Rat Colon Tumorigenesis Research Articles

Consumption of Low-Dose of Ethanol Suppresses Colon Tumorigenesis in 1,2-Dimethylhydrazine-Treated Rats.

The effect of low-dose of ethanol consumption on the development of colon cancer is unclear. This study aimed to investigate the effects of low-dose ethanol (0.5%, 1%, and 2% [v/v] ethanol in drinking water) for 28 wk on colon tumor incidence in rats injected with 1,2-dimethylhydrazine. Body weight, fluid and food consumption, and the total numbers of colon adenomas (mild-, moderate-, and severe-grade dysplasia) per rat were unaffected by ethanol consumption. However, the numbers of severe-grade dysplasia were significantly reduced by 1% ethanol compared with the control (0% ethanol; -93%) but not by 0.5% and 2% ethanol. Although the numbers of total adenocarcinomas were unaffected, those of total of adenomas and adenocarcinomas together were significantly reduced by 0.5% and 1% ethanol (-39% and -41%, respectively). Intriguingly, real-time PCR assay indicated the abundance of cecal Clostridium leptum (a putative immunosuppressor) was the least in rats received 1% ethanol. Furthermore, 1% ethanol markedly increased colonic mRNA of IL-6, a putative suppressor of regulatory T-cells and cytoprotector. This study provides the first evidence for the potential of 1% ethanol, but not 2% ethanol, to prevent colon tumorigenesis in rats, supporting the J-curve hypothesis of the effect of low-dose alcohol on health. Further, the modulation of C. leptum and expression of IL-6, potentially linking to carcinogenesis, by 1% ethanol may provide an insight into the underlying mechanisms of the anti-colon tumor effect.

Chemopreventive Action by Ethanol-extracted Brazilian Green Propolis on Post-initiation Phase of Inflammation-associated Rat Colon Tumorigenesis.

Propolis has since long been utilized in numerous folk medicines with a variety of medicinal properties. In this study, the effects of ethanol-extracted (EEP) and water-extracted (WEP) Brazilian green propolis on the post-initiation phase of inflammation-associated rat colon tumorigenesis were directly compared. Male F344 rats at 6 weeks of age were subcutaneously injected with 1,2-dimethylhydrazine (DMH) at 40 mg/kg body weight twice during the first week, followed by 1% dextran sodium sulfate (DSS) in drinking water for one week. After a 1-week no-treatment period, animals were administered either basal Oriental MF powdered diet, or 1% EEP or 1% WEP in the basal diet until week 32. Post-initiation treatment with EEP significantly reduced the multiplicity of colorectal carcinomas compared to the control (0.40±0.13/rat vs. 2.29±0.84/rat, respectively, p<0.05), and EEP also reduced the tumor volume. Immunohistochemically, expression of inflammation-associated proteins inducible nitric oxide synthase, tumor necrotic factor alpha, nuclear factor kappa B and glutathione peroxidase-2 were significantly diminished in colorectal tumors from EEP-treated rats. Suppression of inflammation and oxidative stress, which had been triggered by DMH and promoted by DSS, was a primary mechanism by which EEP suppressed carcinogenesis.

Anti-inflammatory and proapoptotic effects of umbelliferone in colon carcinogenesis.

Colorectal cancer (CRC) is a serious health problem throughout the world. 5-Flurouracil, the first-line chemotherapy of colorectal cancer often produces more toxicity to neighboring cells; however, it is still used for CRC treatment. To overcome this, umbelliferone (UMB), a less toxic bioflavonoid has been used to test its anticancer effects on animal model. The objective of the present study is to evaluate the anticancer activity of UMB on 1,2-dimethylhydrazine (DMH)-induced rat colon tumorigenesis to determine the development of aberrant crypt foci (ACF), agyrophylic nucleolar organizer regions (AgNORs), mast cell recruitment, pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β and also study the expressions of inducible nitric oxide synthase, cyclooxygenase (COX)-2, and apoptotic markers. DMH-induced rats showed increased ACF number (incidence), multiplicity and its distribution, counts of AgNORs, mast cells, inflammatory markers and apoptotic proteins. Interestingly, UMB supplementation to DMH-induced rats (group 4) significantly (p < 0.05) suppressed ACF development, AgNORs, mast cells, and inflammatory markers and increased the apoptotic markers as compared to DMH-induced rats (group 2). We concluded that UMB is a potential anticancer agent that can be used for the prevention and treatment of CRC.

Fermentable Carbohydrates Differentially Affect Colon Tumor Formation in Azoxymethane-Induced Male Fischer 344 Rats

Background: The role of fermentation compared with the source or type of the fermentable material in colon tumorigenesis remains an issue in refining the definition of dietary fiber (DF).Objective: The aim of this study was to investigate the fermentation and source-specific effects of various carbohydrates in a medium-term colon tumorigenesis model.Methods: Six-week-old male Fischer 344 rats were randomly allocated into 6 groups (n = 36/group) to receive either AIN-93G (control) or diets containing fructooligosaccharides, wheat bran (WB), oat bran (OB), polydextrose, or high-amylose maize starch (HAMS), each adjusted to contain a total DF concentration of 7% (wt:wt) and have a fermentability of 3% (wt:wt). After 2 wk, 24 rats/group received 2 subcutaneous doses of azoxymethane (at 15 mg/kg body weight) 1 wk apart while 12 rats/group were injected with a saline vehicle; all rats were maintained on the assigned diets for 24 wk postinjection and then killed. Colon tumor outcomes and pathology together with cecal short-chain fatty acid composition were assessed.Results: No tumors were found in saline-injected rats, and all subsequent analyses were restricted to azoxymethane-injected rats. Colon tumor incidence was significantly lower in the polydextrose (21%) and WB (13%) groups than in the control group (63%; P < 0.05) but not different from the fructooligosaccharide (58%), HAMS (46%), and OB (33%) groups. In comparison to the control group (8 proximal/31 total tumors), fermentable materials reduced the number of tumors (P < 0.05) originating in the proximal colon: HAMS (5/15), polydextrose (2/7), OB (2/9), fructooligosaccharides (1/21), and WB (1/3). The mean ± SEM number of tumors/tumor-bearing rats was significantly lower in the WB (1.00 ± 0.00), OB (1.13 ± 0.13), and HAMS (1.36 ± 0.15) groups than in the control group (2.07 ± 0.27; P < 0.02); other groups did not differ. The mean ± SEM tumor burden/diet group was lower in the WB (1.2 ± 0.7 mm2), polydextrose (6.7 ± 3.2 mm2), and OB (7.0 ± 3.0 mm2) groups than in the control (21.4 ± 5.9 mm2) and fructooligosaccharide (22.1 ± 7.1 mm2; P < 0.05) groups but not significantly different from the HAMS group (15.1 ± 6.1 mm2). Total cecal SCFA concentrations did not differ among diet groups (overall mean ± SEM: 81 ± 4 μmol/g wet weight).Conclusion: The rate and extent of fermentation of the carbohydrate material as well as the characteristics of the material in the lumen of the lower gastrointestinal tract all appear to have an important role in tumor outcomes in the azoxymethane-induced rat colon tumorigenesis assay.

Abstract 2805: Preventive effect of a prostaglandin E receptor EP4 antagonist RQ-00015986 on rat colon tumorigenesis

Abstract Non-steroidal anti-inflammatory drugs (NSAIDs) are thought to have effects against colorectal cancer (CRC), since evidence has emerged that people who routinely use NSAIDs show a lower risk of CRC. Among NSAIDs, cyclooxygenase-2 (COX2) inhibitors are thought to exert its anti-cancer effect through blocking prostaglandin (PG) E2 whose actions are mediated by signaling via four receptors EP1, EP2, EP3, and EP4. Previous animal experiments have demonstrated that the development of colon tumor is suppressed by knocking down of either EP1 or EP4. In the present study, we investigate the effect of a novel small molecule EP4 antagonist on rat colon tumorigenesis. Employed animal is Kyoto Apc Delta (KAD) rat which has Apc mutation and is susceptible to chemically-induced CRC. Five-week-old KAD rats received injection of azoxymethane (20 mg/kg i.p.) and 2% dextran sodium sulfate in drinking water for two weeks, and then they were divided into two groups: no treatment (control) group and the group treated with an EP4 antagonist RQ-00015986 (RQ-15986) which was kindly provided by AskAt Inc. RQ-15986-treated 17-week-old KAD rats showed lower colon tumor incidence (37.5% vs 100% in control group, P &amp;lt; 0.05) and smaller multiplicity (1.33 ± 0.58 vs 2.86 ± 0.69 in control group, P &amp;lt; 0.05). The expression levels of inflammatory cytokines, including TNF-alpha and IL-6, in colonic mucosa were decreased in RQ-15986-treated group. By treatment with RQ-15986, the expression levels of monocyte chemo-attractant protein-1 (MCP-1) and indoleamine 2,3-dioxygenase (IDO) were also down-regulated in colon mucosa. Immunohistochemical analyses of colonic membrane revealed that PCNA-labeling index was lower and that F4/80 positive cells were fewer in RQ-15986-treated group. These findings suggest that RQ-15986 may suppress CRC development through mediating immune system and controlling chronic inflammation in the colon. Citation Format: Yohei Shirakami, Hiroyasu Sakai, Takahiro Kochi, Takayasu Ideta, Tsuneyuki Miyazaki, Masahito Shimizu, Mitsuru Seishima. Preventive effect of a prostaglandin E receptor EP4 antagonist RQ-00015986 on rat colon tumorigenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2805. doi:10.1158/1538-7445.AM2015-2805

Sericin consumption suppresses development and progression of colon tumorigenesis in 1,2-dimethylhydrazine-treated rats

Colon cancer is one of the most common cancers in many regions of the world and is prevented by dietary interventions. This study aimed to examine the chemopreventive effect of silk protein, sericin, against 1,2-dimethylhydrazineinduced colon tumorigenesis in rats in comparison with control casein diet. The result showed that 5 out of 14 of casein fed rats developed colon tumors, whereas only 1 from 14 sericin fed rats exhibited tumors. Consumption of sericin prior to or during carcinogen exposure reduced the number of aberrant crypt foci. In addition to crypt number, crypt multiplicity was less progressive in sericin fed group. The sericin diet also exhibited anti-oxidant activity as evidenced by reduced lipid peroxidation in the colons. This finding suggests that consumption of sericin may reduce the progression of colon tumor development possibly by suppressing the initiation and promotion stages of colon tumorigenesis.

A Role for Milk Proteins and their Peptides in Cancer Prevention

A role for the amount and type of dietary protein in the etiology of cancer has not been studied extensively. Nevertheless, there is no compelling evidence from epidemiological studies to indicate that protein, at levels usually consumed, is a risk factor for cancer. On the other hand, animal studies suggest that certain peptides and amino acids derived from dietary proteins may influence carcinogenesis. The predominant protein in milk, casein, its peptides, but not liberated amino acids, have antimutagenic properties. Animal models, usually for colon and mammary tumorigenesis, nearly always show that whey protein is superior to other dietary proteins for suppression of tumour development. This benefit is attributed to its high content of cystine/cysteine and gamma-glutamylcyst(e)ine dipeptides, which are efficient substrates for the synthesis of glutathione. Glutathione is an ubiquitous cellular antioxidant that directly or through its associated enzymes destroys reactive oxygen species, detoxifies carcinogens, maintains proteins in a reduced state and ensures a competent immune system. Various experiments showed that tumour prevention by dietary whey protein was accompanied by increased glutathione levels in serum and tissues as well as enhanced splenic lymphocyte proliferation, phagocytosis and natural killer, T helper and cytotoxic T cell activity. Whey protein components, beta-lactoglobulin, alpha-lactalbumin and serum albumin were studied infrequently, but results suggest they have anticancer potential. The minor component lactoferrin has received the most attention; it inhibits intestinal tumours and perhaps tumours at other sites. Lactoferrin acts by induction of apoptosis, inhibition of angiogenesis, modulation of carcinogen metabolising enzymes and perhaps acting as an iron scavenger. Supplementing cows with selenium increases the content of selenoproteins in milk, which on isolation inhibited colon tumorigenesis in rats.

Effect of Shiitake mushroom dose on colon tumorigenesis in azoxymethane-treated male Sprague-Dawley rats

We determined the effects of diets containing dry powdered Shiitake mushroom on frequency of azoxymethane-induced colon aberrant crypt foci (ACF) and intestinal tumors in male Sprague-Dawley rats. Pregnant rat dams and their progeny were fed AIN-93G diets containing casein (20%; control diet) or casein supplemented with Shiitake (1% or 4% wt/wt). Casein- and 1% Shiitake–fed rats exhibited identical growth curves, whereas those fed the 4% Shiitake diet were of slightly reduced body weight. The 4% Shiitake diet elicited increased active energy expenditure and reduced adiposity of rats. Small bowel and colon tumors and colon ACF were evaluated in the male progeny at 18 weeks after azoxymethane treatment. Aberrant crypt foci and tumors were most prevalent in the mid and distal regions of the colon. Shiitake intake had no effect on the relative incidence of tumors in the colon or small intestine (duodenum). Consumption of 1% Shiitake stimulated growth of invasive adenocarcinomas in the mid colon ( P < .005) and favored a nonsignificant increase in median frequency of ACF in this same region. In contrast, Shiitake at 4% intake elicited a reduction in colon tumor multiplicity. Results demonstrate stimulatory actions of 1% and inhibitory actions of 4% Shiitake mushroom on indices of rat colon tumorigenesis, which may be associated with altered metabolism.

Dietary exposure to soy or whey proteins alters colonic global gene expression profiles during rat colon tumorigenesis

BackgroundWe previously reported that lifetime consumption of soy proteins or whey proteins reduced the incidence of azoxymethane (AOM)-induced colon tumors in rats. To obtain insights into these effects, global gene expression profiles of colons from rats with lifetime ingestion of casein (CAS, control diet), soy protein isolate (SPI), and whey protein hydrolysate (WPH) diets were determined.ResultsMale Sprague Dawley rats, fed one of the three purified diets, were studied at 40 weeks after AOM injection and when tumors had developed in some animals of each group. Total RNA, purified from non-tumor tissue within the proximal half of each colon, was used to prepare biotinylated probes, which were hybridized to Affymetrix RG_U34A rat microarrays containing probes sets for 8799 rat genes. Microarray data were analyzed using DMT (Affymetrix), SAM (Stanford) and pair-wise comparisons. Differentially expressed genes (SPI and/or WPH vs. CAS) were found. We identified 31 induced and 49 repressed genes in the proximal colons of the SPI-fed group and 44 induced and 119 repressed genes in the proximal colons of the WPH-fed group, relative to CAS. Hierarchical clustering identified the co-induction or co-repression of multiple genes by SPI and WPH. The differential expression of I-FABP (2.92-, 3.97-fold down-regulated in SPI and WPH fed rats; P = 0.023, P = 0.01, respectively), cyclin D1 (1.61-, 2.42-fold down-regulated in SPI and WPH fed rats; P = 0.033, P = 0.001, respectively), and the c-neu proto-oncogene (2.46-, 4.10-fold down-regulated in SPI and WPH fed rats; P < 0.001, P < 0.001, respectively) mRNAs were confirmed by real-time quantitative RT-PCR. SPI and WPH affected colonic neuro-endocrine gene expression: peptide YY (PYY) and glucagon mRNAs were down-regulated in WPH fed rats, whereas somatostatin mRNA and corresponding circulating protein levels, were enhanced by SPI and WPH.ConclusionsThe identification of transcripts co- or differentially-regulated by SPI and WPH diets suggests common as well as unique anti-tumorigenesis mechanisms of action which may involve growth factor, neuroendocrine and immune system genes. SPI and WPH induction of somatostatin, a known anti-proliferative agent for colon cancer cells, would inhibit tumorigenesis.

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.

The Prevention of Colon Carcinogenesis in Rats by Dietary Cellulose Is Greater than the Promotive Effect of Dietary Lard as Assessed by Repeated Endoscopic Observation

We developed a method which we used in the current study to observe the rat colon endoscopically. Our goal was to evaluate the entire course in the development of experimental large bowel tumors through serial observations in the same rat. We compared the effects of dietary lard and cellulose on rat colon tumorigenesis in a 2 x 3 factorial design. Sprague-Dawley rats (n = 90) were divided into 6 diet groups: rats were fed a diet without cellulose that contained 5, 10, and 15 g/100 g lard, or diets containing 15% cellulose diet (15 g cellulose/100 g diet) and the same concentrations of lard. The development of large bowel tumors induced by the administration of 1,2-dimethylhydrazine (25 mg/kg body weight) for 19 wk was examined endoscopically. Tumor induction rates in the 15% cellulose groups were lower than in the 0% cellulose groups (P = 0.008), independent of the lard concentration. These results suggest that the preventive effect of cellulose against large bowel tumorigenesis is greater than the promotive effect of fat under the current experimental conditions.

Dietary Inulin Suppresses Azoxymethane-Induced Aberrant Crypt Foci and Colon Tumors at the Promotion Stage in Young Fisher 344 Rats

This study was designed to determine the effect of 10% dietary long-chain inulin on the azoxymethane (AOM)-induced colonic preneoplastic aberrant crypt foci (ACF) and small intestinal and colon tumors at the initiation (I), promotion (P) and I + P stages (20 rats per treatment) in Fisher 344 male weanling rats. After an acclimatization period of 1 wk, groups of Fisher 344 male weanling rats were assigned to consume AIN 93G diet (control) or AIN 93G diet containing 10% inulin. All the rats received 16 mg/kg body AOM dissolved in saline subcutaneously at 7 wk of age followed by a second injection at 8 wk of age. An additional group of five rats received only saline and consumed the control diet. The rats received the assigned diets until asphyxiation by CO(2) at 16 wk of age for the ACF experiment and 45 wk for the end-point tumor experiment. Feed intake, weight gain, diarrheal index, cecal weight, cecal pH, ACF and tumors in the colon were determined. Rats fed inulin had diarrhea after 2 wk of feeding and recovered by approximately 4 wk. Cecal weight was greater in rats fed inulin and cecal pH was lower. The inulin group had more than 66% fewer aberrant crypts and 60% fewer ACF compared with the control group. Tumor incidences in the small intestine and colon of rats in the control, I, P and I + P groups were: 78, 31, 0 and 11% and 90, 73, 69 and 50%, respectively. The corresponding values for the distal portion of the colon were 87, 63, 45 and 33%, respectively. Colon tumors per tumor-bearing rat were 4.2, 3.09, 1.36 and 1.2 for the control, I, P and I + P groups, respectively. All groups differed, P < 0.05. The results of this study indicate that dietary long-chain inulin suppresses AOM-induced ACF formation, an early preneoplastic marker of colon tumorigenesis in rats, and colon tumors, particularly at the promotion stage.

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.

Fish Oil Blocks Azoxymethane-Induced Rat Colon Tumorigenesis by Increasing Cell Differentiation and Apoptosis Rather Than Decreasing Cell Proliferation

The purpose of this study was to determine whether the protective effect of fish oil against colon carcinogenesis is due to decreased proliferation, increased differentiation and/or increased apoptosis. Male Sprague Dawley rats (n = 260) were fed one of two oils (corn or fish) and two fibers (pectin or cellulose), plus or minus the carcinogen azoxymethane (AOM). Rats were killed at wk 18 (n = 80) or 36 (n = 180) for cytokinetic measurements. In vivo cell proliferation was measured by incorporation of bromodeoxyuridine into DNA, differentiation by binding of Dolichos biflorus agglutinin and apoptosis by immunoperoxidase detection of digoxigenin labeled genomic DNA. Fish oil resulted in a lower adenocarcinoma incidence (56.1 vs. 70.3%) compared with corn oil. There was no effect of fat or fiber on number of proliferative cells/crypt column in either the proximal or distal colon. In contrast, fish oil resulted in a greater degree of differentiation compared with corn oil in both colonic sites. In addition, fish oil resulted in a higher number of apoptotic cells/crypt column in both the proximal and distal colon as compared with corn oil. AOM treatment increased the ratio of proliferative cells/crypt column to apoptotic cells/crypt column in both the proximal and distal colon compared with saline controls. Fish oil, however, resulted in a lower ratio in both sites in the colon as compared with corn oil. These results suggest that an increase in apoptosis and differentiation, rather than a decrease in proliferation, accounts for the protective effect of fish oil against experimentally induced colon tumorigenesis.

Inhibition of Colon Carcinogenesis by Non-nutritive Constituents in Foods.

In addition to mutagens and/ or carcinogens many modulators in carcinogenesis exist in our environment. Some of them are contained in our regular foods and therefore dietary factors play a role in the development of some types of cancers including colon cancer. There are still many unknown constituents and/ or factors in foods that could either enhance or reduce the possibilities for developing cancer. Recent research indicated that in addition to the macro- and micronutrients, many common foods contain nonnutritive components, belonging to different chemical groups, that may protect against certain type of cancer including colon neoplasm. These chemicals are knows as “chemopreventive agents”. The mode of action of most chemopreventive agents is still unknown, although many of them are antioxidants. With increasing the incidence of colon cancer rising certainly, there is an ever increasing need to determine the most effective means to prevent colon cancer and to understand the mechanism(s) underlying successful prevention. Previous studies in our laboratory demonstrated protective effects of several naturally occurring and synthetic compounds against rat colon tumorigenesis. This article will introduce our recent studies in search for the chemopreventive effects of some flavonoids and other naturally occurring products in edible plants on colon carcinogenesis.

Quercetin reduces azoxymethane-induced rat colon tumorigenesis enhanced by stress: [formula omitted]1, T. Sakai 1, Y. Okuyama 1, T. Matsumoto 1, S. Matsumura 1, Y. Sowa [formula omitted], A. Aoike 1, H. Nishino 2 and K. Kawai 1. 1Dept. of Preventive Medicine, Kyoto Prefectural University of Medicine, Kyoto 602, Japan, and 2Cancer Prevention Division, National Cancer Center Research Inst., Tokyo 104,

Quercetin reduces azoxymethane-induced rat colon tumorigenesis enhanced by stress: [formula omitted]1, T. Sakai 1, Y. Okuyama 1, T. Matsumoto 1, S. Matsumura 1, Y. Sowa [formula omitted], A. Aoike 1, H. Nishino 2 and K. Kawai 1. 1Dept. of Preventive Medicine, Kyoto Prefectural University of Medicine, Kyoto 602, Japan, and 2Cancer Prevention Division, National Cancer Center Research Inst., Tokyo 104,

Interaction of dietary fat and route of carcinogen administration on 1,2-dimethylhydrazine-induced colon tumorigenesis in rats.

Since the results of an earlier study indicating no effect of dietary fat on dimethylhydrazine (DMH)-induced colon cancer in rats differed from those of other investigators, the present study was initiated to determine if the modulating effect of fat intake on colon tumorigenesis was dependent on the route of DMH administration. Male weanling Sprague-Dawley rats (160) were fed one of two nutritionally balanced diets containing 5% or 24% corn oil (CO). Following 3 weeks adaptation to their respective diets, 40 rats from each diet group were treated with five doses of DMH (30 mg/kg) by intragastric (i.g.) gavage or subcutaneous (s.c.) injection, over a 3 week period. Rats were sacrificed when they showed clinical signs of colon tumor and surviving animals were killed 51 weeks after the initial DMH treatment. The cumulative probability of death with colon carcinoma did not differ between the dietary or treatment groups. There was no effect of route of administration or dietary fat on total intestinal tumor incidence. The number of rats with colon carcinoma was: 5% CO.IG = 25; 24% CO.IG = 27; 5% CO.SC = 23; 24% CO.SC = 19. Polypoid tumor incidence was significantly higher in the 24% CO.SC group (12/40) compared to the 5% CO.SC group (3/40) (Chi-squared = 5.25; p less than 0.03) while sessile tumor incidence was the inverse. Marginally significant differences in tumor morphology were noted between the IG groups.

Lack of effect of dietary fat on N-nitrosomethyl urea (NMU)-induced colon tumorigenesis in rats.

The effect of alterations in the quality and quantity of dietary fat on N-nitrosomethyl urea (NMU)-induced colon cancer in rats was studied. Weanling Sprague-Dawley rats were fed semipurified diets containing 24% beef fat, 24% corn oil, 24% Crisco or the three fats in equal parts to make a total of 5% fat. Macronutrients and micronutrients were adjusted to balance the nutrient to calorie ratios. After 4 weeks of dietary treatment, all rats, except vehicle-treated animals received NMU (1.5 mg) via intrarectal instillation, twice a week for 2 weeks. The animals continued receiving the experimental diets until intestinal tumors developed and surviving animals were sacrificed at 43 weeks. There was no effect of any of the high fat diets tested on intestinal tumor incidence, latency, distribution or size. Cumulative probability of death with colon carcinoma did not differ significantly among the dietary groups.

Changes in the intestinal microflora in association with colon tumorigenesis in rats treated with 1,2-dimethylhydrazine hydrochloride.

AbstractThe present study was undertaken to determine whether the intestinal microflora change during the tumorigenic process in the colon of rats treated with 1,2‐dimethylhydrazone (DMH), and to compare the intestinal microflora of rats with colon tumors induced by DMH with that of rats with gastric tumors induced by N‐methyl‐N′‐nitro‐N‐nitrosoguanidine (MNNG). When compared with those in the control animals, the numbers of streptococci and bacteroidaceae were moderately increased in the intestinal tract of DMH‐treated rats before the development of visible intestinal tumors. The DMH‐treated rats bearing small intestinal and colonic tumors were found to have markedly increased numbers of enterobacteriaceae, Clostridium perfringens, streptococci, bacteroidaceae, and bifidobacteria. In DMH‐induction the overgrowth of enterobacteriaceae and/or C. perfringens was found to correlate with the size and number of tumors in both the small intestine and colon. The increased number of streptococci in the DMH‐treated rats was principally due to an increase in the number of the streptococci which did not reduce triphenyltetrazolium chloride (TTC). On the other hand, in the rats with gastric tumors induced by MNNG the numbers of enterobacteriaceae and TTC‐reducing streptococci were remarkably increased in the intestinal tract of only the debilitated animals, and Pseudomonas aeruginosa was detected in all of them. The number of anaerobic gram‐positive cocci was significantly but not remarkably increased in the gastric tumor‐bearing rats compared with the controls. These results indicate that the intestinal microflora of rats may change depending on the gastrointestinal site where tumors develop and the degree of malignancy in tumorigenesis.