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To develop an efficient animal model for colitis‐related carcinogenesis, male Crj: CD‐1 (ICR) mice were given a single intraperitoneal administration (10 mg/kg body weight) of a genotoxic colonic carcinogen, azoxymethane (AOM), and a 1‐week oral exposure (2% in drinking water) to a non‐genotoxic carcinogen, dextran sodium sulfate (DSS), under various protocols. At week 20, colonic neoplasms (adenocarcinomas, 100% incidence with 5.60±2.42 multiplicity; and adenomas, 38% incidence with 0.20±0.40 multiplicity) with dysplastic lesions developed in mice treated with AOM followed by DSS. Protocols in which AOM was given during or after DSS administration induced a few tubular adenomas or no tumors in the colon. Immunohistochemical investigation of such dysplasias and neoplasms revealed that all lesions were positive for β‐catenin, cyclooxygenase‐2 and inducible nitric oxide synthase, but did not show p53 immunoreactivity. The results indicate that 1‐week administration of 2% DSS after initiation with a low dose of AOM exerts a powerful tumor‐promoting activity in colon carcinogenesis in male ICR mice, and may provide a novel mouse model for investigating colitis‐related colon carcinogenesis and for identifying xenobiotics with modifying effects.

Pomegranate (Punica granatum L.) seed oil (PGO) contains more than 70% cis(c)9,frans(f)11,c13–18:3 as conjugated linolenic acids (CLN). Our previous short‐term experiment demonstrated that seed oil from bitter melon (Momordica charantia) (BMO), which is rich in c9,t11,t13‐CLN, inhibited the occurrence of colonic aberrant crypt foci (ACF) induced by azoxymethane (AOM). In this study, we investigated the effect of dietary PGO on the development of AOM‐induced colonic malignancies and compared it with that of conjugated linoleic acid (CLA). To induce colonic tumors, 6‐week old male F344 rats were given subcutaneous injections of AOM (20 mg/kg body weight) once a week for 2 weeks. One week before the AOM treatment they were started on diet containing 0.01%, 0.1%, or 1%±PGO or 1% CLA for 32 weeks. Upon termination of the bioassay (32 weeks) colon tumors were evaluated histopathologically. AOM exposure produced colonic adenocarcinoma with an incidence of 81% and multiplicity of 1.88±1.54 at week 32. Administration of PGO in the diet significantly inhibited the incidence (AOM+0.01% PGO, 44%, P<0.05; AOM+0.1% PGO, 38%, P<0.01; AOM+1% PGO, 56%) and the multiplicity (AOM+0.01% PGO, 0.56±0.73, P<0<01; AOM+0.1% PGO, 0.50±0.73, P<0.005; AOM+1% PGO, 0.88±0.96, P<0.05) of colonic adenocarcinomas, although a clear dose‐response relationship was not observed at these dose levels. CLA feeding also slightly, but not significantly, reduced the incidence and multiplicity of colonic adenocarcinomas. The inhibition of colonic tumors by PGO was associated with an increased content of CLA (c9,t11–18:2) in the lipid fraction of colonic mucosa and liver. Also, administration of PGO in the diet elevated expression of peroxisome proliferator activated receptor (PPAR) γ protein in the nontumor mucosa. These results suggest that PGO rich in c9,t11,c13‐CLN can suppress AOM‐induced colon carcinogenesis, and the inhibition is associated in part with the increased content of CLA in the colon and liver and/or increased expression of PPARγ protein in the colon mucosa.

Previously, we proposed a novel mouse model for colitis‐related colon carcinogenesis using azoxymethane (AOM) and dextran sodium sulfate (DSS) (Cancer Sci 2003; 94: 965–73). In the current study, sequential analysis of pathological alterations during carcinogenesis in our model was conducted to establish the influence of inflammation caused by DSS on colon carcinogenesis in this model. Male ICR mice were given a single intraperitoneal injection of AOM (10 mg/kg body weight) and given 2% (w/v) DSS in the drinking water for 7 days, starting 1 week after the AOM injection. They were sequentially sacrificed at weeks 2, 3, 4, 5, 6, 9, 12, and 14 for histopathological and immunohistochemical examinations. Colonic adenomas were found in 2 (40% incidence and 0.40±0.49 multiplicity) of 5 mice at week 3 and colon carcinomas developed in 2 (40% incidence and 2.00±3.52 multiplicity) of 5 mice at week 4. Their incidence gradually increased with time and reached 100% (6.20±2.48 multiplicity) at week 6. At week 14, the multiplicity of adenocarcinoma was 9.75±2.49 (100% incidence). In addition, colonic dysplasia was noted at all time‐points. The scores of colonic inflammation and nitrotyrosine immunohistochemistry were extremely high at early time‐points and were well correlated. Our results suggest that combined treatment of mice with AOM and DSS generates neoplasms in the colonic mucosa via dysplastic lesions induced by nitrosative stress.

In a previous study, we developed a novel mouse model for colitis‐related carcinogenesis, utilizing a single dose of azoxymethane (AOM) followed by dextran sodium sulfate (DSS) in drinking water. In the present study, we investigated whether colonic neoplasms can be developed in mice initiated with a single injection of another genotoxic colonic carcinogen 1,2‐dimethylhydrazine (DMH), instead of AOM and followed by exposure of DSS in drinking water. Male crj: CD‐1 (ICR) mice were given a single intraperitoneal administration (10, 20 or 40 mg/kg body weight) of DMH and 1‐week oral exposure (2% in drinking water) of a non‐genotoxic carcinogen, DSS. All animals were killed at week 20, histological alterations and immunohistochemical expression of β‐catenin, cyclooxygenase (COX‐2) and inducible nitric oxide synthase (iNOS) were examined in induced colonic epithelial lesions (colonic dysplasias and neoplasms). Also, the β‐catenin gene mutations in paraffin‐embedded colonic adenocarcinomas were analyzed by the single strand conformation polymorphism method, restriction enzyme fragment length polymorphism and direct sequencing. The incidences of colonic neoplasms with dysplastic lesions developed were 100% with 2.29 ± 0.95 multiplicity, and 100% with 10.38 ± 4.00 multiplicity in mice given DMH at doses of 10 mg/kg or 20 mg/kg and 2%DSS, respectively. Although approximately half of the mice given DMH at a dose of 40 mg/kg bodyweight were dead after 2–3 days after the injection, mice who received DMH 40 mg/kg and 2%DSS had 100% incidence of colonic neoplasms with 9.75 ± 6.29 multiplicity. Immunohistochemical investigation revealed that adnocarcinomas, induced by DMH at all doses and 2%DSS, showed positive reactivities against β‐catenin, COX‐2 and iNOS. In DMH/DSS‐induced adenocarcinomas, 10 of 11 (90.9%) adenocacrcinomas had β‐catenin gene mutations. Half of the mutations were detected at codon 37 or 41, encoding serine and threonine that are direct targets for phosphorylation by glycogen synthase kinase‐3β. The present results suggests that, as in the previously reported model (AOM/DSS) our experimental protocol, DMH initiation followed by DSS, may provide a novel and useful mouse model for investigating inflammation‐related colon carcinogenesis and for identifying xenobiotics with modifying effects. (Cancer Sci 2005; 96: 69–76)

Ligands for peroxisome proliferator‐activated receptor (PPAR) γ have been implicated in growth inhibition and cell differentiation in certain malignancies. In this study, the effects of troglitazone, a PPARy ligand, given during the postinitiation phase of oral carcinogenesis initiated with 4‐nitroquinoline 1‐oxide (4‐NQO) were investigated in male F344 rats. Rats aged 6 weeks were given 4‐NQO at 20 ppm for 8 weeks to induce tongue neoplasms. Starting 1 week after the cessation of 4‐NQO exposure, animals were fed diets containing 0, 30 or 100 ppm troglitazone for 22 weeks. At the end of the study (week 32), the incidences of 4‐NQO‐induced tongue neoplasms and preneoplasms were determined histo‐pathologically and cell proliferation activity was estimated by counting bromodeoxyuridine (BrdU)‐labeling indices and cyclin D1‐positive cell ratios. In addition, immunohistochemical expression of cyclooxygenase (COX)‐2 and PPARγ was assessed in the tongue lesions. Feeding with 100 ppm troglitazone significantly decreased the incidence of squamous cell carcinoma when compared to the group without troglitazone treatment (5.0% vs. 45.8%, P<0.005). Interestingly, the BrdU‐labeling index and cyclin D1‐positive cell ratio assessed in the non‐lesional tongue squamous epithelium were reduced by dietary administration of troglitazone (P<0.0001–0.005). Additionally, the immunoreactivity of COX‐2 in the tongue lesions was also decreased by the treatment (P<0.01–0.05). These results clearly showed that dietary troglitazone inhibits 4‐NQO‐induced tongue carcinogenesis and such inhibition is related to suppression of increased cell proliferation and/or COX‐2 expression. This study warrants further investigation on the use of PPARy ligands as a novel preventive approach for oral malignancy. (Cancer Sci 2003; 94: 365–371)

The modifying effects of dietary feeding of bovine lactoferrin (bLF) on tongue carcinogenesis initiated with 4‐nitroquinoline 1‐oxide (4‐NQO) were investigated in male F344 rats. The activities of phase II detoxifying enzymes, glutathione S‐transferase (GST) and quinone reductase (QR), polyamine content and ornithine decarboxylase (ODC) activity in the tongue were also examined for mechanistic analysis of possible modifying effects of bLF on carcinogenesis. At 7 weeks of age, all animals except those treated with bLF alone and untreated rats were given 20 ppm 4‐NQO in drinking water for 8 weeks to induce tongue neoplasms. Starting 7 days before 4‐NQO exposure, experimental groups were fed experimental diets containing bLF (0.2% and 2%) for 10 weeks (“initiation feeding”). Starting 1 week after the cessation of exposure to 4‐NQO, the other experimental groups given 4‐NQO and a basal diet were fed the experimental diets for 22 weeks (“postinitiation feeding”). At week 32, the incidence and multiplicity of tongue neoplasms in the “initiation feeding’ groups of 0.2% and 2% bLF and the “post‐initiation feeding” group of 0.2% bLF were lower than those of the 4‐NQO alone group, but without statistical significance. However, “post‐initiation feeding” of 2% bLF caused a significant reduction in the incidence (20% vs. 55%, P=0.02418) and multiplicity (0.25±0.54 vs. 0.70±0.71, P< 0.05) of tongue squamous cell carcinoma (by 64%, P=0.02418). bLF treatment elevated liver and tongue GST activities and liver QR activity. The “post‐initiation feeding' with 2% bLF significantly decreased QR activity, proliferating cell nulcear antigen‐positive index and ODC activity in the tongue. In addition, feeding with bLF decreased tongue polyamine content. These results suggest that bLF, when given at the 2% dose level during the post‐initiation phase, exerts chemopreventive action against tongue tumorigenesis through modification of cell proliferation activity and/or the activities of detoxifying enzymes.

The biological roles of peroxisome proliferator‐activated receptors (PPARs) in various diseases, including inflammation and cancer, have been highlighted recently. Although PPARγ ligand is suspected to play an important role in carcinogenesis, its effects on colon tumorigenesis remain undetermined. The present tune‐course study was conducted to investigate possible modifying effects of a PPARγ ligand, troglitazone, on the development and growth of aberrant crypt foci (ACF), putative precursor lesions for colon carcinoma, induced by azoxymethane (AOM) or dextran sodium sulfate (DSS) in male F344 rats. Oral troglitazone (10 or 30 mg/kg body weight (b.w.)) significantly reduced AOM (two weekly subcutaneous injections, 20 mg/kg b.w.)‐induced ACF. Treatment with troglitazone increased apoptosis and decreased polyamine content and ornithine decarboxylase (ODC) activity in the colonic mucosa of rats treated with AOM. Gastric gavage of troglitazone also inhibited colitis and ACF induced by DSS (1% in drinking water), in conjunction with increased apoptosis and reduced colonic mucosal polyamine level and ODC activity. Our results suggest that troglitazone, a synthetic PPARγ ligand, can inhibit the early stage of colon tumorigenesis with or without colitis.

The modifying effects of dietary feeding of two estrogenic compounds, 4‐tert‐octylphenol (tOP) and benzyl butyl phthalate (BBP), on 3, 2′‐dimethyl‐4‐aminobiphenol (DMAB)‐induced prostatic carcinogenesis were investigated in male F344 rats. We also assessed the effects of the test compounds on the proliferating cell nuclear antigen (PCNA) index in induced neoplasms, prostatic intra‐epithelial neoplasm (PIN), and non‐lesional glands in the prostate. To induce prostatic neoplasms, rats were given subcutaneous injections of DMAB (25 mg/kg body weight) every other week, 10 times in total. They also received the experimental diet containing 10 or 100 ppm tOP and BBP for 40 weeks, starting 1 week after the last dosing of DMAB. DMAB exposure produced prostatic adenocarcinoma with an incidence of 41.2% at the end of the study (week 60). Dietary administration of tOP and BBP did not affect the incidence of prostatic adenocarcinoma: 43.8% in the DMAB→10 ppm tOP group; 25.0% in the DMAB→100 ppm tOP group; 43.8% in the DMAB→10 ppm BBP group; and 43.8% in the DMAB→100 ppm BBP group. The PCNA indices in adenocarcinomas, PIN, and non‐lesional glands in rats treated with DMAB and tOP or BBP were slightly lower than that of the DMAB alone group, but the differences were not statistically significant. These results might suggest that dietary feeding of the estrogenic compounds tOP and BBP did not modulate DMAB‐induced prostatic carcinogenesis in rats.

The modifying effects of dietary feeding of conjugated linolenic acid (CLN) isolated from the seeds of bitter gourd (Momordica charantia) on the development of azoxymethane (AOM)‐induced colonic aberrant crypt foci (ACF) were investigated in male F344 rats to predict its possible cancer chemopreventive efficacy. The effect of CLN on the proliferating cell nuclear antigen (PCNA) index in colonic ACF was also examined. Rats were given subcutaneous injections of AOM (20 mg/ kg body weight) once a week for 2 weeks to induce ACF. They also received the experimental diet containing 0.01%, 0.1% or 1% CLN for 5 weeks, starting one week before the first dosing of AOM. AOM exposure produced a substantial number of ACF (108±21/rat) at the end of the study (week 4). Dietary administration of CLN caused a significant reduction in the frequency of ACF: 87±14 (19.4% reduction, P<0.05) at a dose of 0.01%, 69±28 (36.1% reduction, P<0.01) at a dose of 0.1% and 40±d6 (63.0% reduction, P<0.001) at a dose of 1%. Also, CLN administration lowered the PCNA index and induced apoptosis in ACF. These findings might suggest possible chemopreventive activity of CLN in the early phase of colon tumorigenesis through modulation of cryptal cell proliferation activity and/or apoptosis.

Highly unsaturated fatty acid‐containing phospholipid (HUFA‐PL) has many nutritional and medical applications. We investigated the effect of HUFA‐PL on differentiation of human leukemia HL‐60 cells induced by dibutyryl cyclic adenosine monophosphate (dbcAMP). HUFA‐containing phosphatidylethanolamine (HUFA‐PE), such as salmon testis PE, significantly enhanced dbcAMP ‐induced cell differentiation. A combined treatment of 200 μM dbcAMP with 50 μM HUFA‐PE increased the nitroblue tetrazolium (NBT)‐reducing activity, which is an indicator of differentiation, to a level comparable to that in the case of 500 μM dbcAMP treatment. In contrast, HUFA‐lyso PE (a monoacyl form) did not exert an enhancing effect on dbcAMP‐induced differentiation. The enhancing effect of HUFA‐PE was suppressed by a protein kinase C inhibitor, staurosporine, while a protein kinase A inhibitor, H‐8, did not suppress the enhancing effect. These findings suggest that HUFA‐PE might enhance dbcAMP‐induced differentiation through modulation of the protein kinase C signaling pathway in HL‐60 cells.