Biomedical subjects

Keiichirou Morimura

Publications and source records attributed to Keiichirou Morimura.

At least 37 records · Page 2Linked to original sources

PubMed2005

Lack of large intestinal carcinogenicity of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine at low doses in rats initiated with azoxymethane.

2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), an abundant food-derived heterocyclic amine (HCA), has attracted particular attention as a human colon carcinogen. Humans are in fact exposed to continuous low doses of HCAs during lifetime. Therefore, we focused on rat large intestinal carcinogenicity of PhIP at levels that mimic practical human exposure. A total of 192 6-week-old male F344 rats were subcutaneously injected twice with 15 mg/kg body weight azoxymethane (AOM), then continuously fed various doses (0, 0.001, 0.01, 0.1, 1, 10, 50 and 200 ppm) of PhIP in the diet. At week 16, aberrant crypt foci (ACF) were quantitatively analyzed. At week 36, tumor occurrence was pathologically analyzed. Then immunohistochemical examinations were performed. PhIP was found to enhance strongly AOM-initiated rat large intestinal tumorigenesis at high doses (50 and 200 ppm), while lower doses (0.001-10 ppm) had no apparent effects. High doses also caused variation in tumor histologic types and their distribution throughout the large intestinal segments. Frequencies of ACF/cm(2) did not meaningfully vary between the groups. Cellular proliferation activity in normal-appearing colonic mucosa was significantly increased at high doses. These novel findings may provide evidence of a low-dose potential for PhIP, with a no-observed effect level speculated to be 10 ppm in the present initiation-promotion experimental model.

Animals↗

PubMed2005

Hormesis and dose-response-mediated mechanisms in carcinogenesis: evidence for a threshold in carcinogenicity of non-genotoxic carcinogens.

Recently the idea of hormesis, a biphasic dose-response relationship in which a chemical exerts opposite effects dependent on the dose, has attracted interest in the field of carcinogenesis. With non-genotoxic agents there is considerable experimental evidence in support of hormesis and the present review highlights current knowledge of dose-response effects. In particular, several in vivo studies have provided support for the idea that non-genotoxic carcinogens may inhibit hepatocarcinogenesis at low doses. Here, we survey the examples and discuss possible mechanisms of hormesis using phenobarbital, 1,1-bis(p-chlorophenyl)-2,2,2-trichloroethane (DDT), alpha-benzene hexachloride (alpha-BHC) and other non-genotoxins. Furthermore, the effects of low and high doses of non-genotoxic and genotoxic compounds on carcinogenesis are compared, with especial attention to differences in mechanisms of action in animals and possible application of the dose-response concept to cancer risk assessment in humans. Epigenetic processes differentially can be affected by agents that impinge on oxidative stress, DNA repair, cell proliferation, apoptosis, intracellular communication and cell signaling. Non-genotoxic carcinogens may target nuclear receptors, cause aberrant DNA methylation at the genomic level and induce post-translational modifications at the protein level, thereby impacting on the stability or activity of key regulatory proteins, including oncoproteins and tumor suppressor proteins. Genotoxic agents, in contrast, cause genetic change by directly attacking DNA and inducing mutations, in addition to temporarily modulating the gene activity. Carcinogens can elicit a variety of changes via multiple genetic and epigenetic lesions, contributing to cellular carcinogenesis.

Animals↗

PubMed2005

Lack of potential of low dose N-nitrosodimethylamine to induce preneoplastic lesions, glutathione S-transferase placental form-positive foci, in rat liver.

Induction of liver lesions in male F344 rats by the genotoxic and carcinogenic N-nitrosodimethylamine (NDMA) was studied at a wide range of dose levels, i.e. from 0.001 to 10 ppm, in drinking water for 16 weeks. Dose related and statistically significant increase of glutathione S-transferase placental form-positive foci, endpoint markers for hepatocarcinogenesis in rats, at 1 and 10 ppm dose groups was obtained, but no increment in foci could be detected with the lower doses (0.001, 0.01, and 0.1 ppm). This finding of a no-observed effect level supports our hypothesis that a threshold, at least in practical terms, exists in carcinogenesis proposed on the basis of extensive wide range dose-dependence studies of other genotoxic carcinogens.

Animals↗

PubMed2005

Enhancement by estradiol 3-benzoate in thioacetamide-induced liver cirrhosis of rats.

As part of an investigation on the role of estrogen in liver disease, we tested the effects of estradiol-3-benzoate (EB) in the thioacetamide (TAA)-induced rat liver cirrhosis model. Male F344 rats (n = 100) were divided into six groups. Animals of groups 1-4 received TAA (0.03% in drinking water) for 12 weeks, and groups 5 and 6 served as controls without TAA. For the exposure period, EB pellets were implanted subcutaneously to give doses of 0 (groups 1 and 5), 1 (group 2), 10 (group 3), and 100 mug (groups 4 and 6) simultaneously. All animals were sacrificed at week 12. Significant increase of liver cirrhosis, liver weight, collagen content, and lipid peroxidation in the livers was evident in groups 3 and 4 (p < 0.05) compared with group 1. Formation of 8-hydroxy-2'-deoxyguanosine (8-OHdG) was significantly elevated in group 4 (p < 0.01), along with expression of alpha-smooth muscle actin (alpha-SMA) and stellate cell activation-associated protein (STAP), as determined by RT-PCR analysis (p < 0.01). However, there were no differences in liver weight, collagen content, lipid peroxidation, 8-OHdG formation, and alpha-SMA and STAP mRNA expression between groups 5 and 6. We conclude that EB treatment enhances TAA-induced cirrhosis, associated with increase of oxidative stress and activation of hepatic stellate cells.

Actins↗

PubMed2005

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.

1,2-Dimethylhydrazine↗

PubMed2005

Lack of urinary bladder carcinogenicity of sodium L-ascorbate in human c-Ha-ras proto-oncogene transgenic rats.

Sodium L-ascorbate (Na-AsA) is widely known to be a tumor promoter of rat bladder carcinogenesis but tests negative in standard 2-year bioassays. In the present study, bladder-cancer-susceptible transgenic rats designated Hras128 were used to further examine the tumorigenicity of Na-AsA. A total of 40 7-week-old male transgenic (Tg) and 42 littermate nontransgenic (Non-tg) rats were divided into 4 groups and given powdered MF diet with or without 5% Na-AsA for 57 weeks. Tg rats showed significantly short survival compared with Non-tg, independent of Na-AsA treatment. Tg rats treated with Na-AsA showed a slightly higher incidence of carcinoma (29.6%) as compared to those without Na-AsA treatment (15.4%), but this was without statistical significance. Moreover, the total bladder tumor incidences, including papillomas, did not differ statistically (with Na-AsA, 37.0%; without Na-AsA, 30.8%). No bladder tumor was detected in Non-tg rats. Various kinds of other lesions in various organs were noted in Tg rats treated with or without Na-AsA treatment, but no intergroup differences were evident. In conclusion, Na-AsA did not show tumorigenicity in highly bladder-cancer-susceptible transgenic Hras128 rats. These results suggest that Na-AsA is a pure promoter but not a complete carcinogen in rats.

Animals↗

PubMed2005

Persistence of liver cirrhosis in association with proliferation of nonparenchymal cells and altered location of alpha-smooth muscle actin-positive cells.

This study was carried out to achieve pathological understanding for the persistence of cirrhosis induced by thioacetamide (TAA). Forty-five, male,21-day-old, F344 rats were randomly allocated to group I and received drinking water as a control, and groups 2 and 3 given 0.015% or 0.03%TAA, respectively for 12 weeks. Two-third of animals per group were sacrificed, and remainder were maintained for a further 4 weeks without TAA treatment. Liver cirrhosis was induced in all animals in group 3 at week 12, with obvious increase of collagen content, and this persisted after cessation of TAA. Proliferating cell nuclear antigen (PCNA) positive labeling indices of nonparenchymal cells were increased significantly after cessation in groups 2 and 3 (p < 0.01). RT-RCR analysis of a-smooth muscle actin (alpha-SMA) showed significant increase in group 3 compared to that of control at both time points (p < 0.05). Immunohistochemical staining of it demonstrated positive cells to mainly be located around regenerating hepatic nodules at week 12, however, they were focused into enlarged portal areas consisting of fibrous tissues and pseudo-bile ductular cells after the cessation. Taken together, we conclude persistence of liver cirrhosis could be associated with the proliferation of nonparenchymal cells and altered location of alpha-SMA positive cells.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed2005

Dose-dependence of promotion of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline-induced rat hepatocarcinogenesis by ethanol: evidence for a threshold.

Although ethanol is thought to be a tumor-promoter, there are conflicting results concerning its effects on experimental hepatocarcinogenesis. Furthermore, the relationship between the amount of ethanol consumed and tumor promoting effects has hitherto not been investigated in detail. In the present study, 21-day-old F344/DuCrj rats were fed 200 p.p.m. 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) in their diet for 8 weeks and thereafter received ethanol at doses of 0, 0.1, 0.3, 1, 3, 10 and 20% in drinking water ad libitum for 16 weeks. The incidences of hepatocellular adenoma and total tumors increased dose-dependently with statistical significance at doses of 10% and 20%, compared to the initiated control value. Similarly, dose dependence was observed for the incidence of hepatocellular carcinoma, which was elevated significantly at the dose of 20%. No alteration in development of preneoplastic glutathione-S-transferase placental form positive foci or tumors was observed with 0.1-1%. Cell proliferation also increased dose-dependently and CYP2E1 protein induction was recognized in centrilobular regions without alteration in mRNA levels, but no effects were evident on formation of 8-hydroxy-2'-deoxyguanosine, an oxidative DNA damage marker, or lipid peroxidation in any of the initiated groups. The mRNA expression of cyclin D1 increased dose dependently. The results demonstrated that ethanol dose-dependently promotes hepatocarcinogenesis induced by MeIQx, but with no adverse influence at doses of 1% or less, comparable to sensible drinking levels in humans.

Adenoma↗

PubMed2004

Understanding arsenic carcinogenicity by the use of animal models.

Although numerous epidemiological studies have indicated that human arsenic exposure is associated with increased incidences of bladder, liver, skin, and lung cancers, limited attempts have been made to understand mechanisms of carcinogenicity using animal models. Dimethylarsinic acid (DMA), an organic arsenic compound, is a major metabolite of ingested inorganic arsenics in mammals. Recent in vitro studies have proven DMA to be a potent clastogenic agent, capable of inducing DNA damage including double strand breaks and cross-link formation. In our attempts to clarify DMA carcinogenicity, we have recently shown carcinogenic effects of DMA and its related metabolites using various experimental protocols in rats and mice: (1) a multi-organ promotion bioassay in rats; (2) a two-stage promotion bioassay by DMA of rat urinary bladder and liver carcinogenesis; (3) a 2-year carcinogenicity test of DMA in rats; (4) studies on the effects of DMA on lung carcinogenesis in rats; (5) promotion of skin carcinogenesis by DMA in keratin (K6)/ornithine decarboxylase (ODC) transgenic mice; (6) carcinogenicity of DMA in p53(+/-) knockout and Mmh/8-OXOG-DNA glycolase (OGG1) mutant mice; (7) promoting effects of DMA and related organic arsenicals in rat liver; (8) promoting effects of DMA and related organic arsenicals in a rat multi-organ carcinogenesis test; and (9) 2-year carcinogenicity tests of monomethylarsonic acid (MMA) and trimethylarsine oxide (TMAO) in rats. The results revealed that the adverse effects of arsenic occurred either by promoting and initiating carcinogenesis. These data, as covered in the present review, suggest that several mechanisms may be involved in arsenic carcinogenesis.

Animals↗

PubMed2004

No-observed effect levels for carcinogenicity and for in vivo mutagenicity of a genotoxic carcinogen.

To elucidate the relationship between in vivo carcinogenic and mutagenic potentials of genotoxic carcinogens, low doses were tested in the livers of Big Blue transgenic rats with 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx). Male Big Blue rats were fed a diet containing 0.001, 0.01, 0.1, 1, 10, or 100 ppm of MeIQx for 16 weeks, and the frequencies of lacI mutants and glutathione S-transferase placental form (GST-P) positive foci in the liver were determined. The mutation frequencies significantly increased at doses of 10 and 100 ppm, and GST-P positive foci significantly increased at a dose of 100 ppm. However, no statistical increases in both frequencies were observed at lower doses. MeIQx most frequently induced G frameshifts, followed by G to T transversions. Thus, no observed effect level (NOEL) was demonstrated for both carcinogenicity in terms of preneoplastic lesion induction and in vivo mutagenicity of MeIQx, and the NOEL for in vivo mutagenicity was lower than that for carcinogenicity.

Animals↗

PubMed2004

Lack of carcinogenicity of enzymatically modified isoquercitrin in F344/DuCrj rats.

The present study was conducted to evaluate the potential carcinogenicity of enzymatically modified isoquercitrin, administered in the diet at doses of 0.5% or 1.5% to groups of 50 male and female F344/DuCrj rats. Control males and females (50 rats each) were maintained on basal diet. Animals were observed for 104 weeks. There were no treatment-related clinical signs of toxicity in the treated groups. Body weights, feed consumption, survival rates and hematological findings for exposed rats of both sexes showed no variations among the groups. There was a slight but significant dose-dependent decrease in relative spleen weights in all treated groups, albeit with no histopathological variation. Overall histopathological evaluation of neoplasms and all tissues after 2 years showed that tumors developed in all groups including the controls. There was a non-significant tendency for increase in the incidence of pituitary gland adenomas in the high dose-treated females (45.5%) as compared to controls (27.7%), with a slight increase in hemorrhage incidences, but values for males were low and similar in both control and treated rats. There were no apparent effects of isoquercitrin on development of kidney neoplasms, hyperplasias or chronic nephropathy. Parathyroid adenomas or hyperplasias were found not affected by isoquercitrin treatment, and there were no differences in mammary gland fibroadenomas or hyperplasias between treated and control rats. Various tumors were found in other organs with no significant differences between the groups. In conclusion, under the conditions of this 2-year feeding experiment, no evidence was obtained of carcinogenicity of enzymatically modified isoquercitrin in male or female F344 rats.

Animals↗

PubMed2004

alpha(2)-Macroglobulin: a novel cytochemical marker characterizing preneoplastic and neoplastic rat liver lesions negative for hitherto established cytochemical markers.

We tried to identify a novel marker characteristic for rat hepatocellular preneoplastic and neoplastic lesions, undetectable by well established cytochemical markers. Glutathione S-transferase placental (GST-P)-negative hepatocellular altered foci (HAF), hepatocellular adenoma (HCA), and hepatocellular carcinoma (HCC) were generated by two initiation-promotion models with N-nitrosodiethylamine (NDEN) and peroxisome proliferators, Wy-14,643 and clofibrate. Total RNAs isolated from laser-microdissected GST-P-negative HAF (amphophilic cell foci) and adjacent normal tissues were applied to microarray analysis. As a result, five up-regulated genes were identified, and further detailed examinations of the gene demonstrating most fluctuation, ie, that for alpha(2)-macroglobulin (alpha(2)M) were performed. In reverse transcriptase-polymerase chain reaction, alpha(2)M mRNA was overexpressed not only in amphophilic GST-P-negative HAF but also in amphophilic GST-P-negative HCA and HCC. In situ hybridization showed accumulation of alpha(2)M mRNA to be evenly distributed within GST-P-negative HAF (predominantly amphophilic cell foci). Distinctive immunohistochemical staining for alpha(2)M could be consistently demonstrated in GST-P-negative HAF, HCA, and HCC induced not only by peroxisome proliferators but also N-nitrosodiethylamine alone. Thus our findings suggest that alpha(2)M is an important novel cytochemical marker to identify hepatocellular preneoplastic and neoplastic lesions, particularly amphophilic cell foci, undetectable by established cytochemical markers and is tightly linked to rat hepatocarcinogenesis.

Adenoma↗

PubMed2004

Induction of DNA-adducts and increase of 8-hydroxy-2-deoxyguanosine, but no development of preneoplastic lesions in offspring liver with transplacental and trans-breast milk exposure to 2-amino-3,8-dimethylimidazo [4,5-f ]quinoxaline (MeIQx) in rats.

Humans may be exposed to 2-amino-3,8-dimethylimidazo[4,5-f ]quinoxaline (MeIQx) at low doses during the period of gestation and lactation, and thereafter throughout life. The current study was designed to examine the possibility that early exposure may increase the risk of liver tumor development and related genetic changes. Male and female F344 rats were therefore administered MeIQx in diet (1, 10 and 100 ppm) for 4 weeks before mating and also during gestation and lactation. We also examined the carcinogenic risk of low-dose maternal and post-weaning exposure (MeIQx at doses of 1 and 10 ppm). Surviving male F1 rats were sacrificed under ether anesthesia at 19 weeks of age for analyses of glutathione S-transferase placental form-positive foci in the liver and aberrant crypt foci in the colon, as putative preneoplastic lesions. Transplacental and trans-breast milk exposure to MeIQx did not enhance development of the lesions, and levels of cell proliferation in the liver also did not differ from control values. However, excretion of MeIQx into breast milk and transfer to the fetus and offspring were observed with resultant hepatic MeIQx-DNA adducts and 8-hydroxy-2'-deoxyguanosine formation. Thus, our data suggest that maternal exposure to MeIQx during the period of pregnancy and lactation may not increase the risk of hepatocarcinogenesis in male offspring, despite causing genetic damage. If this result can be extrapolated to humans, exposure to MeIQx may not increase carcinogenic risk in offspring at usual human exposure levels.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed2004

Possible distinct molecular carcinogenic pathways for bladder cancer in Ukraine, before and after the Chernobyl disaster.

After the Chernobyl accident in 1986, the incidence of urinary bladder cancers in the Ukraine increased gradually from 26.2 to 43.3 per 100,000 people between 1986 and 2001. In the areas of low level but persistent cesium-137 (137Cs) radio-contamination, a unique atypical radiation-related urinary bladder cystitis named 'Chernobyl cystitis', a possible pre-neoplastic condition in humans, has been detected. We have previously documented high incidences of bladder lesions, including severe dysplasias and/or carcinoma in situ, in association with this cystitis and correlating with oxidative DNA damage. To further investigate the molecular mechanisms underlying bladder carcinogenesis with this specific etiology, mutation analysis of p53 gene (exon 5-8) was performed for 11 and 18 paraffin-embedded bladder cancers in Ukrainians, respectively collected before and after the Chernobyl disaster. DNAs were extracted and subjected to nested PCR-single-strand conformational polymorphism analysis followed by direct DNA sequencing, as well as p53 immunohistochemistry (IHC). The incidences of p53 gene mutation were 54.5 and 16.7% for before and after the Chernobyl disaster, respectively, the difference being statistically significant. Also a tendency for higher p53 IHC score was apparent in the earlier group of lesions. No significant difference was noted for the proportions of historical types. These results point to possible distinct molecular carcinogenic pathways of bladder cancer formation, before and after the Chernobyl disaster, on the basis of variation in p53 gene alteration.

Adult↗

PubMed2004

Effect of duodenogastric reflux on N-methyl-N'-nitro-N-nitrosoguanidine-induced glandular stomach tumorigenesis in Helicobacter pylori-infected Mongolian gerbils.

Both Helicobacter pylori (Hp) and bile acids are gastric carcinogens. An experimental model of duodenogastric reflux in Mongolian gerbils was developed and was used to study the effects of Hp infection and duodenogastric reflux on N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced glandular stomach tumorigenesis independently and synergistically. Male Mongolian gerbils underwent both inoculation with Hp, and had duodenogastric reflux (DR) induced, or neither, followed by MNNG administration. Animals were sacrificed at week 40, and histopathological examination of their excised stomachs and serological investigation were performed. Glandular stomach adenocarcinomas were observed in animals that underwent Hp inoculation and/or induction of DR after MNNG administration, and glandular stomach adenomas were found in animals inoculated with Hp after MNNG administration. The incidence of glandular stomach tumors was significantly higher in animals inoculated with Hp after MNNG administration and in animals undergoing combined Hp inoculation, DR induction and MNNG administration than in animals only administered MNNG. These findings indicate that Hp infection has a stronger tumorigenic effect than the exposure to duodenal contents, and duodenal contents may attenuate the effect of Hp on glandular stomach tumorigenesis.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed2004

Suppressive effect of CPT-11 on rat esophageal tumorigenesis induced by N-nitrosomethylbenzylamine.

Irinotecan hydrochloride (CPT-11) is a potent anti-cancer drug with suppressive effects against gastric and colorectal cancers. However, no evaluation of CPT-11 for esophageal squamous cell carcinoma has been performed in vivo. In this study, we examined the tumor suppressive effects of CPT-11 on N-nitrosomethylbenzylamine (NMBA)-induced rat esophageal tumorigenesis. One hundred and fourteen rats were divided into six groups. Rats in groups 1-5 were treated with subcutaneous injection of NMBA at a dose of 0.5 mg/kg 3 times per week for 5 weeks. Rats in group 6 served as a control. Rats in groups 2 and 3 were treated with intragastric (i.g.) administration of CPT-11 at doses of 20 and 40 mg/kg, respectively, once a week simultaneously with NMBA-initiation up to the end of the experiment. Rats in groups 4 and 5 were treated with i.g. administration of CPT-11 at doses of 20 and 40 mg/kg, respectively, once a week after the NMBA-initiation period up to the end of the experiment. The incidence of papilloma and hyperplasia in the esophagus showed no difference between NMBA-treated groups. However, the multiplicity of hyperplasia was significantly reduced in all CPT-11 administration groups. Immunohistochemically, expression of proliferating cell nuclear antigen (PCNA) was decreased on carcinogen-exposed squamous epithelium and preneoplastic lesions, although no significant differences were detected in the expression of single-strand DNA (ssDNA) and p53. These data suggest that CPT-11 has suppressive effects for esophageal tumors in the early step of the multistep process of carcinogenesis through antiproliferative mechanism.

Animals↗

PubMed2003

Induction of glutathione S-transferase placental form positive foci in liver and epithelial hyperplasia in urinary bladder, but no tumor development in male Fischer 344 rats treated with monomethylarsonic acid for 104 weeks.

The carcinogenicity of monomethylarsonic acid (MMA(V)), a major metabolite of inorganic arsenics in human and experimental animals, was investigated in male Fischer 344 rats. A total of 129 rats at 10 weeks of age were randomly divided into three groups and received drinking water containing MMA(V) at doses of 0 (Control), 50, and 200 ppm ad libitum for 104 weeks. No significant differences were found between the control and the MMA(V)-treated groups regarding clinical signs, mortality, hematological, and serum biochemistry findings. Quantitative analysis of glutathione S-transferase placental form (GST-P) positive foci in liver revealed a significant increase of numbers and areas in the 200 ppm MMA(V)-treated group. In the urinary bladder MMA(V) induced simple hyperplasia and significantly elevated the proliferating cell nuclear antigen (PCNA)-positive index in the urothelium. A variety of tumors developed in rats of all groups, including the controls, but all were histologically similar to those known to occur spontaneously in F344 rats and there were no significant differences among the groups. Thus, it could be concluded that, under the present experimental conditions, MMA(V) induced lesions in the liver and urinary bladder, but did not cause tumor development in male F344 rats even after 2 years exposure.

Administration, Oral↗

PubMed2003

Chemopreventive effect of JTE-522, a selective cyclooxygenase-2 inhibitor, on 1, 2-dimethylhydrazine-induced rat colon carcinogenesis.

Selective COX-2 inhibitors have been suggested to be an effective strategy in the prevention of colon cancer without the adverse side effects of non-selective, nonsteroid anti-inflammatory drugs. The present experiment was designed to assess the potential chemopreventive properties of JTE-522, a new selective cyclooxygenase-2 inhibitor, on the induction of 1,2-dimethylhydrazine (DMH)-induced colonic aberrant crypt foci (ACF), a marker of rat colon carcinogenesis. A total of 80 male F344 rats were treated with 3 or 10 mg/kg of body weight JTE-522 or vehicle by oral gavage five times weekly from the start of the experiment. One week later, rats received s.c. injections of saline or 20 mg/kg of body weight DMH once weekly for four successive weeks. At the end of 12 weeks after the start of experiment, all rats were sacrificed and colons were evaluated for ACF. 10 mg/kg JTE522 significantly suppressed the total ACF/colon. No inhibitory effect was observed in the 3 mg/kg JTE-522 treatment group. This result suggests that JTE-522 possesses chemopreventive activity against colon carcinogenesis.

1,2-Dimethylhydrazine↗