Effect of different levels of calorie restriction on azoxymethane-induced colon carcinogenesis in male F344 rats

Epidemiological and animal model studies indicate that increased calorie intake increases the risk for colon cancer development. Previous studies in animal models restricted the calorie intake severely, and none of these studies have investigated a dose-response effect of different levels of calorie restriction on colon carcinogenesis. The present study was designed to investigate the effect of various levels of calorie restriction on colon carcinogenesis in male F344 rats fed the low and high fat diets and the effect of these diets on the activities of colonic mucosal and tumor ornithine decarboxylase (ODC) and protein tyrosine kinase. Starting at 5 weeks of age, groups of male F344 rats were fed the low fat or high fat diets ad libitum. At 7 weeks of age, all animals except the vehicle-treated groups were given s.c. injections of azoxymethane (AOM) (15 mg/kg body weight, once weekly for 2 weeks). Four days after the second injection, groups of animals were restricted to 90, 80, or 70% of total calories consumed by the high fat ad libitum group (i.e., 10, 20, and 30% calorie restriction, respectively). In the low fat groups, animals were restricted to 80% of total calories consumed by the low fat ad libitum group (i.e., 20% restriction). Thirty-six weeks after AOM injections, all animals were necropsied and colon tumors were used for histopathology and ODC and protein tyrosine kinase analysis. In the second experiment, the protocol was the same as above except that the animals were sacrificed 5 days after the second AOM injection and colonic mucosal ODC and protein tyrosine kinase activities were assayed. The incidence and multiplicity of colon tumors were significantly inhibited in animals fed the high fat 20% calorie-restricted and high fat 30% calorie-restricted diets, as compared to those fed the high fat ad libitum diet. The regression coefficient representing the dose-response effect of different levels of calorie restriction in both high fat groups is significant. Results also indicate that AOM treatment significantly increased the colonic mucosal ODC and protein tyrosine kinase activities. This stimulation was inhibited by feeding the calorie-restricted diets. ODC and protein tyrosine kinase activities were lower in the colon tumors of animals fed the calorie-restricted diets.     

Inhibition of chemically induced mammary and colon tumor promotion by caloric restriction in rats fed increased dietary fat

Tumor promotion associated with increased dietary fat may be inhibited by reduction in total caloric intake. This hypothesis was tested in rats given either 7,12-dimethylbenz(a)anthracene to induce mammary tumors or 1,2-dimethylhydrazine to induce colon tumors. One week after dosage with either carcinogen, the rats were fed semipurified diets that provided 4% fat with ad libitum calories or 13.1% fat with a reduction of calories by 40% from ad libitum intake. Rats treated with 7,12-dimethylbenz(a)anthracene and subjected to caloric restriction weighed 40% less than those fed ad libitum; rats treated with 1,2-dimethylhydrazine were heavier at the onset of caloric restriction and lost weight and weighed approximately 40% less than animals fed ad libitum. At 20 weeks after 7,12-dimethylbenz(a)anthracene administration, rats fed ad libitum had 80% tumor incidence while in those fed restricted calories, 20% had tumors (P less than 0.001). All other measures of mammary tumor growth were significantly reduced in rats given restricted calories. Six months after 1,2-dimethylhydrazine administration, colon tumor incidence was 100% in rats fed ad libitum and 53% in those fed the calorie-restricted diet (P less than 0.001). This reduction of colonic carcinogenesis was seen despite a significant increase in mucosal labeling index following [3H]thymidine autoradiography. This paradoxical finding may be due to the increased fat content of the calorie-restricted diet. These data demonstrate that the tumor-promoting effects of dietary fat can be more than offset by a reduction in total caloric intake and that the promoting effect of fat may be due, at least in part, to its greater caloric density.     

Inhibitory effect of dietary p-methoxybenzeneselenol on azoxymethane-induced colon and kidney carcinogenesis in female F344 rats

The effect of dietary p-methoxybenzeneselenol on colon carcinogenesis induced by azoxymethane [(AOM) CAS: 25843-45-2] was studied in female F344 rats. Starting at 5 weeks of age, animals were fed the high-fat diet (control diet) or high-fat diet to which 50 ppm of p-methoxybenzeneselenol (experimental diet) had been added. At 7 weeks of age, all animals except the vehicle-treated controls were administered sc injections of AOM (15 mg/kg body wt, once weekly for 3 wk). Animals were fed the control and experimental diets until 1 week after carcinogen treatment when those animals receiving the p-methoxybenzeneselenol diet were fed the control diet until termination of the experiment. p-Methoxybenzeneselenol in the diet significantly inhibited the incidence (percentage of animals with tumors) of tumors in the colon and kidney, as well as the colon tumor multiplicity (adenomas and adenocarcinomas per animal).     

Effect of different levels of dietary trans fat or corn oil on azoxymethane-induced colon carcinogenesis in F344 rats

The effect of various levels of dietary corn oil or trans fat on azoxymethane (AOM; CAS: 25843-45-2)-induced carcinogenesis was investigated in female F344 rats fed the AIN-76 semipurified diets. Starting at 5 weeks of age, groups of rats were fed the low-fat diet containing 5% corn oil (designated as low-fat control diet). At 7 weeks of age, all animals except the vehicle-treated controls, were given sc injections of AOM (15 mg/kg body wt, once weekly) for 3 weeks. After 1 week, groups of animals were transferred to semipurified diets containing 13.6% corn oil and 23.5% corn oil or high-fat diets containing 5.9% corn oil plus 5.9% trans fat plus 11.8% Oleinate (low trans fat), 5.9% corn oil plus 11.8% trans fat plus 5.9% Oleinate (intermediate trans fat), and 5.9% corn oil plus 17.6% trans fat (high trans fat). Fecal bile acids were measured in vehicle-treated rats. All animals were necropsied 34 weeks after the last AOM injection. The animals fed the 23.5% corn oil diet had a higher incidence of colon tumors than did those in the groups fed the 5 and 13.6% corn oil diets. There was no difference in colon tumor incidence between the 5 and 13.6% corn oil diet groups. The animals fed the high-fat diets containing low trans fat, intermediate trans fat, and high trans fat developed significantly fewer liver and colon tumors and more small intestinal tumors than did the rats fed 23.5% corn oil diet. The excretion of fecal deoxycholic acid, lithocholic acid, and 12-ketolithocholic acid was higher in animals fed the 23.5% corn oil diet compared to the excretion in animals fed the other diets.     

Chemoprevention of colon carcinogenesis by the synthetic organoselenium compound 1,4-phenylenebis(methylene)selenocyanate.

The chemopreventive effect of 40% and 80% maximum tolerated dose (MTD) levels of 1,4-phenylenebis(methylene)selenocyanate (p-XSC) administered in the diet during the initiation phase (2 weeks before, during, and up to 3 days after carcinogen administration) and the post-initiation phase (3 days after carcinogen treatment until termination) of azoxymethane (AOM)-induced colon carcinogenesis was studied in male F344 rats. The MTD of p-XSC was determined in male F344 rats and found to be 50 ppm. Beginning at 5 weeks of age, all animals were divided into various experimental groups (42 rats/group) and fed the high-fat semipurified diet or diets containing 20 (40% MTD) and 40 (80% MTD) ppm p-XSC. At 7 weeks of age, all animals (30 rats/group) except the vehicle-treated groups (12 rats/group) were administered s.c. injections of AOM (15 mg/kg body weight/week for 2 weeks). Three days after the second injection of AOM or vehicle (normal saline), groups of animals fed the p-XSC diets and control diet were transferred, respectively, to control diet and p-XSC diets and continued on these diets until the termination of the study. All animals were necropsied during the 36th week after AOM treatment. Colonic mucosal prostaglandin E2 and selenium-dependent glutathione peroxidase were measured in animals fed the control and p-XSC diets at the termination of the study. The results indicate that 40 ppm p-XSC administered during the initiation phase significantly inhibited the colon tumor incidence (percentage of animals with tumors). Dietary p-XSC administered at 20 and 40 ppm levels during the initiation phase significantly inhibited colon tumor multiplicity (tumors/animal and tumors/tumor-bearing animal). Colon tumor incidence and multiplicity were significantly reduced in groups fed 20 and 40 ppm p-XSC diets at the postinitiation phase of carcinogenesis. Colonic mucosal selenium-dependent glutathione peroxidase activity was increased, and prostaglandin E2 was reduced in animals fed the p-XSC diet compared to animals fed the control diet. Whereas the precise mechanisms of p-XSC-induced inhibition of colon carcinogenesis remain to be elucidated, it is likely that the effect during the initiation and postinitiation phases may be due to alteration in carcinogen metabolism and to modulation of prostaglandin synthesis and selenium-dependent glutathione peroxidase activity.     

Promotion of azoxymethane-induced intestinal cancer by high-fat diet in rats.

Promotional properties of a high-fat diet in intestinal cancer were studied by feeding a 30% beef fat diet to 8 groups of rats (25 rats/group) for time periods varying from 1 to 21 weeks after 8 weekly s.c. injections of azoxymethane (AOM) (8 mg/ kg). Two other groups were fed the high-fat diet, one for 8 weeks prior to and the other during AOM injections. A 5% fat diet was fed to rats when not on the 30% fat diet and to a control group of 25 animals. High fat diet increased intestinal tumor frequency up to 2-fold when given for at least 4 weeks after but not during or prior to AOM injections; this increase occurred even after a prolonged interval (10 weeks) between the last AOM injection and the high-fat diet. In general, tumor frequency increased according to the length of time animals were fed the high-fat diet after AOM. Therefore, the high-fat diet in this model exhibited most of the properties of promoters developed from murine skin cancer, thus adding support to the concept that excess dietary fat acts at the promotional phase of carcinogenesis.     

Mechanisms in the chemoprevention of colon cancer: modulation of protein kinase C, tyrosine protein kinase and diacylglycerol kinase activities by 1,4-phenylenebis-(methylene)selenocyanate and impact of low-fat diet

Epidemiological and experimental studies suggest an inverse relationship between the intake of dietary selenium and/or low fat-intake and colon cancer risk. Efficacy studies in rodents suggest that the organoselenium compound 1, 4-phenylenebis(methylene)selenocyanate (p-XSC), is a more effective and less toxic chemopreventive agent than other organic or inorganic selenium compounds such as selenomethionine and Na2SeO3. The efficacy of p-XSC against colon cancer is significantly augmented by a low-fat diet. To explore the mechanisms by which this combined inhibiting effect against colon carcinogenesis comes about, we have investigated protein kinase C (PKC), tyrosine protein kinase (TPK), diacylglycerol kinase (DGK) activities and 8-isoprostane levels in colonic mucosa and tumor tissues in an azoxymethane (AOM)-induced rat colon cancer model. Weanling male F344 rats were fed the semipurified AIN-76A diet until seven weeks of age. Then various experimental groups were fed the low- or high-fat diets containing 0 or 20 ppm p-XSC (10 ppm as selenium). At seven weeks of age, groups of rats were injected s.c. with azoxymethane (AOM; 15 mg/kg body wt., once weekly for 2 weeks) and continued on their respective experimental diets until 38 weeks after the second AOM treatment. They were then sacrificed and colonic mucosal and tumor samples were evaluated for PKC, TPK, DGK and 8-isoprostane levels. Administration of p-XSC along with a low-fat diet significantly inhibited Ca+2-dependent and -independent PKC (P<0.05-0.01) activities in colonic mucosa and tumors. Administration of p-XSC either low-fat or high-fat diet significantly suppressed both colonic mucosal and tumor TPK activity (P<0.05-0.01). Suppression of TPK activity was more pronounced in rats maintained on a low-fat diet containing p-XSC. In contrast, rats receiving p-XSC with either low- or high fat diet showed significantly increased DGK activity (P<0.01-0.0001). Rats fed low-fat or high-fat plus p-XSC had lower-levels of 8-isoprostane in the colonic tumors than animals who had been given low- or high-fat diets without the organoselenium compound. Interestingly, 8-isoprostane levels were lower in the colon tumors of the rats fed the low-fat diet than those fed the high-fat diet. Our findings suggest that p-XSC induced down-regulation of PKC and TPK activities and up-regulation of DGK activity. These events may in part be responsible for the chemopreventive activity against colon carcinogenesis. Further, this study implies that p-XSC with a low-fat dietary regimen will augment regulation of PKC, TPK and DGK activities in the colon.     

Effect of dietary alfalfa, pectin, and wheat bran on azoxymethane-or methylnitrosourea-induced colon carcinogenesis in F344 rats.

The effect of dietary alfalfa, pectin, and wheat bran on colon carcinogenesis was studied in female inbred F344 rats. Weanling rats were fed semipurified diets containing 0 or 15% alfalfa, pectin, or wheat bran. At 7 weeks of age, all animals except controls were given azoxymethane (AOM) sc at a dose rate of 8 mg/kg body weight/week for 10 weeks or methylnitrosourea (MNU) intrarectally at a dose rate of 2 mg/rat twice a week for 3 weeks. The AOM-treated group was autopsied 40 weeks and the MNU-treated group 30 weeks after the first injection of the carcinogen. No tumors were observed in the colon or other organs of untreated rats fed the various diets. The animals fed the alfalfa diet and treated with MNU had a higher incidence of colon tumors than did those fed the control diet or the diets containing pectin or wheat bran. The incidence of MNU-induced colon tumors did not differ between the animals fed the control diet or the diets containing pectin or wheat bran. However, the incidence of AOM-induced colon tumors in rats fed diets containing pectin or wheat bran was lower than that in rats fed the control diet or the alfalfa diet. These results thus indicate that the effect of fiber in colon carcinogenesis depends on the type of fiber and, possibly, the fiber's mode of action.     

Enhancement of mammary carcinogenesis by high levels of dietary fat: a phenomenon dependent on ad libitum feeding

Female 55-day-old Sprague-Dawley rats were treated with a single intravenous dose of 7,12-dimethylbenzanthracene (DMBA), 2 mg/100 g of body weight each. At 60 days of age, the rats were divided into four dietary groups (41-42 rats/group):I, 5% corn oil diet fed ad libitum; II, 20% corn oil diet fed ad libitum; III, 5% corn oil diet fed 12% less than group I; and IV, 20% corn oil diet fed 12% less than group II. The 5% and 20% corn oil diets were purified semisynthetic diets that were isonutrient on a caloric basis. All animals were housed individually in single cages; food consumption of each animal was computed daily throughout the study. Sixteen weeks after carcinogen treatment, mean numbers of mammary carcinomas per rat (+/- SE) in groups I, II, III, and IV were 4.1 +/- 0.6, 6.8 +/- 0.7, 3.0 +/- 0.3, and 4.1 +/- 0.5, respectively. Mean weight of mammary carcinomas per rat (g +/- SE) in groups I, II, III, and IV were 3.5 +/- 0.7, 8.0 +/- 1.3, 3.0 +/- 1.1, and 4.6 +/- 1.3, respectively. Mammary carcinoma number and weight were significantly (P less than .01) increased in the animals fed the 20% corn oil diet ad libitum when compared with those fed the 5% corn oil diet ad libitum; however, no significant differences in mammary tumor number or weight were observed between the animals fed a restricted, 20% corn oil diet and those fed a restricted, 5% corn oil diet. The study involving the animals fed the 12%-restricted diets was repeated (38-42 rats/group), with virtually identical results, i.e., the mean number of mammary carcinomas per rat in the groups fed the restricted 5% fat and 20% fat diets at termination of the study was 3.1 +/- 0.4 and 3.7 +/- 0.3, respectively, and the mean weight (g) of mammary carcinomas per rat was 4.3 +/- 1.2 and 4.0 +/- 1.1, respectively (no significant differences). Thus, high levels of dietary fat can significantly enhance mammary carcinogenesis in female rats, but only in animals on an ad libitum feeding protocol. A slight restriction in amount consumed (12% less than ad libitum) abolished the mammary carcinogenic differential between a high-fat and a low-fat diet.     

Effect of voluntary exercise on azoxymethane-induced hepatocarcinogenesis in male F344 rats.

The effect of voluntary exercise on azoxymethane-induced hepatocarcinogenesis was investigated in male F344 rats. Beginning at 5 weeks of age, all animals were divided into two groups (sedentary and exercise) and fed AIN-76A semipurified diet ad libitum. At 7 weeks of age, animals were given azoxymethane (AOM) s.c. at a dose level of 15 mg/kg of body weight, once weekly for 2 weeks. Four days after the second dose of AOM, all animals in the exercise group were housed in individual wheel-cage units and the animals in the sedentary group were housed in plastic cages. The experiment was terminated at 38 weeks post-AOM treatment. Body weights of animals in the exercise and sedentary groups were comparable. Immunohistochemical staining of glutathione S-transferase placental form (GST-P) was performed in the liver and measured GST-P positive foci. Density (number of GST-P positive foci/cm2 area of liver section), average area of foci and unit area of foci were significantly inhibited in the exercise group, although the incidence of neoplastic nodules and GST-P positive foci were unaffected by the exercise. Thus, energy expenditure due to exercise may reduce hepatocarcinogenesis in a laboratory animal model.     

Inhibition of colon carcinogenesis by prostaglandin synthesis inhibitors and related compounds.

The inhibitory effect of 40 and 80% maximum tolerated dose (MTD) levels of piroxicam, ibuprofen, ketoprofen and glycyrrhetinic acid on colon carcinogenesis was investigated in male F344 rats. The MTD levels of piroxicam, ibuprofen, ketoprofen and glycyrrhetinic acid as determined in male F344 rats were 500, 500, 250 and 3000 p.p.m. respectively. At 5 weeks of age, groups of male F344 rats were fed the control (AIN-76A) diet and 40 and 80% MTD levels of each test agent in AIN-76A diet. At 7 weeks of age, all animals except the vehicle (saline)-treated controls received azoxymethane (AOM) at a dose rate of 15 mg/kg body wt, once weekly for 2 weeks. All animals were necropsied 50 weeks after the second AOM injection and colon tumor incidences were compared among the groups fed the control diet and chemopreventive agents. Animals fed 400 (80% MTD) and 200 p.p.m. (40% MTD) of piroxicam, 400 p.p.m. (80% MTD) of ibuprofen and 200 p.p.m. (80% MTD) of ketoprofen showed a significant inhibition of colon tumorigenesis as compared to those fed the control diet. Results analyzed by the linear regression method suggested a dose-dependent inhibition of colon carcinogenesis with increasing levels of piroxicam or ibuprofen. In contrast, glycyrrhetinic acid had no measurable chemopreventive effect on colon carcinogenesis.     

Effect of diets high in omega-3 and omega-6 fatty acids on initiation and postinitiation stages of colon carcinogenesis.

The effect of dietary menhaden oil containing omega-3 fatty acids and corn oil rich in omega-6 fatty acids fed during the initiation and/or postinitiation stages of colon carcinogenesis was investigated in male F344 rats. At 5 weeks of age, all animals were divided into seven groups (39 rats/group) and fed the semipurified diets containing 5% corn oil (LCO), 23.5% corn oil (HCO), or 18.5% menhaden oil plus 5% corn oil (HFO). At 7 weeks of age, all animals except the vehicle (normal saline)-treated groups were given two weekly s.c. injection of azoxymethane (AOM) at a dose rate of 15 mg/kg body weight, once weekly. Three days after the second injection of AOM, groups of animals fed LCO, LCO, HCO, HCO, HCO, HFO, or HFO diets were transferred, respectively, to LCO, HCO, LCO, HCO, HFO, HCO, or HFO and continued on these diets until termination of the experiment. All animals were necropsied 42 weeks after carcinogen treatment. Body weights of animals fed various experimental diets during the initiation and postinitiation periods were comparable. As expected, the HCO diet fed during the postinitiation period significantly increased the AOM-induced incidence and multiplicity of colon adenocarcinomas, whereas the HCO diet fed during the initiation phase of carcinogenesis had no effect. Colon tumor incidence and multiplicity were significantly reduced in groups fed the HFO diet at either initiation and/or postinitiation phases of carcinogenesis as compared with those fed the HCO diet. Whereas the precise mechanisms producing the difference between the high menhaden oil (HFO) diet as compared with high corn oil (HCO) diet remain to be elucidated, it is likely that the effect during the initiation and postinitiation phases may be due to alteration in carcinogen metabolism and to modulation of prostaglandin synthesis, respectively.     

Enhancement of pancreatic carcinogenesis in hamsters fed a high-fat diet ad libitum and at a controlled calorie intake

An enhancement of pancreatic cancer induced by N-nitrosobis-(2-oxopropyl)amine (BOP) was reported previously in Syrian hamsters fed high-fat diet following carcinogen treatment. The purpose of our research was to determine if this enhancement was due to the consumption of more calories by the hamsters fed the high-fat diet. Male hamsters were treated with a single injection of BOP (20 mg/kg body weight s.c.) at 8 weeks of age. One week later they started either on a low-fat diet (4.3% corn oil) or a high-fat diet (20.5% corn oil) that was fed until the end of the experiment at 92 weeks after BOP. Diets were fed either ad libitum or in a control-fed protocol. The control-fed groups had equivalent calorie intakes and were restricted slightly in comparison with the ad libitum-fed hamsters. BOP treatment reduced survival slightly but survival did not differ significantly in accordance with dietary assignment. Body weight was elevated in the hamsters fed high-fat diet ad libitum in comparison with those fed low-fat diet ad libitum. However, differences were not observed in hamsters fed low- and high-fat diets by the control-fed protocol. Pancreatic carcinogenesis was enhanced about 3- to 4-fold when hamsters were fed high-fat diet by either protocol. The degree of enhancement did not differ with the feeding regimen. However, the higher death rate with pancreatic cancer occurred earlier in the ad libitum-fed hamsters than in the control-fed hamsters.     

Inhibition by dietary benzylselenocyanate of hepatocarcinogenesis induced by azoxymethane in Fischer 344 rats

The effect of dietary benzylselenocyanate (BSC), a novel organoselenium compound and its sulfur analog, benzylthiocyanate (BTC), on hepatocarcinogenesis induced by azoxymethane (AOM) was investigated in male F344 rats. Eighty-one weanling rats were divided into 3 groups and were raised on a semipurified diet (control diet). Starting from 5 weeks of age, groups of animals consuming the control diet were fed one of the experimental diets containing 25 ppm BSC or BTC. An additional group was continued on the control diet. At 7 weeks of age, animals were given weekly sc injections of AOM (15 mg/kg body weight once weekly for 2 weeks). One week after the second AOM injection, those groups receiving BSC and BTC diets were transferred to the control diet and continued on this diet until termination of the experiment at 34 weeks after the last AOM injection. For quantitative analysis of enzyme-altered liver cell foci, glutathione S-transferase placental form was stained by an immunohistochemical technique. The results indicate that the incidence and the density of the enzyme-altered foci were significantly lower in AOM-treated rats fed the diet containing 25 ppm BSC (foci incidence 56%, foci density 2.43/cm2) than in AOM-treated animals fed the control diet (foci incidence 92%, foci density 4.79/cm2). The incidence of small altered foci was significantly inhibited in rats fed the BTC diet (35%) as compared to those fed the control diet (68%), but the degree of inhibition was more pronounced in animals fed the BSC diet than in those fed the BTC diet.     

Effect of Konjac mannan on 1,2-dimethylhydrazine-induced intestinal carcinogenesis in Fischer 344 rats

The effect of Konjac mannan (KM) on 1,2-dimethylhydrazine (DMH-induced intestinal carcinogenesis was studied in male F344 rats. Rats were fed a diet containing 5% KM at 5 weeks of age. At 6 weeks of age, all animals were given a weekly intraperitoneal injection of 20 mg DMH/kg body wt for 13 weeks and autopsied 13 weeks after the last injection of DMH. The weight gain was lower in rats fed the KM diet than in rats fed the control diet throughout the experiment (P less than 0.05). The incidence of DMH-induced colon tumors was lower in animals fed the KM diet compared to animals fed the control diet (P less than 0.05). The number of colon adenocarcinoma per animal was also lower in animals fed the KM than in animals fed the control diet (P less than 0.05). However, the incidence of tumors of the small intestine did not significantly differ between the groups fed the KM and control diets. The present study demonstrated that colon tumorigenesis induced by DMH in F344 rat was inhibited by maintaining the KM diet.     

Effect of different levels of dietary corn oil and lard during the initiation phase of colon carcinogenesis in F344 rats

The effect of various levels of polyunsaturated fat (corn oil) and saturated fat (lard) fed during the initiation stage of colon carcinogenesis was studied in male F344 rats. The animals were fed the diets containing 5, 13.6, and 23.5% corn oil or lard 2 weeks before, during, and until 1 week after sc injection of 15 mg azoxymethane [(AOM) CAS: 25843-45-2]/kg body weight, once weekly for 2 weeks (designated as initiation). One week after AOM treatment, groups of animals were transferred to their respective 5% corn oil or lard diets. Additional groups consuming 5% corn oil or lard were transferred to 23.5% corn oil or lard, respectively (post-initiation stage). All animals were fed these diets until the termination of the experiment. Fecal bile acids and colonic mucosal ornithine decarboxylase activity were measured in vehicle-treated animals fed the experimental diets for 14 weeks. Body weights and intakes of total calories, protein, nonnutritive fiber, and micronutrients were comparable among the various dietary groups. The animals fed the 23.5% corn oil diet during the postinitiation stage had a higher incidence of colon tumors than did those fed the 5% corn oil diet, whereas feeding of 23.5 and 13.6% corn oil diets during the initiation stage had no effect. In contrast, animals fed the 23.5 and 13.6% lard diet during the initiation stage and 23.5% lard diet during the postinitiation stage developed more colon adenocarcinomas than did those fed the 5% lard diet. The excretion of fecal deoxycholic acid, lithocholic acid, and 12-ketolithocholic acid and the activity of colonic mucosal ornithine decarboxylase activity were higher in animals fed the 23.5% corn oil or lard diet during the postinitiation compared to the levels in animals fed the 5% corn oil or lard diet.     

Interactions of selenium deficiency, vitamin E, polyunsaturated fat, and saturated fat on azoxymethane-induced colon carcinogenesis in male F344 rats

The effect of the interaction of selenium deficiency, excess vitamin E, and type of fat on colon carcinogenesis induced by azoxymethane (AOM) was studied in male F344 rats. The experimental diets, based on a Torula yeast diet and containing 20% stripped corn oil or 20% stripped lard, were as follows: 1) selenium deficient with adequate (50 mg/kg diet) vitamin E, 2) selenium deficient with excess (750 mg/kg diet) vitamin E, 3) selenium adequate with adequate vitamin E, and 4) selenium adequate with excess vitamin E. Starting at about 3 weeks of age, animals were fed the experimental diets, and at 7 weeks of age all animals except the vehicle-treated controls were given sc injections of AOM (15 mg/kg body wt) once weekly for 2 weeks. Animals were fed the experimental diets until termination of the experiment. Selenium deficiency significantly inhibited the incidence (percentage of animals with tumors) and multiplicity (tumors per animal) of colon adenocarcinomas and adenomas, whereas excess vitamin E had no effect on colon carcinogenesis. There was no interaction between the selenium status and vitamin E; the selenium status and type of fat; vitamin E and type of fat; and among selenium status, vitamin E, and type of fat.     

Net energy effects of dietary fat on chemically induced mammary carcinogenesis in F344 rats

The effect of net energy, as distinct from kilocalorie intake or the percent of fat in the diet, on 7,12-dimethylbenz[a]anthracene [(DMBA) CAS: 57-97-6]-induced mammary tumorigenesis in female inbred F344 rats was investigated. Rats were fed a 5% corn oil diet from weaning until DMBA administration, when they were switched to one of three dietary regimens: 5% corn oil diet, low-fat diet fed ad libitum (LF); 30% corn oil diet, high-fat diet fed ad libitum (HF); or 30% corn oil diet fed at a level providing a calculated net energy equivalent to the group on LF [high-fat diet fed at a restricted level (HF-R)]. Calculated relative net energy values of the amounts of diet actually consumed by the groups on HF-R, LF, and HF were, respectively, 0.90, 1.00, and 1.07 (kcal equivalent to 34.1, 42.2, and 40.8, respectively). Weight gain for the groups on LF and HF-R was the same throughout the experiment (24 wk), while rats on HF weighed significantly more at 6 weeks and thereafter. Body composition analyses at 24 weeks established that the groups on HF and HF-R were equivalent in fat: protein ratio, whereas the group on LF had about 35% less body fat and 15% more body protein. Carcass energy was in the following order for rats in these diet groups: HF greater than HF-R greater than LF. At 24 weeks, tumor incidences for the groups on HF, LF, and HF-R were, respectively, 73, 43, and 7%. These data indicated that tumor appearance does not depend on the percent fat in the diet per se but rather on a complex interaction involving energy intake, energy retention, and body size.     

Modifying effects of Terminalia catappa on azoxymethane-induced colon carcinogenesis in male F344 rats.

The modifying effects of dietary administration of an herb, Terminalia catappa (TC), were investigated on rat colon carcinogenesis induced by a carcinogen azoxymethane (AOM). The number of aberrant crypt foci (ACF) and beta-catenin accumulated crypts (BCACs) in the colon, and proliferating cell nuclear antigen (PCNA) labelling index in the colonic epithelium were examined in a total of 36 male F344 rats. All animals were randomly divided into five experimental groups (4-10 rats in each group). At 6 weeks of age, rats in groups 1, 2 and 3 were given s.c. injections of AOM once a week for 2 weeks at a concentration of 20 mg/kg body weight. One week before the first injection of AOM, rats in groups 2 and 3 were fed a diet containing 0.02 and 0.1% TC, respectively, throughout the experiment. Rats in group 4 were fed a diet containing 0.1% TC. Rats in group 5 were served as untreated controls. All animals were sacrificed at the experimental week 5 after the start of the experiment. Oral administration of TC at both doses significantly decreased the numbers of both ACF/colon/rat (P<0.05 for 0.02% TC, P<0.005 for 0.1% TC) and BCAC/cm/rat (P<0.05 for both 0.02 and 0.1% TC), when compared with the control group (group 1). Colonic PCNA labelling index in groups 2 and 3 was also significantly lower than that in group 1 (P<0.001 for 0.02% TC, P<0.005 for 0.1% TC). These results suggest that TC has a potent short-term chemopreventive effect on biomarkers of colon carcinogenesis and this effect may be associated with the inhibition of the development of ACF and BCACs.     

Inhibition by Dietary Benzylselenocyanate of Hepatocarcinogenesis Induced by Azoxymethane in Fischer 344 Rats1

The effect of dietary benzylselenocyanate (BSC), a novel organoselenium compound and its sulfur analog, benzylthiocyanate (BTC), on hepatocarcinogenesis induced by azoxymethane (AOM) was investigated in male F344 rats. Eighty-one weanling rats were divided into 3 groups and were raised on a semipurificd diet (control diet). Starting from 5 weeks of age, groups of animals consuming the control diet were fed one of the experimental diets containing 25 ppm BSC or BTC. An additional group was continued on the control diet. At 7 weeks of age, animals were given weekly sc injections of AOM (15 mg/kg body weight once weekly for 2 weeks). One week after the second AOM injection, those groups receiving BSC and BTC diets were transferred to the control diet and continued on this diet until termination of the experiment at 34 weeks after the last AOM injection. For quantitative analysis of enzyme-altered liver cell foci, glutathione S-transferase placental form was stained by an immunohistochemical technique. The results indicate that the incidence and the density of the enzyme-altered foci were significantly lower in AOM-treated rats fed the diet containing 25 ppm BSC (foci incidence 56%, foci density 2.43/cm²) than in AOM-treated animals fed the control diet (foci incidence 92%, foci density 4.79/cm²). The incidence of small altered foci was significantly inhibited in rats fed the BTC diet (35%) as compared to those fed the control diet (68%), but the degree of inhibition was more pronounced in animals fed the BSC diet than in those fed the BTC diet.