Yoko Fukaura

Inhibitory effects of natural carotenoids, α-carotene, β-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 week 1, and a daily gavage of de-escalated doses of carotenoids during weeks 2 and 5. Lycopene, lutein, α-carotene and palm carotenes (a mixture of α-carotene, β-carotene and lycopene) inhibited the development of aberrant crypt foci quantitated at week 6, but β-carotene did not. The results suggested that lycopene and lutein in small doses may potentially prevent colon carcinogenesis.

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 ω‐3 polyunsaturated fatty acids (PUFAs) suppress the risk of colon cancer. The optimal amount to prevent colon carcinogenesis with perilla oil high in ω‐3 PUFA α‐linolenic acid in a 12% medium‐fat diet was investigated in female F344 rats. For comparison, safflower oil high in ω‐6 PUFA linoleic acid was used.

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 μ/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.

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 redutase 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.

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 PGE2in 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 PGE2production in the carcinoma tissue. The results suggest that increased local blood PGE2could enhance the metastasis formation, and increased peripheral blood PGE2may be useful in the detection of such metastasis in colorectal cancer.

Inhibitory Effect of Dietary Perilla Oil Rich in the n-3 Polyunsaturated Fatty Acid α-Linolenic Acid on Colon Carcinogenesis in Rats

The inhibitory effect of dietary perilla oil rich in the n‐3 polyunsaturated fatty acid α‐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.

Increased mucosal ornithine decarboxylase activity in large bowel with multiple tumors, adenocarcinoma, and adenoma.

The polyamine biosynthetase, ornithine decarboxylase (ODC), involved in tumor promotion, was investigated in grossly normal mucosa obtained from surgically resected large bowel; 48 cases with and six cases without large bowel cancer. The mucosal ODC activity was significantly higher in 17 multiple tumor cases bearing adenocarcinoma(s) plus adenoma(s) than in 31 solitary tumor cases bearing one adenocarcinoma alone. It was higher in the mucosa of the two groups of cases than in the mucosa of individuals without large bowel cancer. Furthermore, the enzyme activity in left‐sided cancer cases was significantly higher than that in right‐sided cancer cases. Carcinoma tissue showed a remarkable high level of enzyme activity, compared with the normal mucosa. The results indicate the larger the number of tumors the higher the level of the ODC activity in the normal mucosa, particularly in left‐sided cancer cases. It is concluded that the mucosal ODC may provide a good biological marker to detect individuals at higher risk for large bowel cancer due to exogenous or endogenous factors, and thus contribute to the prevention of mortality from large bowel cancer.

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 faces 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.

Chemoprevention by the Oxygenated Carotenoid β‐Cryptoxanthin of N‐Methylnitrosourea‐induced Colon Carcinogenesis in F344 Rats

β‐Cryptoxanthin (βCx), 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 βCx throughout the experiment. The colon cancer incidence at week 30 was significantly lower in the βCx (25 ppm) diet group, but not in the βCx (5 ppm) and βCx (1 ppm) diet groups, than in the control diet group: 68%, 84%, 80% vs. 96%. The results suggested that dietary βCx may affect colon carcinogenesis after accumulation in the colonic mucosa, perhaps due to absorption from the colon as well as the small intestine.

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.