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 dietary excess of inorganic selenium during initiation and postinitiation phases of colon carcinogenesis in F344 rats

The effect of supplemental inorganic selenium given during the initiation or postinitiation phase of colon carcinogenesis induced by azoxymethane [(AOM)CAS:25843-45-2] was studied in male F344 rats. Weanling animals were raised on AIN-76A semipurified (control) diet. Starting at 4 wk of age, groups of animals intended for initiation study were fed the semipurified diets containing 0.5 and 2.5 ppm selenium in the form of sodium selenite, and those intended for postinitiation study were continued on the control diet. At 7 wk of age, all animals except the vehicle-treated controls were injected s.c. with AOM (15 mg/kg body weight, once weekly for 2 wk). One wk following AOM treatment, animals in the initiation study receiving the supplemental selenium were transferred to the control diet whereas those in the postinitiation study receiving the control diet were transferred to the diets containing 0.5 and 2.5 ppm selenium. These animals were continued on this regimen until the termination of the experiment at 34 wk post-AOM injection. Tissue and blood glutathione peroxidase activity was measured in vehicle-treated animals fed the control and selenium-supplemented diets. The results indicate that body weights were comparable among the various dietary groups. Feeding of diets containing 0.5 and 2.5 ppm selenium during the initiation phase had no effect on colon tumor incidence, but the multiplicity of adenomas was slightly inhibited in animals fed the 2.5 ppm selenium diet. The incidence and multiplicity of colon adenocarcinomas and the multiplicity of colon adenomas were inhibited in animals fed the 2.5-ppm selenium diet during the postinitiation phase of carcinogenesis. The incidence of small intestinal tumors was higher in animals fed the 2.5-ppm selenium diet during the initiation phase than in animals fed the control diet and 0.5-ppm selenium diet. Selenium-dependent glutathione peroxidase activity was increased in kidneys and small and large intestinal mucosae of animals fed the 2.5-ppm selenium diet compared to those fed the 0.5-ppm selenium and control diets.     

Dose-related inhibition of colon carcinogenesis by dietary piroxicam, a nonsteroidal antiinflammatory drug, during different stages of rat colon tumor development

The effect of four dose levels of piroxicam administered during different stages of colon tumor development was studied in male F344 rats to obtain a data base on the efficacy of piroxicam as an inhibitor of colon carcinogenesis. Piroxicam was added at levels of 25, 50, 75, and 150 ppm to the NIH-07 open-formula diet and fed to male F344 rats starting 1, 13, and 23 wk after the carcinogen administration. At 7 wk of age, while the animals were consuming the control diet, all animals except the vehicle-treated controls were given s.c. injection of azoxymethane (CAS:25843-45-2; 29.6 mg/kg body weight, once) to induce intestinal tumors. Forty wk after AOM injection, all animals were necropsied, and tumor incidences were compared among the various dietary groups. Colon tumor incidence (percentage of animals with tumors) was inhibited in a dose-dependent manner in rats fed the diets containing 25, 50, 75, and 150 ppm piroxicam starting 1 and 13 wk after carcinogen treatment. The colon tumor incidences in animals fed the diets containing 0, 25, 50, 75, and 150 ppm of piroxicam starting at 1 wk after carcinogen treatment were 89, 61, 58, 50, and 39%, respectively. When the diets containing 0, 25, 50, 75, and 150 ppm were fed 13 wk after carcinogen treatment, the colon tumor incidences were 89, 69, 69, 44, and 33%, respectively. Colon tumor multiplicity (tumors/animal; tumors/tumor-bearing animal) was also significantly inhibited in animals fed the diets containing 25 to 150 ppm piroxicam starting 1 and 13 wk after carcinogen administration. The number of colon tumors/animal was inhibited by about 80 to 84% in animals fed the 150 ppm piroxicam diet. When the diets containing different levels of piroxicam were fed 23 wk after carcinogen treatment, the colon tumor incidence was significantly inhibited in animals fed the 75 and 150 ppm piroxicam diets. The colon tumor incidences in animals fed the diets containing 0, 25, 50, 75, and 150 ppm were 89, 78, 67, 64, and 64%, respectively. The colon tumor multiplicity (colon tumors/animal) was slightly but significantly inhibited in animals fed the diets containing 25 to 150 ppm piroxicam. The results of this study demonstrate that increasing levels of piroxicam in the diet, when fed 1 or 13 wk after carcinogen insult, inhibit colon tumor incidence in a dose-dependent manner.     

Chemoprevention of colon carcinogenesis by concurrent administration of piroxicam, a nonsteroidal antiinflammatory drug with D,L-alpha-difluoromethylornithine, an ornithine decarboxylase inhibitor, in diet

The effect of three levels of piroxicam and three levels of D,L-alpha-difluoromethylornithine (DFMO) fed individually and in combination during the postinitiation phase of carcinogenesis was studied in male F344 rats to generate a data base on the efficacy and synergistic and additive effects of these compounds as inhibitors of colon carcinogenesis. The maximum tolerated dose of DFMO was determined in male F344 rats and found to be 5000 ppm in the AIN-76A diet. Piroxicam at levels of 25, 75, and 150 ppm and DFMO at concentrations of 400, 1000, and 4000 ppm (20, 50, and 80% maximum tolerated dose) in AIN-76 diet were tested individually and in combinations. At 7 weeks of age, while the rats were consuming the control diet (AIN-76A), all animals except the vehicle (saline)-treated controls were given a single s.c. injection of azoxymethane (CAS: 25843-45-2) at a dose level of 29.6 mg/kg body weight to induce intestinal tumors. One week after azoxymethane injection, animals were transferred to their respective experimental diets containing piroxicam and DFMO. Fifty-six weeks after azoxymethane injection, all animals were necropsied and colon and small intestinal tumor incidences and multiplicity were compared among the various dietary groups. Feeding of diets containing 75 and 150 ppm piroxicam or 1000 and 4000 ppm DFMO significantly inhibited the incidence (percentage of animals with tumors) of colon adenocarcinomas compared to that of control diet. The multiplicity (number of tumors/rat) of adenocarcinomas was significantly inhibited in animals fed the 25, 75, and 150 ppm piroxicam or 400, 1000, and 4000 ppm DFMO diets. Results analyzed by the linear regression method suggested a dose-dependent inhibition in colon adenocarcinoma incidence with increasing levels of piroxicam or DFMO. The incidence and multiplicity of colon adenocarcinomas were significantly inhibited in animals fed the diets containing combinations of 25, 75, and 150 ppm piroxicam and 400, 1000, and 4000 ppm DFMO. Piroxicam and DFMO administered together had a stronger inhibitory effect than did those given individually. Piroxicam and DFMO when administered individually had no significant inhibitory effect on colon adenoma incidence and multiplicity; in contrast, combinations of these compounds significantly inhibited colon adenomas. No consistent differences were found in the incidence and multiplicity of small intestinal tumors among the dietary groups.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effect of different levels of omega-3 and omega-6 fatty acids on azoxymethane-induced colon carcinogenesis in F344 rats

The effect of various levels of dietary Menhaden fish oil containing omega-3 fatty acids plus corn oil containing omega-6 fatty acids fed during the postinitiation phase of colon carcinogenesis was studied in male F344 rats. Starting at 5 weeks of age, groups of animals were fed the 5% corn oil (5% CO) diet. At 7 weeks of age, all animals except the vehicle-treated controls were administered s.c. injections of azoxymethane (15 mg/kg body wt/week for 2 weeks). 4 days after carcinogen or vehicle treatment, groups of animals were transferred to experimental diets containing 4% Menhaden oil + 1% corn oil (4% MO + 1% CO), 23.5% corn oil (23.5% CO), 17.6% corn oil + 5.9% Menhaden oil (17.6% CO + 5.9% MO), 11.8% corn oil + 11.8% Menhaden oil (11.8% CO + 11.8% MO), or 5.9% corn oil + 17.6% Menhaden oil (5.9% CO + 17.6% MO) and fed these diets until termination of the experiment at Week 38 after carcinogen treatment. An additional group consuming a 5% CO diet was continued on these diets. Colon mucosal ornithine decarboxylase activity and microsomal fatty acid composition of colon mucosa were measured in vehicle-treated animals fed experimental diets for 14 weeks. Fatty acids were also analyzed in the microsomal fraction of colon tumors at termination of the experiment. The body weights of animals fed various experimental diets were comparable. Feeding of high fat diets containing 17.6% CO + 5.9% MO, 11.8% CO + 11.8% MO, or 5.9% CO + 17.6% MO significantly inhibited the incidence (percentage of animals with tumors) of colon adenocarcinomas compared to that of 23.5% CO diet. However, the multiplicity (number of tumors/rat) of colon adenocarcinomas was significantly inhibited only in groups fed the 5.9% CO + 17.6% MO compared to those fed the 23.5% CO diet. The incidence and multiplicity of adenocarcinomas were greater in animals fed the 23.5% CO diet compared to those fed the 5% CO diet. Colonic mucosal ornithine decarboxylase activity was lower in animals fed the 11.8% CO + 11.8% MO, 5.9% CO + 17.6% MO, 5% CO, and 4% MO + 1% CO diets compared to the levels in animals fed the 23.5% CO diet. The increasing levels of Menhaden oil in the diet significantly increased the omega-3 fatty acids such as eicosapentaenoic acid and docosahexaenoic acid and decreased the omega-6 fatty acids such as linoleic acid, linolenic acid, and arachidonic acid in microsomal fractions from colonic mucosa and tumors.     

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.     

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.     

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.     

Inhibitory effects of benzyl thiocyanate and benzyl isothiocyanate on methylazoxymethanol acetate-induced intestinal carcinogenesis in rats

The effects of two aromatic thiocyanates, benzyl thiocyanate(BTC) and benzyl isothiocyanate (BITC), on methylazoxymethanol(MAM) acetate-induced intestinal carcinogenesis were examinedusing female ACI/N rats. Starting at 5 weeks of age, animalswere fed diets containing 100 or 400 p.p.m. BTC, 400 p.p.m.BITC or a control diet At 6 weeks of age, all animals were treatedwith i.p. injections of MAM acetate (25 mg/kg body wt, onceweekly for 3 weeks) or saline. Animals fed experimental dietswere changed to the control diet from a week after the lastcarcinogen treatment Three groups of animals fed the controldiet were switched to 100 p.p.m. BTC, 400 p.p.m. BTC or 400p.p.m. BITC diet from a week after carcinogen treatment Animalsgiven the high-dose BTC diet at the initiation and the post-initiationphase showed smaller incidence (5% and 17%) and multiplicity(0.05 ± 0.21 and 0.17 ± 0.37) of tumors in smallintestine compared with those of rats exposed to the carcinogenalone (61% and 1.06 ± 1.18). The incidence and multiplicityof tumors in small intestine (21% and 032 ± 0.73) andthe incidence of colon tumors of rats given BITC in the initiationphase (47%) were significantly lower than those of animals treatedwith carcinogen alone (61%, 1.06 ± 1.18 and 83%). Bromodeoxyuridinelabeling indices of the intestinal mucosal cells were measured.The labeling indices were reduced by BTC and BITC exposure atinitiation phase in both small intestine and colon. The resultsof measurement of labeling indices correlated with the decreasedtumor incidence and multiplicity in the intestine. These datasuggest that BTC and BITC could be promising chemopreventiveagents for human intestinal neoplasia.     

Chemoprevention of experimental mammary carcinogenesis by the synthetic organoselenium compound, benzylselenocyanate, in rats

The effect of the dietary organoselenium compound, benzylselenocyanate (BSC) along with its sulphur analogue, benzylthiocynanate (BTC) and sodium selenite (Na2SeO3), on 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary carcinogenesis was examined in female Sprague-Dawley rats during the initiation phase of carcinogenesis. Semipurified diets containing 25 p.p.m. of BSC and 25 p.p.m. BTC, and 4 p.p.m. Selenium as Na2SeO3 in drinking water were given to 5-week-old rats for 3 weeks starting 2 weeks before, during and until 1 week after carcinogen treatment. At 7 weeks of age animals were given a single dose of DMBA (10 mg) in 1 ml olive oil by oral intubation. One week after DMBA treatment, the groups receiving BSC- and BTC-supplemented diets were transferred to the unsupplemented standard diets and the group of rats receiving Na2SeO3 in drinking water was transferred to regular tap water for the duration of the experiment. The results indicate that the rats receiving BSC in their diet showed a highly significant inhibition of tumor incidence and tumor multiplicity as well as a prolonged latency period when compared to the group fed the control diet. Neither BTC nor Na2SeO3 had any effect on the subsequent development of mammary tumors. These results indicate that dietary BSC inhibits mammary tumor incidence during the initiation phase of carcinogenesis and is a considerably more potent inhibitor than its sulphur analogue BTC and inorganic selenium. This is the first report that demonstrates the inhibition of mammary carcinogenesis by a synthetic organoselenium compound.     

Effect of dietary corn bran and autohydrolyzed lignin on 3,2'-dimethyl-4-aminobiphenyl-induced intestinal carcinogenesis in male F344 rats

The effect of dietary corn bran and autohydrolyzed lignin on 3,2'-dimethyl-4-aminobiphenyl (DMAB)-induced intestinal carcinogenesis was studied in male inbred F344 rats. Groups of weanling rats were fed semipurified diets containing 15% corn bran or 7.5% lignin or a semipurified diet without these fibers (control diet). At 7 weeks of age, all animals, except vehicle-treated controls, were given sc injections of 50 mg DMAB/kg body weight/week for 20 weeks. All animals were autopsied 20 weeks after the last injection of DMAB. The incidence of colon tumors (percentage of animals with tumors) and colon tumor multiplicity (tumors/animal) were increased in rats fed the corn bran diet as compared to the tumor incidence and multiplicity in rats fed the control diet. The incidence of small intestinal tumors was slightly lower in rats fed the corn bran diet as compared to the incidence in rats fed the control diet. The concentrations (mg/g dry feces) of fecal deoxycholic acid and total bile acids and the daily output of fecal deoxycholic acid, lithocholic acid, hyodeoxycholic acid, and total bile acids were increased in rats fed the corn bran diet as compared to the concentrations and daily output in rats fed the control diet. The incidence and multiplicity of small intestinal tumors as well as the number of colon adenocarcinomas per tumor-bearing animal were lower in animals fed the lignin diet than in those fed the control diet. Lignin had no effect on the concentrations of fecal bile acids, but the daily output of total bile acids was increased in animals fed the lignin diet as compared to the daily output in rats fed the control diet. This study thus indicates that the protection against colon cancer depends on the type of fiber.     

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.     

Dose-response studies of the effect of dietary butylated hydroxyanisole on colon carcinogenesis induced by methylazoxymethanol acetate in female CF1 mice

The effect of dietary butylated hydroxyanisole (BHA) on methylazoxymethanol acetate [(MAM AC) CAS: 592-62-1; methyl-ONN-azoxy)methanol acetate]-induced intestinal carcinogenesis was studied in female CF1 mice. BHA was added at levels of 0, 0.03, 0.1, 0.3, and 0.6% to the NIH-07 open-formula diet and at 0 and 0.6% to the AIN-76 semipurified diet and fed to mice, starting at 5 weeks of age until termination of the experiment. At 7 weeks of age, all animals except the vehicle-treated controls were given ip injections of MAM AC (15 mg/kg body wt for four times in 11 days for the low-dose group: total dose, 60 mg/kg body; 15 mg/kg body wt for eight times in 22 days for the high-dose group: total dose, 120 mg/kg body wt). With a low dose of carcinogen, the lung tumor incidence was inhibited in mice fed the NIH-07 diet containing 0.03-0.6% BHA and the AIN-76 diet containing 0.6% BHA compared to lung tumor incidence in those fed the diets without BHA; with a high dose of carcinogen, the inhibition was observed in mice fed the NIH-07 diet containing 0.1-0.6% BHA. Colon tumor incidence and colon tumor multiplicity (number of tumors per animal and number of tumors per tumor-bearing animal, respectively) were lower in mice fed the NIH-07 diets with 0.03-0.6% BHA or fed the AIN-76 diet with 0.6% BHA, as well as treated with a low dose of carcinogen, than in animals fed no BHA; with a high dose of carcinogen, colon tumor multiplicity and colon tumor incidence were inhibited in animals fed the NIH-07 diet containing 0.1-0.6% BHA. Consumption of the NIH-07 diets containing 0.03-0.6% BHA resulted in increased glutathione transferase activity of liver and small intestinal and colon mucosae in a dose-related manner.     

Effect of dietary wheat bran and dehydrated citrus fiber on 3,2'-dimethyl-4-aminobiphenyl-induced intestinal carcinogenesis in F344 rats

The effect of dietary wheat bran and dehydrated citrus fiberon 3,2'-dimethyl-4-aminobiphenyl (DMAB)-induced colon and smallintestinal carcinogenesis was studied in male F344 rats. Weanlingrats were fed semipurified diets containing 5% alphacel, 5%alphacel + 15% wheat bran or 5% alphacel + 15% citrus fiber.At 7 weeks of age, all animals, except vehicle-treated controls,received weekly s.c. injections of 50 mg DMAB/kg body weightfor 20 weeks. The DMAB- or vehicle-treated groups were autopsied20 weeks after the last injection of DMAB. The animals fed thewheat bran diet and treated with DMAB had a lower incidence(number of animals with tumors) and multiplicity (number oftumors/tumor-bearing animal) of colon and small intestinal tumorsthan did those fed the control diet and treated with DMAB. Animalsfed the diet containing citrus fiber developed fewer small intestinaltumors (incidence and multiplicity) than did the rats fed thecontrol diet; the number of adenocarcinomas was reduced in ratsfed the citrus fiber diet. This study thus indicates that dietscontaining wheat bran and citrus fiber reduce the risk for DMAB-inducedintestinal cancer and that the protection against colon cancerdepends on the type of fiber.     

Chemoprevention of colon carcinogenesis by dietary administration of piroxicam, alpha-difluoromethylornithine, 16 alpha-fluoro-5-androsten-17-one, and ellagic acid individually and in combination.

The chemopreventive action of 40 and 80% maximum tolerated dose (MTD) levels of piroxicam, D,L-alpha-difluoromethylornithine (DMFO), 16 alpha-fluoro-5-androsten-17-one (DHEA analogue 8354), and ellagic acid (EA) administered in diet individually and in combination before and during initiation and postinitiation phases of azoxymethane-induced neoplasia of the intestine was studied in male F344 rats. The MTD levels of piroxicam, DFMO, DHEA analogue, and EA were determined in male F344 rats and found to be 500, 5,000, 500, and 10,000 ppm, respectively, in modified AIN-76A diet. When these agents were fed in combination, the MTD levels were: piroxicam plus DFMO, 250 and 2500 ppm; piroxicam plus DHEA analogue, 250 and 250 ppm; piroxicam plus EA, 250 and 5000 ppm; piroxicam plus DFMO plus DHEA analogue, 250, 2500, and 250 ppm; and piroxicam plus DFMO plus EA, 250, 2500, and 5000 ppm. From these MTD values, 40 and 80% MTD levels were calculated and tested for their efficacy. At 5 weeks of age, animals were fed the modified AIN-76A (control) diet and experimental diets containing 40 and 80% MTD levels of piroxicam, DFMO, DHEA analogue, and EA individually and in combination. At 7 weeks of age, all animals except the vehicle-treated groups were administrated s.c. injections of azoxymethane (15 mg/kg body weight/week for 2 weeks). Animals intended for vehicle treatment received s.c. injections of an equal volume of normal saline. Fifty-two weeks after azoxymethane and saline treatment all the animals were necropsied, and colon and small intestinal tumor incidence (percentage of animals with tumors) and multiplicity (tumors/animal) were compared among various dietary groups. The results indicate that 40 and 80% MTD levels of dietary piroxicam and DFMO significantly (P less than 0.001) inhibited colon and small intestinal tumor incidence and multiplicity. DHEA analogue at 40% MTD level significantly decreased the small intestinal and colon tumor incidences (P less than 0.05), whereas 80% MTD of DHEA analogue inhibited only small intestinal tumor incidence. EA at 40 and 80% MTDs had no significant effect on colon tumor incidence (P greater than 0.05), but 80% MTD of EA showed a significant inhibitory effect on the incidence of small intestinal adenocarcinomas (P less than 0.01). In the combination study, 40 and 80% MTD levels of piroxicam plus DFMO significantly (P less than 0.001) inhibited colon adenocarcinoma incidence (8.3%) and multiplicity (0.08 +/- 0.04) (SE) when compared to colon adenocarcinoma incidence (72.2%) and multiplicity (1.14 +/- 0.18) in control diet-fed animals.(ABSTRACT TRUNCATED AT 400 WORDS)     

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.     

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.     

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.     

Inhibition by dietary oltipraz of experimental intestinal carcinogenesis induced by azoxymethane in male F344 rats

Epidemiological studies suggest that consumption of cruciferous vegetables rich in dithiolethiones is associated with a reduction in the incidence of cancer in man. The effect of two dose levels of dietary oltipraz [5-(2-pyrazinyl)-4-methyl-1, 2- dithiole-3-thione], a substituted dithiolethione, on azoxymethane (AOM)-induced intestinal carcinogenesis and on serum levels was studied in male F344 rats. The maximum tolerated dose (MTD) of oltipraz was determined in male F344 rats and found to be 500 p.p.m. Oltipraz at levels of 200 p.p.m. (40% MTD) and 400 p.p.m. (80% MTD) diet was tested as inhibitor of intestinal carcinogenesis. At 5 weeks of age, animals were fed the modified AIN-76A (control) diet and experimental diets containing oltipraz. At 7 weeks of age, all animals except the vehicle-treated animals were administered s.c. injection of AOM (15 mg/kg body wt/week for 2 weeks). Animals intended for vehicle treatment were administered s.c. with an equal volume of normal saline. Fifty-two weeks later, all animals were killed and colon and small intestinal tumor incidences and multiplicity were compared among the dietary groups. The results indicate that feeding of 200 and 400 p.p.m. of oltipraz significantly inhibited the incidence of adenocarcinomas in colon and small intestine and multiplicity of colon adenomas and small intestinal adenocarcinomas. Animals fed 400 p.p.m. oltipraz showed increased levels of oltipraz in the serum as compared to those fed 200 p.p.m. oltipraz. The results of this study indicate that dietary oltipraz inhibits intestinal carcinogenesis.     

Mechanism of benzylselenocyanate inhibition of azoxymethane-induced colon carcinogenesis in F344 rats

Benzylselenocyanate (BSC), a novel organoselenium compound, has been found to inhibit azoxymethane (AOM)-induced colon carcinogenesis in rats during initiation. To investigate its mechanism of action, we examined the effects of BSC feeding on the following parameters: (a) metabolism of [14C]AOM to 14CO2 in vivo; (b) metabolic activation of AOM to MAM and of MAM to formic acid and methanol by rat liver microsomes in vitro; and (c) AOM-induced DNA methylation in rat livers and colons. Five-week-old male F344 rats were fed modified (23% corn oil) AIN-76A diets containing 0 (control), 25, or 50 ppm of BSC or benzylthiocyanate (BTC), a sulfur analogue of BSC which does not inhibit the colon carcinogenicity of AOM. After 3 weeks, rats were either sacrificed for the isolation of liver microsomes or were given 15 mg/kg of [14C]AOM s.c. to determine the rate of carcinogen metabolism in vivo. No difference in [14C]AOM metabolism was found between rats fed the BTC diets and those fed the control diet. In contrast, the rate of [14C]AOM metabolism, as determined by exhaled radioactivity, was 2-3 times higher in rats fed the BSC diets. While liver microsomes from rats fed the BTC diets metabolized AOM and MAM at rates not significantly different from those obtained with control liver microsomes, the metabolic activation of AOM as well as of MAM was stimulated severalfold when assayed with liver microsomes from rats fed the BSC diets. An increase in total liver cytochrome P-450 was also observed in the BSC-fed rats. Following the administration of 15 mg/kg AOM, significantly less O6-methylguanine and 7-methylguanine was present in the colon DNA from rats consuming the BSC diets than in rats fed the BTC or control diets. The body weight gains of rats fed the 25- and 50-ppm BSC-containing diets for 3 weeks were less (27 and 43%, respectively) than those of rats fed either the control or BTC-containing diets. These results indicate that dietary BSC significantly induces the hydroxylation of AOM and the oxidation of MAM in rat liver. An increase in the rates of AOM and MAM metabolism in the liver due to enzyme induction by BSC will result in decreased delivery of MAM to the colon via the bloodstream. This will be reflected in decreased DNA alkylation, as observed, and is likely to be a major factor in the inhibition of AOM-induced colon carcinogenesis by BSC.