks after the start of the experiment. Compared with the AOM alone group, KYN-54 at both doses reduced the incidence and multiplicity of tumors in entire intestine (small and large intestines). In the 200 p.p.m. KYN-54 fed group especially, tumor incidence and multiplicity in the entire intestine were lower compared with the AOM alone group (P < 0.005 and P < 0.05 respectively). Also, the number of ACF/cm2 colon in the groups of rats treated with AOM and KYN-54 at both doses were significantly lower than that of rats treated with AOM alone (P < 0.05). Colonic ODC activity and BrdUrd labeling index in the groups of rats treated with AOM and KYN-54 at both doses were slightly lower than those treated with AOM alone. KYN-54 at 200 p.p.m. significantly lowered BrdUrd labeling index induced by AOM (P < 0.005). These results suggest that KYN-54 might be a promising chemopreventive agent for intestinal neoplasia.     

Chemoprevention of azoxymethane-induced rat colon carcinogenesis by a xanthine oxidase inhibitor, 1'-acetoxychavicol acetate

In our studies to find natural compounds with chemopreventive efficacy in foods, using azoxymethane (AOM)-induced colonic aberrant crypt foci and colonic mucosal cell proliferation as biomarkers, a xanthine oxidase inhibitor, 1'-acetoxychavicol acetate (ACA), present in the edible plant Languas galanga from Thailand was found to be effective. This study was conducted to test the ability of ACA to inhibit AOM-induced colon tumorigenesis when it was fed to rats during the initiation or post-initiation phase. Male F344 rats were given three weekly s.c. injections of AOM (15 mg/kg body weight) to induce colonic neoplasms. They were fed diet containing 100 or 500 ppm ACA for 4 weeks, starting one week before the first dosing of AOM (the initiation feeding). The other groups were fed the ACA diet for 34 weeks, starting one week after the last AOM injection (the post-initiation feeding). At the termination of the study (week 38), AOM had induced 71% incidence of colonic adenocarcinoma (12/17 rats). The initiation feeding with ACA caused significant reduction in the incidence of colon carcinoma (54% inhibition by 100 ppm ACA feeding and 77% inhibition by 500 ppm ACA feeding, P = 0.03 and P = 0.001, respectively). The post-initiation feeding with ACA also suppressed the incidence of colonic carcinoma (45% inhibition by 100 ppm ACA feeding and 93% inhibition by 500 ppm ACA feeding, P = 0.06 and P = 0.00003, respectively). Such inhibition was dose-dependent and was associated with suppression of proliferation biomarkers, such as ornithine decarboxylase activity in the colonic mucosa, and blood and colonic mucosal polyamine contents. ACA also elevated the activities of phase II enzymes, glutathione S-transferase (GST) and quinone reductase (QR), in the liver and colon. These results indicate that ACA could inhibit the development of AOM-induced colon tumorigenesis through its suppression of cell proliferation in the colonic mucosa and its induction of GST and QR. The results confirm our previous finding that ACA feeding effectively suppressed the development of colonic aberrant crypt foci. These findings suggest possible chemopreventive ability of ACA against colon tumorigenesis.     

Treatment of A2-B2 prostatic cancer: results of a hormonoradiotherapy combination in the PSA era

The effect of the dose of oyster mushroom in the diet (1.0, 2.5, and 5.0%) and of the period of application (8, 16, 28, and 52 wk) on cholesterol accumulation in blood and body organs was studied in weanling male Wistar rats fed a diet containing 0.3% cholesterol. Reduction of cholesterol in serum and body organs was found to be dependent on the amount of dietary oyster mushroom administered. A negative correlation between the mushroom dose and cholesterol level was found after 8 and 28 wk of feeding (r=-0.9821 and -0.9803, respectively; P < 0.02 for both cases). The dose of 1% oyster mushroom did not affect cholesterol levels in serum or body organs. A significant reduction of cholesterol levels was observed in serum (31-46%) and liver (25-30%) at a dose of 5% of oyster mushroom for all periods. Reduced cholesterol content in very low-density lipoproteins (VLDL) was also observed at this level. The highest dose of oyster mushroom induced a decrease in conjugated diene levels in erythrocytes and an increase in the levels of reduced glutathione in the liver and stimulated the activities of catalase and glutathione peroxidase in the liver in the final period of the experiment.     

The role of apoptosis in the modulation of colon carcinogenesis by dietary fat and by the organoselenium compound 1,4-phenylenebis(methylene)selenocyanate

Studies in laboratory animals have demonstrated that dietary supplements of organoselenium, 1,4-phenylenebis(methylene)selenocyanate (p-XSC) inhibit colon carcinogenesis. Diverse chemopreventive agents and clinically used anticancer drugs have been shown to induce apoptosis in colonic tumors. Inducing apoptosis is a key mechanism for the effectiveness of some chemopreventive agents; however, failure of apoptosis is now believed to contribute to the development of human cancer. In this study, we determined the number of apoptotic bodies in the colon tumors of rats fed a low-fat (LF) or a high-fat (HF) diet with or without p-XSC treatment. At 5 weeks of age, male F344 rats were divided into four groups, which were then maintained on one of the following diets: LF, 5% corn oil; HF, 23.5% corn oil; and LF and HF supplemented with 20 ppm p-XSC. In addition, the LF or HF diet with p-XSC supplements was administered either during the initiation stage or postinitiation. At 7 weeks of age, all rats except those intended for vehicle (normal saline) treatment were given 15 mg/kg of body weight of azoxymethane once weekly for 2 weeks. The animals were sacrificed 38 weeks after carcinogen treatment, and their colonic tumors were examined for appearance of apoptosis. The LF diet significantly increased the percentage of apoptosis as compared to the HF diet; the percentage of apoptosis in LF and HF diets were 12.4 and 2.9. The colon tumors that were present in the groups fed p-XSC together with a LF or a HF diet after carcinogen administration (postinitiation period) had a higher number of apoptotic bodies than those that were present in the animals fed p-XSC before carcinogen treatment (initiation period). The extent of apoptosis was weak when p-XSC was given with a HF diet (4.4%) during the initiation phase, but it was high significant when p-XSC was administered with LF diet (25.2%). Taken together, our data suggest that administration of LF diet supplemented with p-XSC increases apoptosis as compared to a HF diet alone.     

Effect of soya bean saponins on azoxymethane-induced preneoplastic lesions in the colon of mice

The effect of saponins isolated from soya bean flour on the incidence of aberrant crypt foci (ACF) induced by azoxymethane (AOM) in the colonic wall of CF1 mice was investigated. Four weekly injections of AOM, a known colon carcinogen, were administered to mice. One week after the last injection, mice were placed on an AIN-76 diet supplemented with 3% soya bean saponins or continued on the basal AIN-76 diet. Another group of mice was placed on the saponin diet without AOM initiation to observe the effect of saponins on the growth characteristics of mice. Dietary intake of soya saponins significantly reduced the incidence of ACF at the end of 14 weeks (postinitiation). Noninitiated mice maintained on a similar soya bean saponin-supplemented diet did not show any adverse effects on the growth and overall health of the animals. These findings suggest that soya bean saponins can play an important role in inhibiting the incidence of ACF in the colon of mice.     

Inhibitory effect of the non-steroidal anti-inflammatory drugs, indomethacin and piroxicam on 2-acetylaminofluorene-induced hepatocarcinogenesis in male ACI/N rats

The modifying effects of the non-steroidal anti-inflammatory drugs, indomethacin (IMC) and piroxicam (PC) on hepatocarcinogenesis induced by 2-acetylaminofluorene (AAF) were investigated in male ACI/N rats. Rats were divided into 6 groups: group 1 was fed a diet containing 200 ppm AAF for 16 weeks, starting at 6 weeks of age; group 2 was fed an AAF together with 130 ppm PC-containing diet; group 3 received an AAF diet and IMC (10 ppm) in their drinking water; group 4 was fed a PC diet alone; group 5 was given IMC alone; and group 6 served as controls. The PC diet, or the drinking water containing IMC, was given to the rats starting at 5 weeks of age until 1 week after the carcinogen exposure. At termination of the experiment (week 36), the incidences of iron-excluding altered liver cell foci (24.2 +/- 5.2/cm2) and liver cell tumors (1/10, 10%), and the tumor multiplicity (0.10/rat) in rats of group 2 were significantly smaller than those of group 1 (foci incidence, 42.6 +/- 6.7/cm2; tumor incidence, 10/10, 100%; and multiplicity, 4.00/rat) (P < 0.05). Similarly, the incidence of iron-excluding hepatocellular foci (27.4 < 1.2/cm2) and liver cell tumors (1/10, 10%) and the tumor multiplicity (0.10/rat) in rats of group 3 were significantly lower than those of group 1 (P < 0.05). There were no liver cell lesions (foci and neoplasms) in rats of groups 4, 5 and 6. Thus, PC and IMC inhibited the hepatocarcinogenesis induced by AAF when administered concurrently with the carcinogen and the results may indicate possible involvement of altered arachidonic metabolism in the initiation phase of AAF-induced liver carcinogenesis.     

Sulindac enhances cell proliferation in DMH-treated mouse colonic mucosa

In a previous study we reported that the NSAID sulindac had a marked inhibitory effect on the development of colonic tumours in mice treated with the carcinogen 1,2-dimethylhydrazine (DMH). In this study we examined the effects of sulindac in respect of cell-kinetic changes in mouse colonic mucosa as determined by flash labelling with the thymidine analogue bromodeoxyuridine (BrdUrd) at varying intervals during the process of colonic carcinogenesis. We also investigated the possibility that these changes may be modulated by misoprostol a prostaglandin E1 analogue. Four groups of 36 mice each were treated for 18 weeks with the following drug/s respectively: (1) DMH; (2) DMH and sulindac; (3) DMH, sulindac and misoprostol; and (4) DMH and misoprostol. Three animals from each group were killed each week between the sixth week and the eighteenth week after the start of the experiment. A 1-h flash label technique was employed and paraffin sections of colonic mucosa were examined. For each animal a total of 50 perfect axially cut crypts were chosen and the following parameters determined: crypt length, labelling index and labelling index distribution: the data were analysed using the computer program GLIM. For each of the four groups, crypt lengths increased significantly with the duration of treatment with no significant difference between the groups. In sulindac-treated animals the labelling index for all positions increased with duration of treatment whereas for animals not treated with sulindac there was no significant difference in labelling index with respect to duration of treatment. The administration of misoprostol did not appear to significantly alter the effects of sulindac. It is postulated that the observed increase in cell proliferation could be a compensatory phenomenon occurring secondary to loss of crypt epithelial cells by apoptosis induced by sulindac. Also the finding of an increase in labelling index mediated by a chemopreventive agent indirectly questions the rationale behind the therapeutic manipulation of crypt cell proliferation in order to reduce the risk of colon cancer.     

Inhibitory effect of sarcophytol A on pancreatic carcinogenesis after initiation by N-nitrosobis(2-oxypropyl)amine in Syrian hamsters

Sarcophytol A (SaA), a cembrane-type diterpene, inhibits pancreatic carcinogenesis induced by N-nitrosobis(2-oxypropyl)amine (BOP) in hamsters. The experimental groups received two injections of BOP at 70 mg/kg dose, followed 2 weeks later by a 20 mg/kg dose injection, and were fed a basal diet or 0.01 and 0.05% SaA diets starting 1 week after the second injection of BOP. Control groups were injected with normal saline and fed the basal diet or the 0.05% SaA diet. All animals were killed 30 weeks after the start of the experiments. Seventeen BOP-treated hamsters fed the basal diet developed pancreatic tumors (77.3%) while only 12 of 21 hamsters fed the 0.01% SaA diet (57.1%) and 12 of 23 hamsters fed the 0.05% SaA diet (52.2%) developed pancreatic tumors. Pancreatic lesions included ductal hyperplasia, atypical ductal hyperplasia, and carcinoma in situ. Microscopic invasive carcinoma induced by BOP and the incidence of larger pancreatic tumors in hamsters were significantly higher in hamsters fed the basal diet than in hamsters fed the SaA diet (p < 0.05). The proliferating cell nuclear antigen (PCNA) labeling index of pancreatic carcinoma in BOP-treated hamsters fed the basal diet was 41.2 +/- 13.4%, whereas BOP-treated hamsters fed 0.01 and 0.05% SaA diets yielded PCNA indexes of 26.8 +/- 8.3 and 28.4 +/- 7.0%, respectively. k-ras mutation was detected in 40% of cancers in both groups. No pancreatic tumors developed in saline-treated groups, and no differences in body weights or histological findings in their organs, including the pancreas, were observed in either group. These findings suggest that SaA not only inhibits BOP-induced pancreatic carcinogenesis in hamsters, but also provides antipromotion and antiprogression effects on these tumors, even when SaA commences 1 week after the initiation of pancreatic carcinogenesis.     

Update on pediatric heart transplantation. Long-term complications

We have previously observed changes in colon cell proliferation in growing rats fed different levels of dietary fat as beef tallow or corn oil. Here we measured cellular proliferation at 18 and 30 weeks in the colon of rats fed beef tallow or corn oil and treated with the chemical carcinogen azoxymethane. Additionally, we assessed colon cell membrane lipid composition after 18 weeks on the defined diets and tumor incidence at 30 weeks. Dietary fat type and quantity significantly affected colon cell proliferation. Membrane phospholipids and free fatty acids were significantly affected by fat type. Tumor incidence was not affected by diet type. We conclude that dietary fat induces changes in cell membrane lipid composition and proliferation in the colon and these changes may be related to the development of tumors.     

Malignant degeneration of experimental ulcerative colitis of the rat following s.c. injection of 1,2-dimethylhydrazine (author's transl)

Animal experiments were performed to answer the question whether ulcerative colitis is predisposed to malignant degeneration. Male Wistar rats were given aqueous solutions of degraded Carrageenan (4%; w/v). After induction of ulcerative colitis, 1,2-Dimethylhydrazine (DMH; 132 mg/kg body weight) was applicated during a period of 7 weeks. 17 of 18 rats developed multiple adenocarcinomas in the distal colon 15 weeks after the last injection of DMH. The Carrageenan induced colitis was localized predominantly in the distal part of the large bowel. Only 3 rats of a control group of 18 animals exposed to DMH only showed carcinomas of the colon. The difference is proven significant (P less than 0.01). Carrageenan for itself caused no malignancy. The results of the experiments demonstrate that, during ulcerative colitis, the colon of the rat is more susceptible to induction of cancer than the intact one.     

Genomic organization of the genes encoding dihydroflavonol 4-reductase for flower pigmentation in the Japanese and common morning glories

BACKGROUND: Colonic crypt cell hyperproliferation characterizes malignant and premalignant conditions of the colon and may be modified by dietary manipulation. This study compared the effect of dietary arginine supplementation on colonic crypt cell proliferation during the initiation and promotion stages of colorectal carcinogenesis. Materials and METHODS: One hundred and twenty male Wistar rats were divided into 5 groups of 24 animals each. Groups D, DA, FA, and LA received subcutaneous injections of 1, 2-dimethylhydrazine for 20 weeks. Group D received no arginine supplement. l-arginine was given as a 1% solution instead of drinking water to Group DA for 22 weeks, to Group FA for the first 10 weeks, and to Group LA for the last 12 weeks. EDTA animals were given subcutaneous injections of EDTA for 20 weeks. Colonic crypt cell proliferation was assessed in 6 animals from each of the five groups and in 6 normal rats not given DMH or EDTA. RESULTS: The BrdUrd-labeling index and proliferative zone were significantly decreased in all arginine groups (DA, FA, LA). The greatest reduction was evident in Group FA in which tumor incidence and tumor size were also significantly lowered. CONCLUSIONS: When given during the initiation phase of carcinogenesis l-arginine significantly reduced colorectal tumor production and crypt cell hyperproliferation.     

Effect of missed hemodialysis treatments on mortality in patients with end-stage renal disease

Dietary fibre is believed to protect against a range of Western diseases, including colorectal cancer. Whole plant cell walls make up most of the dietary fibre in Western diets, but their role in disease protection has rarely been studied. At least in vitro, suberized plant cell walls possess novel properties that suggest they could have exceptional potential for cancer protection. Our aim was to test in a rat model the abilities of suberized cell walls from potato skins and commercial cork to decrease gastrointestinal transit time and to protect against the development of aberrant crypts, an early marker of colon cancer. Groups of six rats were fed a modified AIN-76 diet as the control diet and this diet supplemented with 5% dietary fibre from the following sources: commercial cork, commercial-cork cell walls and potato-skin cell walls. A diet supplemented with wheat bran was used as a positive control. The colon carcinogen IQ (2-amino-3-methylimidazo[4,5-f]quinoline) was administered for 3 weeks and after another 12 weeks the number of aberrant crypts determined. Transit times were determined after feeding the diets for 4 weeks. Compared with rats fed the control diet, rats fed diets supplemented with the suberized cell-wall preparations had decreased transit times and had significantly fewer aberrant crypts, with no aberrant crypt foci containing four or more crypts. The diets supplemented with suberized cell walls were more effective than thediet supplemented with wheat bran. We conclude that suberized and lignified cell walls, but particularly suberized, may play an important role in protection against Western diseases, including colorectal cancer. Failure to distinguish suberized and lignified plant cell walls from other sources of non-starch polysaccharides may provide a major limitation in current assessments of the role of dietary fibre in preventing colorectal cancer in humans.     

Lamivudine treatment for acute hepatitis B after liver transplantation

Although epidemiological and experimental studies indicate a strong relationship between different dietary fats and risk of colon cancer, the modulating effects of these nutritional factors at the molecular level are not fully elucidated. Activated ras genes have been implicated in the etiology of many human malignancies, including colon cancer. It is well established that the transforming ability of ras-p21 depends on its correct localization in plasma membrane. We have previously demonstrated that ingestion of a relatively higher amount of dietary fish oil leads to reduced plasma membrane levels of ras-p21 with concomitant increase in its cytoplasmic contents during the promotion and progression phases of chemically-induced colon tumorigenesis. In this follow-up experiment, we have found that intake of a high amount of corn oil, one of the most widely used fats in the American diet, enhances the expression of farnesyl protein transferase (FPTase). This enzyme catalyses farnesylation of ras precursors in a critical step during post-translational modification of ras oncoproteins, thereby enabling their anchorage to plasma membrane. In contrast, consumption of high amounts of fish oil, which is rich in omega-3 polyunsaturated fatty acids, reduces the levels of FPTase expression, thus inhibiting post-translational processing of ras precursors resulting in decreased ras function both in colonic mucosa as well as in colon tumors. These results correlate with increased incidence and multiplicity of grossly visibly colon tumors in carcinogen-treated animals fed a high corn oil diet versus decreased incidence and multiplicity of colon tumors in their counterparts fed the high fish oil diet. This dietary inhibition of FPTase may have a practical chemopreventive potential.     

Citrus auraptene exerts dose-dependent chemopreventive activity in rat large bowel tumorigenesis: the inhibition correlates with suppression of cell proliferation and lipid peroxidation and with induction of phase II drug-metabolizing enzymes

In our previous short-term experiment, Citrus auraptene inhibited the development of azoxymethane (AOM)-induced aberrant crypt foci, which are precursor lesions for colorectal carcinoma. In the present study, the possible inhibitory effect of dietary administration of auraptene was investigated using an animal colon carcinogenesis model with a colon carcinogen AOM. Male F344 rats were given s.c. injections of AOM (15 mg/kg body weight) once a week for 3 weeks to induce colon neoplasms. They also received diets containing 100 or 500 ppm auraptene for 4 weeks in groups of "initiation" feeding, starting 1 week before the first dosing of AOM. The diets containing auraptene were also given to rats for 38 weeks in groups of "postinitiation" feeding. At the termination of the study (38 weeks), dietary administration of auraptene caused dose-dependent inhibition in AOM-induced large bowel carcinogenesis. Auraptene feeding during the initiation phase reduced the incidence of colon adenocarcinoma by 49% at 100 ppm (P = 0.099) and 65% at 500 ppm (P = 0.0075). Auraptene administration during the postinitiation phase inhibited the incidence of colon adenocarcinoma by 58% at 100 ppm (P = 0.021) and 65% at 500 ppm (P = 0.0075). Also, the multiplicity of colon carcinoma was significantly reduced by initiation feeding at a dose level of 500 ppm (P < 0.01) and postinitiation feeding at a level of 100 and 500 ppm (P < 0.05 and P < 0.01, respectively). Feeding of auraptene suppressed the expression of cell proliferation biomarkers (ornithine decarboxylase activity and polyamine content) in the colonic mucosa and reduced the production of aldehydic lipid peroxidation [malondialdehyde and 4-hydroxy-2(E)-nonenal]. In addition, auraptene increased the activities of Phase II drug-metabolizing enzymes (glutathione S-transferase and quinone reductase) in the liver and colon. These findings suggest that the inhibitory effects of auraptene on AOM-induced colon tumorigenesis at the initiation level might be associated, in part, with increased activity of Phase II enzymes, and those at the postinitiation stage might be related to suppression of cell proliferation and lipid peroxidation in the colonic mucosa.