Prevention of N-methylnitrosourea-induced colon carcinogenesis in rats by oxygenated carotenoid capsanthin and capsanthin-rich paprika juice.

Epidemiological and animal studies have provided evidence that dietary carotenoids may reduce the risk of certain types of cancer. An inhibitory activity of oxygenated carotenoid capsanthin, a potent antioxidant, and paprika juice rich in capsanthin (3.54 mg/100 ml) against colon carcinogenesis was investigated in F344 rats. In Experiment I (short-term assay), six rats each were given a gavage of 5 mg, 0.2 mg, or 0.008 mg capsanthin six times a week for Weeks 2-6 after receiving three intrarectal doses of 4 mg N-methylnitrosourea in Week 1. The number of colonic aberrant crypt foci, preneoplastic lesions, at Week 6 was significantly fewer (by 42%) in the 0.2 mg capsanthin group, but not in other groups, than the control group. In Experiment II (long-term assay), five groups of 30 or 25 rats each received an intrarectal dose of 2 mg N-methylnitrosourea three times a week for Weeks 1-3, and had either of 10 p.p.m. or 2 p.p.m. capsanthin solutions, 1:2.5 and 1:16.7 diluted solution of paprika juice (containing 10 p.p.m. or 2 p.p.m. capsanthin), and tap water (control fluid) as drinking fluid throughout the experiment. The experimental groups were fed 0.2 mg or 0.04 mg capsanthin/day/rat. The colon cancer incidence at Week 30 was significantly lower in the highly diluted paprika juice group (40%), but not in the moderately diluted paprika juice group (60%) and the capsanthin solution groups (68% and 68%) than the control group (83%). The results suggested that paprika juice may affect colon carcinogenesis. However, capsanthin alone failed to inhibit colon tumorigenesis, in spite of suppression of aberrant crypt foci formation in the short-term assay. Further studies are needed to explain this discrepancy.

Chemoprevention by the oxygenated carotenoid beta-cryptoxanthin of N-methylnitrosourea-induced colon carcinogenesis in F344 rats.

Beta-cryptoxanthin (betaCx), one of 4 major carotenoids in the blood, was investigated for anticarcinogenic activity in F344 rats. Four groups of 25 rats each received an intrarectal dose of 2 mg of N-methylnitrosourea 3 times a week for 5 weeks, and were fed the diet supplemented with 0 ppm (control), 25 ppm, 5 ppm or 1 ppm betaCx throughout the experiment. The colon cancer incidence at week 30 was significantly lower in the betaCx (25 ppm) diet group, but not in the betaCx (5 ppm) and betaCx (1 ppm) diet groups, than in the control diet group: 68%, 84%, 80% vs. 96%. The results suggested that dietary betaCx may affect colon carcinogenesis after accumulation in the colonic mucosa, perhaps due to absorption from the colon as well as the small intestine.

Inhibitory effects of ursodeoxycholic acid on N-methylnitrosourea-induced colon carcinogenesis and colonic mucosal telomerase activity in F344 rats.

Bile acids are known to promote colon carcinogenesis. However, one study showed that ursodeoxychlic acid (UDCA) prevented azoxymethane-induced rat colon tumorigenesis. The aim of the present study with 3 sets of experiments was to explore the inhibitory effect of UDCA supplemented in the diet on colon carcinogenesis induced by the intrarectal administration of N-methylnitrosourea (MNU) in F344 rats. In experiment I, 5 rats per group were fed a diet supplemented with 0% (control), 0.4%, 0.08% or 0.016% UDCA or chenodeoxycholic acid (CDCA) for 5 weeks after receiving 3 intrarectal doses of 4 mg MNU in week 1. The formation of colonic aberrant crypt foci (ACFs, preneoplastic lesions) at week 6 showed a 24% and 23% reduction in the 0.4% and 0.08% UDCA groups, respectively, as compared to the control group, while it increased for the 0.4% and 0.08% CDCA groups, and was unaffected in the 0.016% UDCA and CDCA groups. In experiment II based on the results of experiment I, all rats received an intrarectal dose of 2 mg MNU 3 times a week for 3 weeks, and then were administered with 0%, 0.4% or 0.08% UDCA for 27 weeks. At week 30, the incidence of colon tumors in the UDCA groups was significantly lower than that in the control group: 20/50 (40%) and 9/25 (36%) vs. 17/25 (68%). The number of large-sized ACFs with 4 or more ACs showed a 47% and 59% reduction in the normal-appearing mucosa in the UDCA groups as compared to the control group, while the number of small-sized ACFs with 1-3 ACs was similar in all groups. The normal-appearing mucosa showed a noticeable level of telomerase activity (semiquantitative PCR-based TRAP assay) in the control group, and significantly reduced levels in the UDCA groups compared to the control group: 19.8 and 32.7 vs. 71.0 TPG unit in mean value. The colon tumors showed a high level of enzyme activity in both the control and UDCA groups. In experiment III, 6 rats per group were fed a diet supplemented with 0%, or 0.4% UDCA or CDCA for 5 weeks after receiving 3 intrarectal doses of 4 mg MNU in week 1. Two control groups did not receive any treatment with MNU and bile acids. The MNU-treated groups showed significantly elevated levels of colonic mucosal telomerase activity at week 6 as compared to the control group (6.5 TPG unit in mean value). It was noted that both UDCA and CDCA administration reduced the enzyme activity as compared to the group with MNU treatment alone: 24.7 and 25.2 vs. 40.1 TPG unit in mean value. Thus, the present study suggested that orally administered UDCA inhibited the growth of ACFs and the development of carcinomas in the colon of rats treated with MNU. Also, UDCA may suppress MNU-induced telomerase activation in normal-appearing but ACF-containing colon mucosa, and its mechanism appears to be different from that responsible for the anti-tumor promoting action of UDCA.

Prevention of N-methylnitrosourea-induced colon tumorigenesis by ursodeoxycholic acid in F344 rats.

Bile acids are known to promote colon carcinogenesis. However, there is one study showing that ursodeoxycholic acid (UDCA) supplemented in the diet at the concentration of 0.4% prevented azoxymethane-induced rat colon tumorigenesis. The aim of our study was to explore the inhibitory effect of a much smaller dose of UDCA on colon carcinogenesis in rats. One hundred 7-week-old F344 rats were given 2 mg of N-methylnitrosourea 3 times a week for 3 weeks by intrarectal instillation, and were fed a 0% (control), 0.4% or 0.08% UDCA-supplemented diet for the next 27 weeks. All the rats were killed and examined for tumor development at week 30. The tumor incidence and number were significantly lower and smaller, respectively, in the UDCA-fed rats than in the control rats: 40% and 36% vs. 68%; 0.5 +/- 0.1 (mean +/- SEM) and 0.4 +/- 0.1 vs. 1.0 +/- 0.2. All the tumors were located in the distal half of the colon and were plaque-shaped or polypoid, being well-differentiated adenocarcinomas restricted to the mucosa or submucosa. Bile acids in the feces and the blood obtained at weeks 20 and 30, respectively, were analyzed by HPLC. A significant increase of UDCA was confirmed in both the feces and the blood of the UDCA-fed rats compared with the control rats. The results suggest that the continuous feeding of a small dose of UDCA may prevent colon carcinogenesis.

Prevention of N-methylnitrosourea-induced colon carcinogenesis in F344 rats by lycopene and tomato juice rich in lycopene.

Epidemiological studies have suggested a protective effect of lycopene and lycopene-rich tomatoes against various cancers. Here, the inhibition of colon carcinogenesis by lycopene and tomato juice was investigated. Seven-week-old female F344/NSlc rats received an intrarectal dose of 2 mg (experiment I) or 4 mg (experiment II) of N-methylnitrosourea 3 times a week for 3 weeks, and had free access to one of 4 drinking fluids: plain water (control group), 17 ppm lycopene water solution (Ly group), and diluted tomato juice containing 17 ppm (Tj group) or 3.4 ppm (tj group) lycopene, throughout the experiments. The colon cancer incidence at week 35 was significantly lower in the Tj group, but not in the Ly group, than in the control group: 21% and 33% vs. 54%, in experiment I (24 rats in each group). It was significantly lower in the Tj group than in the tj and control groups, 40% vs. 72% and 84%, in experiment II (25 rats in each group). An appreciable amount of lycopene (0.02 microgram/g) was detected in the colon mucosa of rats in the Tj group, but not in the tj group. The results suggest that tomato juice rich in lycopene may have a protective effect against colon carcinogenesis.

Castability of a commercial castable glass ceramics.

This study was carried out to determine the design and thickness of the cervical margin of a castable ceramic restoration from the point of view of its castability. Castability of castable ceramics was lower compared to Ag-Pd-Au and Co-Cr alloy with the use of the mesh pattern and rod pattern test (p < 0.05). It was more dependent on the pattern thickness than alloys (p < 0.05), and perfect reproducibility with non-measurable variability could be estimated to reach 1.0 mm thickness of the original pattern (p < 0.001). Marginal shape was certainly more reproducible in a right angle shoulder than in 30, or 45 degree bevels (p < 0.05). From these results, it is suggested that a right angle shoulder margin with 1.0 mm thickness is more suitable to castable glass ceramic restoration than any other design.

Chemopreventive efficacy of low dose of pravastatin, an HMG-CoA reductase inhibitor, on 1,2-dimethylhydrazine-induced colon carcinogenesis in ICR mice.

Potential chemopreventive action of de-escalated doses of pravastatin (Pr), an HMG-CoA reductase inhibitor, on 1,2-dimethylhydrazine.2HCl (DMH)-induced colon tumorigenesis was evaluated in ICR mice. Thirty mice each in 4 groups received an intraperitoneal injection of 20 mg DMH/kg body weight once weekly for 10 weeks, and were given drinking water dissolved Pr at the concentration of 10 ppm, 5 ppm, or 0 ppm (control) throughout the experiment. The incidence of colon tumors examined at week 35 was significantly lower in the Pr-treated groups than the control group: 20%. 21% and 23% vs. 55%. However, the tumor multiplicity/tumor-bearing animal was increased in the Pr-treated groups compared to the control group. Of all the tumors, 66 were adenocarcinomas in the distal colon and 5 were squamous cell carcinomas at the anus. The Pr treatment showed no hypocholesterolemic effect but did significant decrease of colonic mucosal cholesterol. The results seems to suggest that a small dose of Pr may reduce the incidence of colon cancers, perhaps being related, at least in part, to modulation of cholesterol synthesis in situ at the colonic mucosa.

Inhibitory effects of natural carotenoids, alpha-carotene, beta-carotene, lycopene and lutein, on colonic aberrant crypt foci formation in rats.

Inhibitory effect of four carotenoids prevalent in human blood and tissues against the formation of colonic aberrant crypt foci was examined in Sprague-Dawley rats. They received three intrarectal doses of N-methylnitrosourea in weak 1, and a daily gavage of de-escalated doses of carotenoids during weeks 2 and 5. Lycopene, lutein, alpha-carotene and palm carotenes (a mixture of alpha-carotene, beta-carotene and lycopene) inhibited the development of aberrant crypt foci quantitated at week 6, but beta-carotene did not. The results suggested that lycopene and lutein in small doses may potentially prevent colon carcinogenesis.

Chemoprevention by pravastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, of N-methyl-N-nitrosourea-induced colon carcinogenesis in F344 rats.

A potential chemopreventive action of pravastatin (Pr), a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, on colon carcinogenesis was evaluated in F344 rats. All rats at 7 weeks of age received an intrarectal dose of 2 mg of N-methyl-N-nitrosourea 3 times weekly for 2 weeks in experiment I (2 groups of 16 rats each), and for 3 weeks in experiment II (4 groups of 30 rats each). They were given drinking water containing 0 ppm (control) or 200 ppm Pr during weeks 1 to 40 in experiment I, and containing 0 ppm (control), 25 ppm, 5 ppm and 1 ppm Pr during weeks 4 to 40 in experiment II. The body weight gains, and food and water intakes were similar in all the groups. The incidence of colon carcinomas at termination of the experiment at week 40 was not different in the 200 ppm Pr and control groups in experiment I (63% vs. 69%), while it was significantly lower in the 25 ppm and 5 ppm groups, but not in the 1 ppm Pr group, compared with the control group in experiment II (50%, 48%, and 77% vs. 80%). This inhibitory effect of Pr against colon carcinogenesis was not related to the cholesterol-lowering effect of this agent. We postulate that Pr inhibits the promotion stage of colon carcinogenesis, perhaps through modulation of cholesterol synthesis in situ in the colonic mucosa, thereby suppressing farnesyl isoprenylation of growth-regulating proteins such as p21 ras.

Prevention of 1,2-dimethylhydrazine-induced colon tumorigenesis by HMG-CoA reductase inhibitors, pravastatin and simvastatin, in ICR mice.

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, pravastatin (Pr) and simvastatin (Si), suppressed 1,2-dimethylhydrazine (DMH)-induced colon cancer development in female ICR mice. All mice received an i.p. injection of 10 mg DMH/kg body wt once weekly for 15 weeks. Pr was administered at 0.01, 0.005 and 0.001% levels in drinking water, and Si at 0.01 and 0.002% levels in the diet. All animals had access to Pr or Si throughout the experiments which were terminated at weeks 25 or 30. Histologically most of the tumors were well-differentiated adenocarcinomas. The incidence of colon tumors examined at weeks 25 or 30 was reduced by 67% in the 0.01% Pr group, by 30% in the 0.005% Pr and 0.01% Si groups, and by 24% in the 0.001% Pr and 0.002% Si groups, compared with their respective controls. However, the differences did not reach statistical significance. The number of tumors per mouse was significantly reduced in all groups administered Pr and Si except the 0.001% Pr group as compared to their respective controls. The results from those three independent experiments seem to suggest that HMG-CoA reductase inhibitors may prevent colon tumorigenesis in laboratory animal model.

Colon cancer prevention with a small amount of dietary perilla oil high in alpha-linolenic acid in an animal model.

BACKGROUND: Epidemiologic and experimental studies suggest that dietary fish oil and vegetable oil high in omega-3 polyunsaturated fatty acids (PUFAs) suppress the risk of colon cancer. The optimal amount to prevent colon carcinogenesis with perilla oil high in omega-3 PUFA alpha-linolenic acid in a 12% medium-fat diet was investigated in female F344 rats. For comparison, safflower oil high in omega-6 PUFA linoleic acid was used. METHODS: Thirty or 25 rats at 7 weeks of age in each group received an intrarectal dose of 2 mg N-methyl-N-nitrosourea 3 times weekly in weeks 1 and 2 and were fed the diets with various levels of perilla oil and safflower oil throughout the experiment. RESULTS: The incidence of colon cancer at the termination of the experiment at week 35 was 40%, 48% and 32% in the rats fed the diets with 3% perilla oil plus 9% safflower oil, 6% perilla oil plus 6% safflower oil, and 12% perilla oil plus 0% safflower oil, respectively, whereas it was 67% in the rats fed the control diet with 0% perilla oil plus 12% safflower oil. The amount of diet consumed and the body weight gain were identical in all of the dietary groups. The ratios of omega-3 PUFA to omega-6 PUFA in the serum and the colonic mucosa at week 35 were increased in parallel to the increased intake of perilla oil. CONCLUSIONS: The results suggest that a relatively small fraction of perilla oil, 25% of total dietary fat, may provide an appreciable beneficial effect in lowering the risk of colon cancer.

A very low dose of green tea polyphenols in drinking water prevents N-methyl-N-nitrosourea-induced colon carcinogenesis in F344 rats.

The effect of tea polyphenols, major constituents of tea, on colon carcinogenesis was investigated. A total of 129 female F344 rats were given an intrarectal instillation of 2 mg of N-methyl-N-nitrosourea 3 times a week for 2 weeks, and received a water solution of green tea extract (GTE) as drinking water throughout the experiment. Autopsies at week 35 revealed significantly lower incidence of colon carcinomas in rats ingesting 0.05%, 0.01% or 0.002% GTE solution than in controls ingesting 0% GTE solution: 43%, 40% and 33% vs. 67%. The data suggest that GTE, even at a very low dose (0.002% solution), has a potent inhibitory effect on colon carcinogenesis.

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.

Calorie restriction suppresses subgenomic mink cytopathic focus-forming murine leukemia virus transcription and frequency of genomic expression while impairing lymphoma formation.

Calorie restriction suppresses mammary proviral mRNA expression and protooncogene activation in breast tumor-prone C3H/Ou mice while inhibiting tumor formation. To determine whether the beneficial effects of chronic energy-intake restriction (CEIR) can be extended to an organ site of retrovirus-induced tumorigenesis where the dynamics of growth and sexual maturity are not paramount as they are in breast tissue, calorie restriction of 40% was imposed on thymic lymphoma-prone AKR mice when 4 weeks old. Recombination between various murine leukemia virus (MuLV) mRNAs, resulting in the generation of an 8.4-kilobase genomic-length transcript with mink cytopathic focus-forming (MCF) characteristics, is considered the proximal retroviral event in AKR lymphomagenesis. Thymic expression of subgenomic MCF MuLV mRNA was uniformly suppressed among 6- and 8-week-old CEIR mice (P less than 0.02). This suppression of MuLV transcription preceded a 25% reduction in the appearance of genomic-length MCF transcripts among CEIR mice and a 28% reduction in cumulative lymphoma mortality. The latency to median tumor incidence was extended greater than 3 months by calorie restriction, and median lifespan was extended approximately 50%. Survival curves for the full-fed and CEIR dietary cohorts were found to be significantly different (P less than 0.0001), with full-fed mice experiencing a 3 times greater risk of lymphoma mortality. These findings extend the known range of pathologic states influenced by CEIR in inbred mice and show that retroviral mechanisms involved in generation of lymphoid malignancy can be significantly impaired by calorie restriction.

Inhibitory effect of dietary perilla oil rich in the n-3 polyunsaturated fatty acid alpha-linolenic acid on colon carcinogenesis in rats.

The inhibitory effect of dietary perilla oil rich in the n-3 polyunsaturated fatty acid alpha-linolenic acid against colon carcinogenesis was investigated in rats. Four groups of 26 F344 rats each received an intrarectal dose of 2 mg of N-methyl-N-nitrosourea 3 times a week for 2 weeks, and received a diet containing 12% perilla oil, 6% or 12% safflower oil (rich in the n-6 polyunsaturated fatty acid linoleic acid), or 12% palm oil (rich in saturated and monounsaturated fatty acids). At week 35, the incidence of colon cancer was significantly lower in perilla oil-fed rats than in other dietary groups; 19% vs. 46%, 56% and 58%. When examined at week 10, the concentration of fecal bile acids, known to be tumor promoters, was not significantly different among the dietary groups, and the intrarectal deoxycholic acid-induced colonic mucosal ornithine decarboxylase activity, a marker of tumor promotion, was significantly lower in perilla oil-fed group than in other groups. The serum and colonic mucosal fatty acid compositions and the blood plasma prostaglandin E2 level directly reflected the fatty acid composition of each dietary fat. The results suggest that the anti-tumor-promoting effect of dietary perilla oil was a result of a decreased sensitivity of colonic mucosa to tumor promoters arising from the altered fatty acid composition in membrane phospholipid of colonic epithelial cells, and was not a consequence of a decrease of promoters such as bile acids.

Dietary restriction permits normal parturition and lactation but suppresses mouse mammary tumor virus proviral transcription even after mammary involution.

Dietary restriction of C3H/Ou mice prevents development of spontaneous mammary adenocarcinoma by suppressing mammary expression of the mouse mammary tumor virus (MMTV) via a mechanism which may involve prolactin. In the present study, dietary restriction of 40% was imposed for 16 weeks on nulliparous C3H/Ou mice, interrupted by ad libitum consumption at mating and continued only during pregnancy and lactation, with 40% energy restriction reimposed at the end of lactation. The results show that mammary MMTV mRNA expression levels of chronic energy intake restricted (CEIR) mice and ad libitum fed mice are similar and elevated during early lactation, when all mice of both groups are being fed ad libitum energy levels. In spite of this, and in marked contrast, when CEIR dams are returned to 40% dietary restriction following the weaning of litters, mammary MMTV transcription is suppressed to levels 4-5-fold less than those measured in mammary glands from ad libitum fed controls. Within the 38 weeks of study, 73% of ad libitum fed uniparous mice at risk and 11% of CEIR uniparous mice at risk developed mammary tumors, yet mice of both dietary groups delivered and weaned healthy litters with comparable efficiency. When dietary restriction is maintained in CEIR mice during pregnancy and lactation, efficiency of conception and litter size are reduced, and MMTV transcription is suppressed even during lactation. Mean serum prolactin levels were not significantly different among dietary groups. These findings show that the level of MMTV transcription is rigorously influenced by dietary energy level, and that 40% dietary restriction of C3H/Ou mice not only suppresses mammary MMTV transcription and prevents mammary tumor development in uniparous mice, but also permits normal conception, gestation, lactation, and the production of healthy litters as long as the nutritional demands of gestation and lactation are met.

Relationship between blood plasma prostaglandin E2 and liver and lung metastases in colorectal cancer.

The relationship of prostaglandin E2, of which a large amount is produced in various neoplasms, and hematogenous distant metastases was investigated in a total of 44 colorectal cancer patients because of its varied pathophysiologic potentials. The authors found significantly high levels of PGE2 in local venous blood draining the carcinoma and in peripheral blood in cases with liver or lung metastasis, as well as a significantly large amount of PGE2 production in the carcinoma tissue. The results suggest that increased local blood PGE2 could enhance the metastasis formation, and increased peripheral blood PGE2 may be useful in the detection of such metastasis in colorectal cancer.

Inhibition of methylnitrosourea-induced large bowel cancer development in rats by sarcophytol A, a product from a marine soft coral Sarcophyton glaucum.

An antitumorigenic effect of sarcophytol A (SaA), a simple monohydroxycembratetraene isolated from a marine soft coral Sarcophyton glaucum, was investigated in rat colon carcinogenesis. Three groups (26 rats each) of female CD-Fischer rats given an intrarectal dose of 2 mg of N-methyl-N-nitrosourea 3 times weekly for Wk 1 to 3 were fed standard laboratory chow in the control group or the chow containing 0.01% SaA from Wk 1 or from Wk 4 in experimental groups. The body weight gain and the food intake were not different among all 3 groups, and SaA intake was similar in both experimental groups at a dosage of 6.18 and 6.14 mg/kg of body weight/day at Wk 5 and 3.87 and 3.90 mg/kg of body weight/day at Wk 25. At autopsy at Wk 26, the incidence of large bowel tumors was found to be significantly lower and the mean number of tumors per tumor-bearing rat to be insignificantly smaller in experimental groups than in the control group: 50% and 58% versus 85%, 1.8 and 1.8 versus 2.0. The tumors in both experimental groups were generally smaller. All the tumors except two signet ring cell carcinomas were well-differentiated adenocarcinomas. Induction of ornithine decarboxylase activity, a marker of tumor promotion, in the large bowel mucosa of rats which were fed the SaA chow for 1 wk, then received an intrarectal dose of 12, 6, or 1.2 mumol of deoxycholate, a tumor promoter in large bowel carcinogenesis, and were killed 4 h later was significantly lower than in control rats. Thus, it was concluded that SaA inhibited the development of large bowel cancer, probably through an antipromoting mechanism.

Involvement of prostaglandin E2 in bile acid-caused promotion of colon carcinogenesis and anti-promotion by the cyclooxygenase inhibitor indomethacin.

The mechanism of the anti-promoting effect of the prostaglandin (PG) synthesis inhibitor indomethacin in colon carcinogenesis was investigated. Male Sprague-Dawley rats received 0.002% water solution of indomethacin as drinking water freely for 3 days, then a subcutaneous injection of various doses of PGE2 and/or an intrarectal instillation of 12 mumol of sodium deoxycholate as a colon tumor promoter. Ornithine decarboxylase (ODC), a marker of tumor promotion, in the distal colonic mucosa was assayed at 4 hr after deoxycholate instillation. Indomethacin significantly suppressed the deoxycholate-augmented increase of ODC activity, while exogenous PGE2 restored or further increased the augmented ODC activity. The amount of PGE2 and the level of ODC activity were well correlated. However, PGE2 alone without deoxycholate did not increase the activity. Deoxycholate markedly increased colonic mucosal PGE2 at 1 hr after the instillation, and indomethacin decreased it. The results indicate that PGE2, the production of which is stimulated in the colonic mucosa by deoxycholate, is involved in the induction of colonic mucosal ODC. This is probably why PG synthesis inhibitors may inhibit the tumor promotion and prevent cancer development in the colon.