Intestinal Carcinogenesis In Rats Research Articles

Plumbagin (5-Hydroxy-2-methyl-1,4-naphthoquinone) Suppresses NF-κB Activation and NF-κB-regulated Gene Products Through Modulation of p65 and IκBα Kinase Activation, Leading to Potentiation of Apoptosis Induced by Cytokine and Chemotherapeutic Agents

Plumbagin, derived from the medicinal plant Plumbago zeylanica, modulates cellular proliferation, carcinogenesis, and radioresistance, all known to be regulated by the activation of the transcription factor NF-kappaB, suggesting plumbagin might affect the NF-kappaB activation pathway. We found that plumbagin inhibited NF-kappaB activation induced by TNF, and other carcinogens and inflammatory stimuli (e.g. phorbol 12-myristate 13-acetate, H2O2, cigarette smoke condensate, interleukin-1beta, lipopolysaccharide, and okadaic acid). Plumbagin also suppressed the constitutive NF-kappaB activation in certain tumor cells. The suppression of NF-kappaB activation correlated with sequential inhibition of the tumor necrosis factor (TNF)-induced activation of IkappaBalpha kinase, IkappaBalpha phosphorylation, IkappaBalpha degradation, p65 phosphorylation, p65 nuclear translocation, and the NF-kappaB-dependent reporter gene expression activated by TNF, TNFR1, TRAF2, NIK, IKK-beta, and the p65 subunit of NF-kappaB. Plumbagin also suppressed the direct binding of nuclear p65 and recombinant p65 to the DNA, and this binding was reversed by dithiothreitol both in vitro and in vivo. However, plumbagin did not inhibit p65 binding to DNA when cells were transfected with the p65 plasmid containing cysteine 38 mutated to serine. Plumbagin down-regulated the expression of NF-kappaB-regulated anti-apoptotic (IAP1, IAP2, Bcl-2, Bcl-xL, cFLIP, Bfl-1/A1, and survivin), proliferative (cyclin D1 and COX-2), and angiogenic (matrix metalloproteinase-9 and vascular endothelial growth factor) gene products. This led to potentiation of apoptosis induced by TNF and paclitaxel and inhibited cell invasion. Overall, our results indicate that plumbagin is a potent inhibitor of the NF-kappaB activation pathway that leads to suppression of NF-kappaB-regulated gene products. This may explain its cell growth modulatory, anticarcinogenic, and radiosensitizing effects previously described.

Chemopreventive effects of coffee bean and rice constituents on colorectal carcinogenesis

Polyphenolic compound chlorogenic acid (CGA) known to be much contained in coffee beans was found to have a regressive effect on induced aberrant crypt foci (ACF) as well as on development of ACF in azoxymethane (AOM)-induced colorectal carcinogenesis in rats. Rice germ and gamma-aminobutyric acid-enriched defatted rice germ inhibited AOM-induced ACF formation and colorectal carcinogenesis in rats. Ferulic acid (FA) also known to be contained in coffee beans and rice prevented AOM-induced ACF formation and intestinal carcinogenesis in rats. Both of food factors, coffee and rice may be of benefit to prevention of human colorectal cancers.

Prevention of spontaneous and chemically induced carcinogenesis using activated carbon fiber adsorbent. III. Inhibitory effect of the activated carbon fiber adsorbent ‘Aqualen’ on 1,2-dimethylhydrazine-induced intestinal carcinogenesis in rats

Two-month-old outbred female LIO rats were exposed weekly to 15 (experiment I, groups 1, 2 and 3) or to 5 (experiment II, groups 4, 5 and 6) subcutaneous injections of 1,2-dimethylhydrazine (DMH) at a single dose of 21 mg/kg of body weight. From the day of the first injection of the carcinogen, the rats from groups 2, 3, 5 and 6 were given Aqualen® in their diet. In both experiments rats were fed Aqualen five times per week together with lab chow at the daily dose of 0.1 g/kg (groups 2 and 5) or 1.0 g/kg (groups 3 and 6) of body weight. Additionally, other rats were not exposed to the carcinogen and served as an intact control (group 7) or were given Aqualen with the diet at the daily dose of 0.1 g/kg (group 8) or 1.0 g/kg (group 9). These experiments were finalized 6 months after the first injection of DMH. In experiments I and II, the majority of tumors were localized in the descending colon. Tumors of the small intestines developed only in rats from experiment I. The total incidence of colon tumors as well as tumors in different parts of the colon and the mean number of tumors per rat were much higher in rats from all groups in experiment I than in the rats from experiment II. In experiment I supplementation of Aqualen to the diet was followed by a decrease in the incidence of tumors in the ascending colon and by a decrease in the number of tumors per rat in both ascending and descending colons regardless of the dose of the enterosorbent. In experiment II the effect of Aqualen was stronger than in experiment I – the enterosorbent decreased both the tumor incidence and the multiplicity in the total colon, its ascending and descending parts and in the rectum. In experiments I and II the percentage of small colon tumors among rats exposed to Aqualen (groups 2, 3, 5 and 6) was higher than that of the controls (groups 1 and 4). Most of detected intestinal tumors were classified as adenocarcinomas. The level of tumor differentiation was higher in rats exposed to Aqualen. There were no pathological changes observed in rats exposed to Aqualen without DMH. Carcinogen treatment resulted in an increase of serum glucose and cholesterol levels whereas Aqualen normalized these changes. Thus, our results demonstrate the inhibitory effect of activated carbon fiber adsorbent Aqualen on intestinal carcinogenesis in rats.

Promotion of intestinal carcinogenesis by dietary methionine.

The metabolism of the polyamines spermidine and spermine is known to be enhanced in rapidly proliferating cells. Methionine is a precursor of the aminopropyl moieties of these amines. Therefore, it was of interest to study the effects of a methionine supplemented diet on polyamine metabolism and preneoplastic changes occurring in the intestinal tract of rats treated with the chemical carcinogen azoxymethane (AOM). Adult Wistar rats received 15 mg AOM/kg body wt (i.p.) once each week for 2 weeks. Thereafter, the rats were randomly divided into two groups and received controlled isoenergetic diets containing the same amount of folate, choline and vitamin B12 during 12 weeks: one group was kept on a standard diet; the other was fed the same diet, except that 1% L-methionine was added at the expense of carbohydrates. After 12 weeks, the administration of the methionine-supplemented diet stimulated the turnover rate of ileal epithelial cells, indicating enhanced crypt cell proliferation. Furthermore, in this group, a 2-fold increase in the number of aberrant hyperproliferative crypts and the appearance of tumors was observed in the colon. These effects were accompanied by the increased formation of spermidine and spermine due to the enhancement of S-adenosylmethionine decarboxylase activity and by the upregulation of Cdx-1, a homeobox gene with oncogenic potentials. The experimental data do not support the view of a chemopreventive effect of dietary methionine supplementation on intestinal carcinogenesis in rats, even at an early phase of preneoplastic development, but rather suggest that methionine promotes intestinal carcinogenesis.

Inhibitory effects of bovine lactoferrin on intestinal polyposis in the Apc Min mouse

Chemopreventive effects of bovine lactoferrin (bLF), previously shown to strongly inhibit intestinal carcinogenesis in rats (K. Sekine, E. Watanabe, J. Nakamura, N. Takasuka, D.J. Kim, M. Asamoto, V. Krutovskikh, T.H. Baba, T. Ota, M.A. Moore, M. Masuda, H. Sugimoto, H. Nishino, T. Kakizoe, H. Tsuda, Inhibition of azoxymethane-initiated colon tumor by bovine lactoferrin administration in F344 rats, Jpn. J. Cancer Res. 88 (1997) 523–526; K. Sekine, Y. Ushida, T. Kuhara, M. Iigo, H. Baba-Toriyama, M.A. Moore, M. Murakoshi, Y. Satomi, H. Nishino, T. Kakizoe, H. Tsuda, Inhibition of initiation and early stage development of aberrant crypt foci and enhanced natural killer activity in male rats administered bovine lactoferrin concomitantly with azoxymethane, Cancer Lett. 121 (1997) 211–216), on spontaneous intestinal polyp development were assessed in the Apc Min mouse, a model for both familial adenomatous polyposis and sporadic colon cancers. In the experiment, 54 mice at 6 weeks of age were given 2% bLF (15 mice), 0.2% bLF (15 mice) and AIN-93G (24 mice) as basal diet ad libitum for 8 weeks. An overall tendency for a reduction in the total number of polyps in the small intestine was evident in the bLF-treated animals, along with significant suppression in the jejunum at the 2% dose ( P<0.05, 68% of the control). In addition, body growth suppression, presumed to be due to anemia and/or intussusception as a consequence of numerous polyps in the intestine, was alleviated. No toxic effects were observed in the intestinal epithelium. Although not as obvious as observed for the rat case, the data suggest that bLF may be a chemopreventor of intestinal polyposis.

Inhibitory effects of plumbagin and juglone on azoxymethane-induced intestinal carcinogenesis in rats

The effects of two naphthoquinones, juglone and plumbagin, and an isocoumarin, hydrangenol, on intestinal carcinogenesis in rats were examined by dietary exposure during the initiation phase. Starting at 5 weeks of age, male F344 rats were fed the diets containing either of the test chemicals at a concentration of 200 ppm or the control diet without the compounds. At 6 weeks of age, all animals were treated with s.c. injections of azoxymethane (AOM) (15 mg/kg body weight, once weekly for 3 weeks) or saline alone. Animals fed experimental diets were changed to the control diet 1 week after the last carcinogen treatment. Animals given plumbagin together with the carcinogen had a lower incidence (41%) and smaller multiplicity (0.48±0.62) of tumors in the entire intestine compared with those exposed to carcinogen alone (68% and 1.04±0.62) ( P<0.05 and <0.01, respectively). The incidence and multiplicity of tumors in the small intestine (7% and 0.07±0.25) and the multiplicity of tumors in the entire intestine (0.60±0.76) of animals treated with juglone and the carcinogen were significantly less than those of animals treated with carcinogen alone ( P<0.05 in each). Hydrangenol tended to decrease the incidence and the multiplicity of tumors in the entire intestine induced by AOM, but the effect was not statistically significant. The present data suggest that the naphthoquinones, juglone and plumbagin, could be promising chemopreventive agents for human intestinal neoplasia.

Effect of β-carotene, sodium ascorbate and cellulose on 1,2-dimethylhydrazine-induced intestinal carcinogenesis in rats

Male Sprague-Dawley rats were fed a diet containing either 0.005% β-carotene, 0.02% sodium ascorbate or 1.5% cellulose for 14 weeks. Beginning on day 3, all animals were also given weekly subcutaneous injections of 1,2-dimethylhydrazine (DMH; 20 mg/kg body wt.) throughout a 12-week period. The experimental diet was continued for an additional 14 weeks. At the end of the 26th week, surviving animals were sacrificed and the incidence of intestinal carcinomas was examined. A significantly lower incidence of carcinomas was observed in the β-carotene-fed group (55.0%), compared with that in the control group given DMH (82.1%).

Chemopreventive effect of costunolide, a constituent of oriental medicine, on azoxymethane-induced intestinal carcinogenesis in rats.

Modifying effects of costunolide, a constituent of oriental medicines, on intestinal carcinogenesis were examined in a rat model using azoxymethane (AOM). A total of 115 male F344 rats, 6 weeks old, were divided into four groups. Group 1 (30 rats) was fed a diet containing costunolide at a concentration of 0.02% for 4 weeks during which time three s.c. injections of AOM (15 mg/kg) were applied, and then kept on a basal diet until the end of the experiment (33 weeks). Group 2 (30 rats) was given AOM as in group 1 and fed the basal diet throughout, without costunolide. Group 3 (25 rats) was administered costunolide at the start of the experiment, but not given the carcinogen. Group 4 (30 rats) received the basal diet alone throughout the experiment and served as a control. Intestinal tumors were seen in groups 1 and 2, their incidence in group 1 (17%) being significantly lower than in group 2 (50%) (P < 0.05). Furthermore, the number of aberrant crypt foci/cm2 of colon in rats of group 1 at the termination of the experiment was significantly smaller than in group 2 (P < 0.01). BrdU labelling indices of S-phase mucosal cells in the colon of rats in group 1 were significantly lower than those in group 2 (3.9 +/- 3.1 vs. 9.1 +/- 4.5, P < 0.005). The present results suggest that the natural sesquiterpene contained in plants which have been used as oriental drugs, could be a promising chemopreventive agent for human intestinal neoplasia.

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 examined using female ACI/N rats. Starting at 5 weeks of age, animals were 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 treated with i.p. injections of MAM acetate (25 mg/kg body wt, once weekly for 3 weeks) or saline. Animals fed experimental diets were changed to the control diet from a week after the last carcinogen treatment. Three groups of animals fed the control diet were switched to 100 p.p.m. BTC, 400 p.p.m. BTC or 400 p.p.m. BITC diet from a week after carcinogen treatment. Animals given the high-dose BTC diet at the initiation and the post-initiation phase showed smaller incidence (5% and 17%) and multiplicity (0.05 +/- 0.21 and 0.17 +/- 0.37) of tumours in small intestine compared with those of rats exposed to the carcinogen alone (61% and 1.06 +/- 1.18). The incidence and multiplicity of tumors in small intestine (21% and 0.32 +/- 0.73) and the incidence of colon tumors of rats given BITC in the initiation phase (47%) were significantly lower than those of animals treated with carcinogen alone (61%, 1.06 +/- 1.18 and 83%). Bromodeoxyuridine labeling indices of the intestinal mucosal cells were measured. The labeling indices were reduced by BTC and BITC exposure at initiation phase in both small intestine and colon. The results of measurement of labeling indices correlated with the decreased tumor incidence and multiplicity in the intestine. These data suggest that BTC and BITC could be promising chemopreventive agents for human intestinal neoplasia.

Modifying effects of fungal and herb metabolites on azoxymethane-induced intestinal carcinogenesis in rats.

Modifying effects of a fungal product, flavoglaucin, and four plant‐derived chemicals, shikonin, gingerol, oleanolic acid and paeoniflorin, on intestinal carcinogenesis were examined in a rat model using azoxymethane (AOM). A total of 280 male F344 rats, 6 weeks old, were divided into 12 groups. Group 1 (30 rats) was given two subcutaneous injections of 15 mg/kg of AOM at the start of the experiment. Groups 2 (30 rats), 3 (20 rats), 4 (20 rats), 5 (30 rats) and 6 (30 rats) received a test chemical (flavoglaucin, shikonin, gingerol, oleanolic acid or paeoniflorin, respectively) in the diet at a concentration of 0.02% for 3 weeks, during which time AOM was applied, and then kept on basal diet until the end of experiment (one year). Groups 7–11 (each 20 rats) were given a test chemical corresponding to Groups 2–6, respectively. Group 12 (20 rats) served as a control. The incidence and average number of intestinal tumors in Group 2 (47%, 0.57 ± 0.68) were significantly less than in Group 1 (74%, 1.07 ± 0.87) (P < 0.05, respectively). Multiplicity of intestinal neoplasms of Group 3 (0.55 ± 0.60) or 4 (0.47 ± 0.51) was also significantly smaller than that of Group 1 (P < 0.05 and P < 0.01, respectively). These results suggest that flavoglaucin, shikonin and gingerol might be promising chemopreventive agents for intestinal neoplasia.

Inhibitory effect of 5-hydroxy-4-(2-phenyl-( E)-ethenyl)-2(5H)-furanone, a novel synthesized retinoid, on azoxymethane-induced intestinal carcinogenesis in rats

Modifying effects of 5-hydroxy-4-(2-phenyl-(E)-ethenyl)-2(5H)-furanone, a novel synthesized retinoid (KYN-54), on intestinal carcinogenesis were examined in a rat model using azoxymethane (AOM). A total of ninety male F344 rats, 6 weeks old, were divided into 4 groups. Group 1 (20 rats) was fed a diet containing KYN-54 at a concentration of 0.02% for 3 weeks, during which time 2 s.c. injections of azoxymethane (15 mg/kg) were applied and then kept on a basal diet until the end of the experiment (1 year). Group 2 (30 rats) was given azoxymethane as in group 1 and fed the basal diet throughout, without synthetic retinoid exposure. Group 3 (20 rats) was administered KYN-54 at the commencement of the experiment, but not given the carcinogen. Group 4 (20 rats) received a basal diet alone throughout the experiment and served as a control. Intestinal tumors were seen in groups 1 and 2, their incidence and average number in group 1 (74%, 1.07 ± 0.87) being significantly less than in group 2 (39%, 0.56 ± 0.78) (P < 0.02 and P < 0.05, respectively). These results suggest that the synthetic retinoid might be a promising chemopreventive agent for intestinal neoplasia.

Cell kinetic analysis of the mucosal epithelium and assay of ornithine decarboxylase activity during the process of 1-hydroxyanthraquinone-induced large bowel carcinogenesis in rats.

Cell kinetics and activity of ornithine decarboxylase (ODC) were studied during the process of 1-hydroxyanthraquinone (1-HA)-induced intestinal carcinogenesis in rats. Starting at 6 weeks of age, a total of 37 male ACI/N rats were divided into two groups and treated as follows: group I (18 rats) received diet containing 1% 1-HA for 12 months; group II (19 rats) was given the basal diet alone. Sub-groups of 5-7 rats were sequentially killed at 4, 8 and 12 months for evaluation of the length, cell numbers and 5-bromo-2'-deoxyuridine (BrDU) labeling indices of large bowel crypts together with ODC activity. All kinetic and ODC data indicated increased DNA synthesis and proliferation at all time points. Morphological observation of the intestines also revealed melanosis, crypt abscesses and erosion, becoming more pronounced with length of exposure to the anthraquinone. The data thus suggest that cell proliferation in the crypts of the cecum or colon is important for 1-HA-induced intestinal carcinogenesis.

Effect of magnesium hydroxide on 1,2-dimethylhydrazine-induced intestinal carcinogenesis in rats.

Modifying effect of magnesium hydroxide on 1, 2-dimethylhydrazine (DMH)-induced intestinal carcinogenesis was examined in a rat model using 1, 2-dimethylhydrazine (DMH). Although the incidence or multiplicity of the small intestinal tumors of rats of Groups 2-5 which were s.c. injected DMH (20mg/kg, body weight) once 2 weeks for 10 times at the commencement of experiment and were given magnesium hydroxide (250 or 500 or 1000 or 2000ppm in diet) throughout the experiment, were not different from those of Group 1 exposed to DMH alone (Group 1), the incidence or multiplicity of the large intestinal tumors of the groups given the carcinogen and magnesium hydroxide were rather lower or smaller than that of the group given the carcinogen alone. Significant differences were obtained with the mutiplicity between Group 2 or 4 or 5 and Group 1 (P<0.02 or P<0.02 or P<0.05). These results appear to indicate an inhibitory effect of magnesium hydroxide on DMH induced large bowel carcinogenesis and are in agreement with those of our previous study in rats using methylazoxymethanol acetate. The agent could be a promising chemopreventive agent for large bowel carcinogenesis in humans together with other trace elements such as selenium or calcium.

The essential fatty acid requirement for azoxymethane-induced intestinal carcinogenesis in rats.

The essential fatty acid requirement for the development of intestinal carcinogenesis was determined and compared to the overall essential fatty acid status of the animals as measured by the triene/tetraene ratio in the plasma, liver and colon. To induce tumors, male Sprague-Dawley rats were given two weekly injections (20 mg/kg body wt) of azoxymethane. Two weeks after the last injection, the rats were divided into groups of 25 and given one of six diets containing various levels of essential fatty acids (as linoleate). The diets contained 5% total fat and were prepared by mixing safflower oil (high essential fatty acids, beef fat (low essential fatty acids), and medium chain triglyceride oil (no essential fatty acids). One group of rats was fed a 20% beef fat diet. The range of essential fatty acids was from less than 0.03% to 1.28% (w/w). Twenty-six weeks after the first azoxymethane injection, the animals were killed and intestinal tumor incidence and multiplicity were determined. Samples of plasma, liver and colon were also taken for measurement of the triene/tetraene ratio by gas chromatography. Large bowel tumor incidence showed a dependence on the essential fatty acid content of the diet. The results were as follows: (percent essential fatty acids: percent tumor incidence) Group A (1.28: 72.4), Group B (0.60: 73.3), Group C (0.11: 55.2), Group D (0.08: 39.3), Group E (less than 0.03: 37.9) and Group F, which was fed 20% beef fat, (0.34: 88.5).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of the experimental chemopreventative agent, glucarate, on intestinal carcinogenesis in rats.

Dietary calcium glucarate was previously shown to protect effectively against chemically-induced mammary, lung, liver and skin carcinogenesis in rodents, whereas the negative dietary calcium control, calcium gluconate, had no effect. In the present study the chemopreventative activity of dietary calcium glucarate was evaluated in the azoxymethane intestinal carcinogenesis model using the Fischer strain rat. The protocol limited the duration of azoxymethane treatment to 3 weeks to permit the evaluation of the separate effects of glucarate on the initiation and promotion phases. Control rats, treated with azoxymethane and maintained on a low fat chow diet throughout the 32-week experiment had an intestinal adenocarcinoma incidence of 55%, with an equal incidence of 27.7% in the small and large intestines. There was no significant difference between this control group and a negative calcium control group fed 128 mmol/kg chow of calcium as calcium gluconate. In contrast to these two control groups, supplementation of the diet of azoxymethane-treated rats with 128 mmol/kg diet of calcium glucarate during both the initiation and promotion phases significantly inhibited the overall induction of adenocarcinomas in the intestine, the incidence in the entire intestine and in the small and large intestines being 11.8, 5.8 and 5.8%, respectively. When fed only during the initiation phase, the inhibition again was statistically significant, the corresponding values being 11.8%, 5.8 and 5.8%. When calcium glucarate was fed during the promotion phase, a statistically significant inhibition of adenocarcinoma induction was observed only in the colon where the incidence was 5.5%. Weight gain was similar in all groups. These and related data indicate that dietary glucarate exerts a significant inhibitory effect on azoxymethane-induced intestinal and in particular colon carcinogenesis in the rat, decreasing their incidence and size and reducing their metastic potential.

Effect of dietary seaweed preparations on 1,2-dimethylhydrazine-induced intestinal carcinogenesis in rats.

Nineteen preparations from 8 species of edible seaweeds, sodium alginate and cellulose powder were incorporated into a basic diet in proportions ranging from 0.05% to 2.0%, and used as experimental diets. Experimental rats were fed these diets and controls were fed the basic diet for 12 weeks. All rats also received the carcinogen, 1,2-dimethylhydrazine, during above period. After 20 weeks, all rats were autopsied and the incidence of intestinal tumors induced were examined. There was a significant decrease in incidence in rats fed 6 preparations from Eisenia bicyclis, Laminaria angustata, L. angustata var. longissima and Porphyra tenera (P less than 0.05).

Effects of misclerone (clofibrate) on dimethylhydrazine-induced intestinal carcinogenesis in rats.

Intestinal tumors were induced by treatment with dimethylhydrazine (DMH) (14 mg with reference to base/kg body weight, weekly, s.c., for 20 weeks) in male rats supplied by Rappolovo Animal Farm. Some of the animals received 25 mg/day of misclerone (clofibrate) per os, 5 times a week. Clofibrate treatment did not affect the frequency of tumors of the large and small intestine but was followed by a significant decrease in the number of large- and medium-size tumors. The animals which had received clofibrate beginning from 10 days before the first injection of DMH revealed a relatively greater fraction of exophytic intestinal tumors and less invasion of the intestinal wall as compared with the animals treated with DMH alone. Possible mechanisms of the effect of clofibrate are discussed.

Inhibition by bran of the colonic cocarcinogenicity of bile salts in rats given dimethylhydrazine

The effects of incorporating bile salts alone or bile salts and bran in the diet were investigated in 1,2-dimethylhydrazine (DMH)-induced intestinal carcinogenesis in rats. Male Sprague-Dawley albino rats were divided into the following groups: Group I, control; Group II, 0.5% mixed bile salts; Group III, 30 mg/kg DMH (10 weekly oral doses); Group IV, bile salts and DMH; and Group V, bile salts, 20% wheat bran and DMH. The bile salts and bran were added to a standard basal diet. The numbers of grossly observable colonic tumors/rat in Groups III, IV, and V were 10.8, 8.4, and 11.6, respectively. However, microscopic classification of these tumors revealed 37 46 malignant tumors in Group IV when compared to Group III ( 28 68 ) and Group V ( 43 77 ). Thus bile salts were cocarcinogenic but not cotumorigenic, that is, bile salts caused no increase in the number of grossly observable tumors, but rather potentiates the formation of malignant tumors. Bile salts alone increased the labeling index of epithelial cell nuclei in the lower third of the colonic cryts, while in combination with DMH, they increased the number of cells/crypt. Further, addition of bile steroids significantly increased the incidence and number of malignant duodenal tumors. No significant differences in the fecal excretion of acidic steroids were observed between Groups II, IV, and V.

Inhibitory effect of butylated hydroxytoluene (BHT) on intestinal carcinogenesis in rats by azoxymethane

Summary Administration of BHT in the diet to rats concurrently receiving a weekly sc injection of the carcinogen azoxymethane inhibited the development of intestinal tumours: When BHT was fed after a course of treatment with azoxymethane, the number of animals with tumours was not affected but the number of tumours/animal increased slightly.

Intestinal carcinogenesis in rats using 1,2-dimethylhydrazine with or without degraded carrageenan

The phenomena of proliferation, metaplasia, and neoplasia of the intestinal epithelium were studied in Sprague-Dawley rats, by using 1,2-dimethylhydrazine (DMH), which was injected once weekly, subcutaneously, at a dose of 30 mgm/kgm for up to 30 weeks. Degraded carrageenan (C16) was also given either in the diet (7.5 gm/kgm) or in drinking water (5% solution) alone or in combination with DMH for up to 30 weeks. Papillary adenomas, adenomatous polyps, and adenocarcinomas of various grades were observed as having been elicited by DMH. This compound, when given alone, causes the development of tumors that arise from the superficial protion of the intestinal mucosa; when given together with C16, DMH induces proliferation of the deep glandular areas. C16 alone induces transformation of the mucosal epithelium of the distal rectum into stratified squamous epithelium. The administration of C16 in the diet, in contrast to drinking water, elicits earlier changes in proliferation.