Effects of differing purified cellulose, pectin, and hemicellulose fiber diets on fecal enzymes in 1,2-dimethylhydrazine-induced rat colon carcinogenesis

The fecal microflora enzymes, beta-glucuronidase and beta-glucosidase, as well as fecal bacterial counts, were examined during colon carcinogenesis in rats administered parenteral 1,2-dimethylhydrazine and fed nutritionally equivalent diets free of fiber or containing one of three single sources of dietary fiber (cellulose, hemicellulose, and pectin). Whereas pectin-fed animals had increased fecal beta-glucuronidase activities, those fed cellulose and hemicellulose, two fibers protective in dimethylhydrazine colon neoplasia, had decreased activities. Although fecal bacterial counts were not significantly changed, similar differential changes in fecal beta-glucosidase activity were noted: cellulose but not pectin or hemicellulose feeding was associated with reduced activity. Although cellulose fiber may cause differing physiological effects resulting in a reduction in colonic neoplasia development in this experimental animal model, decreased bacterial metabolic enzyme activation of carcinogens or cocarcinogens may lead to diminished exposure of colonic cells to exogenous or endogenous mutagens.     

Utilization of blood analyses to evaluate metabolic changes in control and 1,2-dimethylhydrazine-treated adult male Fischer rats

The synthetic compound 1,2-dimethylhydrazine is employed in carcinogenesis studies because of its reliable and specific ability to produce colon tumors in rodents. Male Fischer rats were treated at 7 weeks of age with a single oral dose of 1,2-dimethylhydrazine (35 mg/kg) and examined at autopsy 1.5 years later when the incidence of colon tumors is approximately 80%. Blood from control and 1,2-dimethylhydrazine-treated animals was taken at autopsy for routine hematoplazia analysis and for biochemical analysis with the Sequential Multiple Analyzer Computer multitest system.The results indicate that the induction of tumors with a single oral dose of this carcinogen is associated with statistically significant changes in the serum levels of some clinically useful metabolic parameters. Clinically significant changes in the serum chemistry were increases in the creatine phosphokinase (CPK) and albumin/globulin values without an increase in the total serum protein. The multitest system has not been previously employed to evaluate the blood chemistry profiles of tumor-bearing animals and, thus, this study provides an illustration of the potential for this technique to evaluate metabolic changes associated with exposure to carcinogens.     

Colon carcinogenesis in germ-free rats with intrarectal 1,2-dimethylhydrazine and subcutaneous azoxymethane.

The effect of intestinal microflora on colon carcinogenesis by 1,2-dimethylhydrazine and azoxymethane was studied, with the use of germ-free and conventional female Fischer rats. At 7 weeks of age, germ-free and conventional rats were treated with 20 weekly intrarectal 1,2-dimethylhydrazine (20 mg per kg body weight per week) or subcutaneous azoxymethane (10 mg per kg body weight per week) doses and were autopsied 15 weeks later. Tumors were induced in the small intestine and colon of germ-free and conventional rats treated with intrarectal 1,2-dimethylhydrazine; the number of rats with colon tumors and the multiplicity of tumors were decreased in germ-free rats, compared with conventional animals. Azoxymethane given subcutaneously increased the incidence and multiplicity of colon tumors in germ-free rats, compared with conventional controls. It is concluded that the intestinal microflora alter the carcinogenic and/or cocarcinogenic effect of different compounds in the large intestine.     

Effect of two kinds of pectin and guar gum on 1,2-dimethylhydrazine initiation of colon tumors and on fecal beta-glucuronidase activity in the rat

The effect of 5% low-methoxylated pectin, high-methoxylated pectin, and guar gum on 1,2-dimethylhydrazine initiation of colon cancer was investigated using groups of 30 rats. The growth of the rats in the different groups was very similar to that of control group fed a fiber-free diet. Both kinds of pectin increased the multiplicity of color tumors, whereas guar gum did not significantly influence carcinogenesis. Bacterial beta-glucuronidase activity in feces and colonic content was the same in pectin-fed rats and controls but significantly lower in the guar gum group. Thus, it was not related to the number of tumors in each group.     

Ceramide-beta-D-glucuronide: synthesis, digestion, and suppression of early markers of colon carcinogenesis

Dietary sphingolipids inhibit chemically induced colon cancer in mice. The most likely mediators of this effect are the metabolites ceramide (Cer) and sphingosine, which induce growth arrest and apoptosis in transformed cells. Sphingolipids are digested in both the upper and the lower intestine; therefore, a more colon-specific method of delivery of sphingolipids might be useful. A Cer analogue with a D-glucuronic acid attached at the primary hydroxyl of N-palmitoyl-D-sphingosine (Cer-beta-glucuronide) was synthesized and evaluated as a substrate for Escherichia coli beta-glucuronidase and colonic digestion, as well as for suppression of early events in colon carcinogenesis in CFI mice treated with 1,2-dimethylhydrazine. Purified beta-glucuronidase (EC 3.2.1.31) and colonic segments (as a source of colonic enzymes and microflora) hydrolyzed Cer-beta-glucuronide to release Cer, as analyzed by tandem mass spectrometry. More than 75% of the Cer-beta-glucuronide was cleaved in an 8-h incubation with the colonic segments. When Cer-beta-glucuronide was administered for 4 weeks as 0.025% and 0.1% of the diet (AIN 76A) to 1,2-dimethylhydrazine-treated mice, there were significant reductions in colonic cell proliferation, as determined by in vivo BrdUrd incorporation, and in the appearance of aberrant crypt foci. The effect of dietary Cer-beta-glucuronide on aberrant crypt foci correlated significantly with the length of the colon, which suggests that Cer-beta-glucuronide was most effective when there was a larger compartment for digestion. Thus, synthetic sphingolipids that target the colon for the release of the bioactive backbones offer a promising approach to colon cancer prevention.     

JTE-522, a selective cyclooxygenase-2 inhibitor, inhibits induction but not growth and invasion of 1,2-dimethylhydrazine-induced tubular adenocarcinomas of colon in rats

We have previously demonstrated that JTE-522, a selective cyclooxygenase-2 (COX-2) inhibitor, inhibited development of aberrant crypt foci (ACF) in rats, a putative preneoplastic lesion in colon, and suggested its inhibitory potential in rat colon carcinogenesis. To evaluate the chemopreventive properties of JTE-522, the present study was design to evaluate the inhibitory effects of JTE-522 on rat colon tumorigenesis induced by 1,2-dimethylhydrazine (DMH). Rats at 6 weeks of age were divided into 4 groups. One week after the start of the experiment, all rats received DMH by s.c. injection at a dose of 40 mg/kg body weight once a week for 4 successive weeks. As the initiation and postinitiation treatment groups, groups 1-3 were fed diets containing 0, 50, or 150 ppm JTE-522, respectively, from the start of the study to the end. As the postinitiation treatment group, group 4 was given 150 ppm JTE-522 from 1 week after the last DMH injection to the end of the study. Forty weeks after the start of the experiment, administration of 150 ppm JTE-522 during both initiation and postinitiation stages significantly inhibited the incidences of tubular adenocarcinomas and total carcinomas, as well as total tumors in the colon. The inhibitory effect of JTE-522 was most prominent for tubular adenocarcinomas, but was not observed in the nontubular carcinomas (signet-ring cell and mucinous carcinomas). Almost equal inhibitory effects on tubular adenocarcinomas were also observed in the rats given 150 ppm JTE-522 during the postinitiation stage, suggesting that its major anticancer action is at the postinitiation phase. However, JTE-522 had no effect on the size or invasive extent of tubular adenocarcinomas. Furthermore, microarray analyses revealed that JTE-522 had no effect on gene expression levels in DMH-induced tubular adenocarcinomas. These findings suggest that JTE-522 possesses chemopreventive activity against induction but not progression of tubular adenocarcinomas in rat colon. In view of the significant inhibitory effects of JTE-522 on ACF, its major anticancer action may occur in the postinitiation stage but before the malignant conversion stage of DMH-induced colon carcinogenesis.     

Chemoprevention of colon cancer by specific cyclooxygenase-2 inhibitor, celecoxib, administered during different stages of carcinogenesis

Epidemiological observations and laboratory research have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of colon cancer and that the inhibition of colon carcinogenesis by NSAIDs is mediated through the modulation of prostaglandin production by rate-limiting enzymes known as cyclooxygenases (COXs). Because traditional NSAIDs inhibit both COX-1 and COX-2, these drugs induce side effects, such as gastrointestinal ulceration and renal toxicity, through the inhibition of the constitutive COX-1. Overexpression of COX-2 has been observed in colon tumors; therefore, specific inhibitors of COX-2 could serve as chemopreventive agents. Our previous study has shown that celecoxib, an inhibitor of COX-2, while sparing COX-1, inhibited azoxymethane (AOM)-induced colon tumorigenesis when administered during both initiation and postinitiation stages, ie., celecoxib administered continuously before, during, and after carcinogen treatment. This study examined the dose-response effect of celecoxib when administered during the initiation and postinitiation stages. In addition, the chemopreventive effects of high-dose celecoxib administered during the promotion/progression stage of colon carcinogenesis, ie., continuous celecoxib administration beginning 14 weeks after the carcinogen treatment, was determined in male F344 rats. We also measured the steady-state levels of celecoxib in the plasma of animals given this inhibitor. Groups of 5-week-old male F344 rats were fed either a control diet or experimental diets containing 500, 1000, or 1500 ppm celecoxib. At 7 and 8 weeks of age, rats scheduled for carcinogen treatment were injected s.c. with AOM at a dose rate of 15 mg/kg body weight/week. Groups of animals destined for the promotion/ progression study and initially receiving the control diet were switched to a diet containing 1500 ppm celecoxib beginning 14 weeks after the second AOM treatment. All rats remained on their respective dietary regimens until the termination of the study, ie., 52 weeks, and were then sacrificed. Colon tumors were evaluated histopathologically. Administration of 500, 1000, or 1500 ppm celecoxib during the initiation and postinitiation stages significantly inhibited the incidence (P < 0.01 to P < 0.0001) as well as the multiplicity (P < 0.01 to P < 0.0001) of adenocarcinomas of the colon in a dose-dependent manner. Importantly, administration of 1500 ppm celecoxib during the promotion/progression stage also significantly suppressed the incidence and multiplicity of adenocarcinomas of the colon (P < 0.01). Also, administration of celecoxib to the rats during the initiation and postinitiation periods and throughout the promotion/progression stage strongly suppressed colon tumor volume (P < 0.0002 to P < 0.001). The steady-state plasma concentration of celecoxib increases somewhat with the dose. Thus, in this model system, the chemopreventive efficacy of celecoxib is dose-dependent when this COX-2 inhibitor is administered during the initiation and postinitiation periods. This study provides the first evidence that celecoxib is also very effective when it is given during the promotion/progression stage of colon carcinogenesis, indicating that the chemopreventive efficacy is achieved during the later stages of colon tumor development. This suggests that celecoxib may potentially be an effective chemopreventive agent for the secondary prevention of colon cancer in patients with familial adenomatous polyposis and sporadic polyps.     

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.     

Chemopreventive efficacy of sulindac sulfone against colon cancer depends on time of administration during carcinogenic process.

Epidemiological and model studies with laboratory animals have provided evidence that nonsteroidal anti-inflammatory drugs reduce the risk of colon cancer. Sulindac, a nonsteroidal anti-inflammatory drug, has been shown to inhibit azoxymethane (AOM)-induced colon carcinogenesis in rats when administered continuously before, during, and after carcinogen treatment (initiation and postinitiation periods) or when given continuously beginning 14 weeks after carcinogen administration (promotion/ progression stage). The present study was designed to investigate the chemopreventive efficacy of sulindac sulfone (exisulind), the sulfone metabolite of sulindac, when administered during the promotion/progression stage of colon carcinogenesis in comparison to the effect during the initiation and postinitiation periods. We have also studied the modulating effect of exisulind on colonic tumor apoptosis. At 5 weeks of age, groups of male F344 rats were fed diets containing 0%, 0.06%, and 0.12% exisulind. At 7 weeks of age, groups of animals were injected s.c. with AOM (15 mg/kg body weight, once weekly for 2 weeks). Animals intended for the promotion/progression study and receiving 0% exisulind were switched to an experimental diet containing 0.12% exisulind at 14 weeks after the second AOM treatment. All rats remained on their respective dietary regimens until the termination of the study, 50 weeks after the second AOM injection. Colon tumors were evaluated histopathologically for tumor type. Administration of 0.06% and 0.12% exisulind during the initiation and postinitiation periods significantly inhibited the incidence and multiplicity of invasive and/or noninvasive adenocarcinomas of the colon. The inhibition of colon tumorigenesis by exisulind was associated with a significant retardation of body weight gain shortly after sulfone administration and increased apoptosis in the colon tumors. In contrast, administration of the higher dose (0.12%) of exisulind during the promotion/progression stage had only minimal effects on colon tumorigenesis and apoptosis in the colon tumors, suggesting that early administration, but not late administration, may be required for chemopreventive efficacy of this drug.     

Inhibitory Effect of Cryptoporic Acid E, a Product from Fungus Cryptoporus volvatus, on Colon Carcinogenesis Induced with N-Methyl-N-Nitrosourea in Rats and with 1,2-Dimethylhydrazine in Mice

The antitumorigenic effect of cryptoporic acid E (CPA-E), a dimeric drimane sesquiterpenoid isolated from the fungus Cryptoporus volvatus , on colon carcinogenesis was investigated. Female F344 rats given an intrarectal instillation of 2 mg of N-methyl-N-nitrosourea 3 times weekly in weeks 1 and 2 were fed diet containing 0.2% CPA-E from week 3. Femal ICR mice given 15 weekly intraperitoneal injections of 10 mg of 1,2-dimethylhydrazine/kg body weight during weeks 1 to 15 were fed diet containing 0.06% CPA-E from week 1. The experiment was terminated at week 35 for rats and at week 25 for mice. The incidence and the number of tumors per animal were reduced in CPA-E-fed animals compared to the controls: 31% vs. 75% (P<0.05) and 0.4±0.2 (SEM) vs. 0.9 ± 0.2 (0.1> P >0.05) in rats, and 31% vs. 63% (0.1>P>0.05) and 0.4±0.2 vs. 2.4 ± 0.8 (P<0.05) in mice (16 animals in each group). Intrarectal deoxycholic acid-induced colonic mucosal ornithine decarboxylase activity was significantly lowered in CPA-E-fed animals compared to controls. This shows an antipromoting activity of CPA-E against colon carcinogenesis. Thus, it was concluded that CPA-E inhibits colon cancer development in both rats and mice treated with 2 different colon carcinogens.     

Inhibitory effect of cryptoporic acid E, a product from fungus Cryptoporus volvatus, on colon carcinogenesis induced with N-methyl-N-nitrosourea in rats and with 1,2-dimethylhydrazine in mice.

The antitumorigenic effect of cryptoporic acid E (CPA-E), a dimeric drimane sesquiterpenoid isolated from the fungus Cryptoporus volvatus, on colon carcinogenesis was investigated. Female F344 rats given an intrarectal instillation of 2 mg of N-methyl-N-nitrosourea 3 times weekly in weeks 1 and 2 were fed diet containing 0.2% CPA-E from week 3. Female ICR mice given 15 weekly intraperitoneal injections of 10 mg of 1,2-dimethylhydrazine/kg body weight during weeks 1 to 15 were fed diet containing 0.06% CPA-E from week 1. The experiment was terminated at week 35 for rats and at week 25 for mice. The incidence and the number of tumors per animal were reduced in CPA-E-fed animals compared to the controls: 31% vs. 75% (P less than 0.05) and 0.4 +/- 0.2 (SEM) vs. 0.9 +/- 0.2 (0.1 greater than P greater than 0.05) in rats, and 31% vs. 63% (0.1 greater than P greater than 0.05) and 0.4 +/- 0.2 vs. 2.4 +/- 0.8 (P less than 0.05) in mice (16 animals in each group). Intrarectal deoxycholic acid-induced colonic mucosal ornithine decarboxylase activity was significantly lowered in CPA-E-fed animals compared to controls. This shows an antipromoting activity of CPA-E against colon carcinogenesis. Thus, it was concluded that CPA-E inhibits colon cancer development in both rats and mice treated with 2 different colon carcinogens.     

Dietary supplementation with pectin and guar gum on 1,2-dimethylhydrazine-induced colon carcinogenesis in rats.

The effect of dietary supplementation with pectin and/or guar gum on 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis was studied using 120 male Sprague-Dawley rats. The rats were given a weekly injection of DMH for 8 weeks and were maintained on a basal fiber-free diet supplemented with 5% cellulose. The rats were then subdivided into four groups and kept on the basal fiber-free diet supplemented with either no fiber, 10% pectin, 10% guar gum or a combination of 5% pectin/5% guar gum for a period of 24 weeks. The 8 weeks of DMH administration were defined as the initiation stage of carcinogenesis and the next 24 weeks were defined as the promotional stage of carcinogenesis. Food and water were available ad libitum. The rats were killed 32 weeks after the start of the experiment and tumor incidence, location and frequency in the colon were determined. Other parameters measured were body weight and caloric intake. Dietary fiber supplementation with 10% pectin or with 10% guar gum but not with the combination of 5% pectin/5% guar gum (fed during the promotional stage of carcinogenesis), was found to suppress colon cancer incidence to a significant extent.     

Multiple dietary factors in the enhancement of dimethylhydrazine carcinogenesis: main effect of indole-3-carbinol

The effects of multiple dietary influences on 1,2-dimethylhydrazine [(DMH) CAS: 540-73-8]-induced colon cancer in rats were studied. A 2(4) factorial experimental design was used to examine the main and interactive effects of 15% wheat bran (WB), 1% cholesterol (CH) with cholic acid, 20% beef tallow (BT), and 0.1% indole-3-carbinol (IC) on 160 male F344 rats treated ip with DMH (10 mg/kg) weekly for 16 weeks. The test diets were fed for 3 weeks before, 16 weeks during, and 12 weeks after DMH administration. At necropsy, total weight gain, liver and spleen weights, serum CH levels, liver aryl hydrocarbon hydroxylase (AHH) activity, and the size, number, incidence, and location of intestinal tumors were analyzed for dietary factor effects. The most significant inducer of tumors was the combination of CH + BT + IC acting in synergism. The single main effect most responsible for tumor morbidity was IC, which appeared to enhance tumorigenesis via its role as an inducer of AHH activity. The WB decreased tumor incidence and burden when added to diets also containing CH, but it otherwise increased tumor burden per tumor-bearing animal and incidence in all other diets. This study demonstrated the need for examining synergistic and antagonistic interactions among dietary initiators and/or promoters of colon carcinogenesis, as well as implicating IC as a significant factor in the development of DMH-induced tumors in rats.     

Green tea catechins enhance tumor development in the colon without effects in the lung or thyroid after pretreatment with 1,2-Dimethylhydrazine or 2,2'-dihydroxy-di-n-propylnitrosamine in male F344 rats

Modifying effects of green tea catechins (GTCs) on the post-initiation stage of colon, lung and thyroid carcinogenesis were examined in F344 male rats. Groups of 20 animals were given subcutaneous injections of 40 mg/kg body wt of 1,2-dimethylhydrazine twice a week for 2 weeks or oral administration of 0.1% 2,2'-dihydroxy-di-n-propylnitrosamine (DHPN) in the drinking water for 2 weeks for initiation. They then received diet containing 1 or 0.1% green tea catechin or basal diet alone for 33 weeks. Histopathological examination after final sacrifice showed that although total incidence and multiplicity of colon tumors were not significantly different from controls, values for colon adenomas were decreased while those for carcinomas and the average size of tumors were significantly increased in the 0.1% GTC group. A similar tendency was observed for the 1% GTC group. Incidences and/or multiplicity of lung hyperplasia and tumors, and thyroid lesions did not significantly vary among the DHPN-treated groups. These results indicate that GTCs do not inhibit, but rather may enhance colon carcinogenesis, while not influencing lung and thyroid carcinogenesis under the present experimental conditions.     

Silymarin,a naturally occurring polyphenolic antioxidant flavonoid,inhibits azoxymethane-induced colon carcinogenesis in male F344 rats

The modifying effect of dietary administration of the polyphenolic antioxidant flavonoid silymarin, isolated from milk thistle [Silybum marianum (L.) Gaertneri], on AOM-induced colon carcinogenesis was investigated in male F344 rats. In the short-term study, the effects of silymarin on the development of AOM-induced colonic ACF, being putative precursor lesions for colonic adenocarcinoma, were assayed to predict the modifying effects of dietary silymarin on colon tumorigenesis. Also, the activity of detoxifying enzymes (GST and QR) in liver and colonic mucosa was determined in rats gavaged with silymarin. Subsequently, the possible inhibitory effects of dietary feeding of silymarin on AOM-induced colon carcinogenesis were evaluated using a long-term animal experiment. In the short-term study, dietary administration of silymarin (100, 500 and 1,000 ppm in diet), either during or after carcinogen exposure, for 4 weeks caused significant reduction in the frequency of colonic ACF in a dose-dependent manner. Silymarin given by gavage elevated the activity of detoxifying enzymes in both organs. In the long-term experiment, dietary feeding of silymarin (100 and 500 ppm) during the initiation or postinitiation phase of AOM-induced colon carcinogenesis reduced the incidence and multiplicity of colonic adenocarcinoma. The inhibition by feeding with 500 ppm silymarin was significant (p < 0.05 by initiation feeding and p < 0.01 by postinitiation feeding). Also, silymarin administration in the diet lowered the PCNA labeling index and increased the number of apoptotic cells in adenocarcinoma. beta-Glucuronidase activity, PGE(2) level and polyamine content were decreased in colonic mucosa. These results clearly indicate a chemopreventive ability of dietary silymarin against chemically induced colon tumorigenesis and will provide a scientific basis for progression to clinical trials of the chemoprevention of human colon cancer.     

Reduction of colonic carcinogenesis by wheat bran independent of fecal bile acid concentration

It has been reported previously that populations with a decreased concentration of fecal bile acids have a lower incidence of colon cancer. We examined the importance of fecal bile acid dilution by wheat bran (WB) in inhibiting colonic tumorigenesis in an experimental animal model. Male F344 rats received oral doses of the colon carcinogen 1,2-dimethylhydrazine [CAS: 540-73-8] and were assigned randomly to groups fed one of four semipurified diets for 26 weeks. The diets were fiber-free (FF), 10% WB, FF + bile salts, or WB + bile salts. The amount of bile salts added was adjusted to produce a fecal bile acid concentration in the group fed WB + bile salts equal to that found in the FF groups. Fecal bile acid concentrations at 12 and 24 weeks in the WB + bile salts group were similar to those in the FF group. Gross and microscopic findings at necropsy revealed a reduced total number and multiplicity of colon tumors in both bran-fed groups. Although the fecal bile acid concentrations of the FF and WB + bile salts groups were equal, the latter showed a significant reduction in tumor yield.     

Effects of Apple Pectin on Fecal Bacterial Enzymes in Azoxymethane-induced Rat Colon Carcinogenesis

Because of the potential significance of colonic bacteria in colon carcinogenesis, we investigated the effect of pectin of different types on fecal bacterial enzymes (β-glucuronidase, β-glucosidase and tryptophanase) at various periods of time after feeding rats with pectin-containing diets during azoxymethane-induced colon carcinogenesis. The diet supplemented with 20% apple pectin or 20% citrus pectin decreased the multiplicity of colon tumors, and the number of tumors was significantly decreased in the group fed apple pectin. The incidence of colon tumors in the apple pectin group was lower than that in the control group. The mean tumor size was similar among the three groups. Apple pectin feeding decreased fecal β-glucosidase and tryptophanase levels. Furthermore, a significant decrease in the activity of β-glucuronidase was observed in the apple pectin group during the initiation phase. These findings suggest that the protective effect of pectin on colon carcinogenesis may be dependent on the type of pectin and be related to the decrease of β-glucuronidase activity in the initiation stage of carcinogenesis.     

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 dietary fiber on the induction of colorectal tumors and fecal beta-glucuronidase activity in the rat.

The purpose of the present study was to investigate whether three different types of dietary fiber, wheat bran, carrot fiber, and citrus pectin, influenced the induction of colorectal tumors produced by 1,2-dimethylhydrazine in rats. In all groups, the tumor yield was high (87 to 97%). In the wheat bran and carrot fiber groups, the incidence of colorectal tumors was not significantly different from that of the group fed on the fiber-free basic diet. The citrus pectin group, however, had a significantly higher incidence of colorectal tumors (p less than 0.001). An increased number of auditory duct tumors was also noted in this group. In a separate experiment, dietary pectin induced a 10-fold increase in fecal beta-glucuronidase activity but did not alter this activity in the bowel wall. It has been suggested that dietary fiber protects against the induction of colorectal tumors, but this was not the case in the experiment. It is possible that the high tumor yield made the demonstration of a weak protective effect of wheat bran impossible. The reason for the increased occurrence of tumors in the citrus pectin group is obscure and will be subjected to further investigation. Fecal beta-glucuronidase activity might be one factor of importance in the activation of the carcinogen.     

Silk protein, sericin, suppresses colon carcinogenesis induced by 1,2-dimethylhydrazine in mice

Male 5-week old ICR mice were examined for the effect of feeding silk protein, sericin on colon carcinogenesis. In experiment 1, mice were fed the diets supplemented with 1.5% or 3% sericin for five weeks, and given weekly injections of 1,2-dimethylhydrazine (DMH) for the initial three weeks. Supplemental sericin caused a dose-dependent decrease in the development of colonic aberrant crypt foci. In experiment 2, mice were fed the diet supplemented with 3% sericin for 115 days, and given weekly injections of DMH for the initial ten weeks. The incidence and number of colon tumors were suppressed by consumption of sericin. The results suggest a potential usefulness of sericin as a chemopreventive agent for colon carcinogenesis.