Induction of cancer of the glandular stomach in rats by 20-methylcholanthrene

The effect of 20-methylcholanthrene (Experiment No. I) and the combined action of ephedrine hydrochloride and 20-methylcholanthrene (Experiment No. 2) on the mucosa of the glandular stomach was studied in 25 rats. The application of the two chemicals was carried out by means of specially constructed containers which were inserted into the wall of the glandular stomach. Polyethylene-encased wicks led from the container, touching the gastric mucosa with their tips. The chemicals were slowly pumped by stomach action through the wicks on to the mucosa. The experiments lasted from 14 to 20 months. In Experiment No. 1 (32 rats) stomach tumours developed in 5 rats, in Experiment No. 2 (21 rats), in 7 rats. Most of the tumours were adenocarcinomas. The tumours were large and invaded the serosa of the stomach. In Experiment No. 2 five tumours out of seven showed metastasis in various organs and tissues of the abdomen.     

Induction of ornithine decarboxylase activity in rat glandular stomach mucosa by bile acids

A single oral instillation of 1.5 g/kg body weight of sodium taurocholate resulted in a rapid, transient stimulation of ornithine decarboxylase activity in rat glandular stomach mucosa, reaching a peak (10 times the control value) 4 to 6 hr after sodium taurocholate treatment and returning to the control level within 48 hr. The degree of stimulation was dose-dependent. Sodium taurodeoxycholate and sodium taurochenodeoxycholate stimulated the enzyme activity similarly.     

Selective induction of glandular stomach carcinoma in F344 rats by N-methyl-N-nitrosourea

To study the carcinogenic action of N-methyl-N-nitrosourea (MNU) on the stomach, MNU in distilled water at a concentration of 400 ppm was provided as drinking water to F344 male rats for 25 weeks (group I) or 15 weeks (group II). Twenty weeks following the cessation of the administration, invasive adenocarcinomas were found in the glandular stomach in 100% of 16 rats in group I and 38% of 21 rats in group II. Bone formation occurred within the stroma of carcinoma in 5 rats in group I. No neoplastic lesions developed in the esophagus, forestomach or duodenum of any rat. Thus, MNU in drinking water selectively induces glandular stomach carcinoma in high incidence in these rats.     

Induction of glandular stomach cancers in Helicobacter pylori-infected Mongolian gerbils by 1-nitrosoindole-3-acetonitrile

Helicobacter pylori (H. pylori) infection and high intake of various traditional salt-preserved foods are regarded as risk factors for human gastric cancer. We previously reported that Chinese cabbage contains indole compounds, such as indole-3-acetonitrile, a mutagen precursor. 1-Nitrosoindole-3-acetonitrile (NIAN), formed by the treatment of indole-3-acetonitrile with nitrite under acidic conditions, shows direct-acting mutagenicity. In the present study, NIAN administration by gavage to Mongolian gerbils (MGs) at the dose of 100 mg/kg two times a week resulted in three adduct spots (1.6 adducts/10(8) nucleotides in total), detected in DNA samples from the glandular stomach by (32) P-postlabeling methods. Treatment with six consecutive doses of 100 mg/kg of NIAN, two times a week for 3 weeks, induced well-and moderately-differentiated glandular stomach adenocarcinomas in the MGs at the incidence of 31% under H. pylori infection at 54-104 weeks. Such lesions were not induced in MGs given broth alone, broth + NIAN or infection with H. pylori alone. Thus, endogenous carcinogens formed from nitrosation of indole compounds could be critical risk factors for human gastric cancer development under the influence of H. pylori infection.     

Induction of gastric intraepithelial neoplasia of glandular stomach of mongolian gerbils by elicobacter pylori

Helicobacter pylori (Hp) infection is corresponding to causes of chronic active gastritis, and stomach cancer, and classified as group-I human carcinogen[1-3]. It was reported that Hp or Helicobacter felis infection induced chronic gastritis or gastric MALT lymphomas in mice, and enhanced gastric carcinogenicity of chemicals[4-6]. However, evidence of carcinogenicity of Hp infection alone in experimental animal was not obtained for a long time. In 1998, Japan scientists reported firstly th…     

Modification of N-methyl-N'-nitro-N-nitrosoguanidine-induced forestomach and glandular stomach carcinogenesis by phenolic antioxidants in rats

The modifying effects of five phenolic antioxidants on N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-initiated forestomach and glandular stomach carcinogenesis were investigated in male F344 rats. Groups of 20 rats were given an intragastric dose of 150 mg/kg body weight MNNG, and starting from 1 week later received diet supplemented with 0.8% catechol (CC), 1.0% 2-tert-butyl-4-methylphenol, 1.5% p-tert-butyl-phenol, 1.5% methylhydroquinone, 1.5% 4-methoxyphenol (4MP), or basal diet alone for 51 weeks. Further groups of 10-15 rats were maintained as controls without prior treatment with MNNG. The incidences of squamous cell carcinoma of the forestomach in MNNG-treated animals were significantly elevated by the diets containing CC (P less than 0.001), 2-tert-butyl-4-methylphenol (P less than 0.001), or p-tert-butylphenol (P less than 0.01), while the development of carcinoma in situ was inhibited by 4MP (P less than 0.01). Treatment with CC, 2-tert-butyl-4-methylphenol, p-tert-butylphenol, or 4MP alone induced forestomach hyperplasia at incidences of 86.7, 40, 93.3, and 100%, respectively. In the pyloric region of the glandular stomach, the development of adenomatous hyperplasia and adenocarcinoma after MNNG treatment was significantly enhanced by diet containing CC (P less than 0.001). Moreover, treatment with CC alone induced 100% adenomatous hyperplasia and induced adenocarcinoma in 20% of animals. These results clearly demonstrated that while antioxidants causing proliferation in forestomach epithelium can markedly enhance carcinogenesis in this tissue, others displaying the same or greater potential for generating a hyperplastic response, like 4MP, can exert an inhibitory effect. In addition, it was shown that CC, which is widely present in our environment, is an unequivocal glandular stomach carcinogen also possessing strong enhancing activity for MNNG-induced lesion development.     

Induction of stomach cancer by the chronic action of arsenic

Out of 18 albino rats which survived 17-24 months after implantation in a partially isolated glandular stomach compartment of a perforated polyethylene capsule containing 8 mg arsenic trioxide in a fat-wax mixture as vehicle, two developed muconodular adenocarcinoma and one--mucoid cystic adenocarcinoma in that gastric compartment; metastasis into the liver was detected in one animal. No malignant tumors were found in 9 rats with the same post-surgical survival time after implantation of a control capsule containing the same mixture without arsenic. Since spontaneous gastric cancers practically fail to appear in laboratory rats, nor have they ever been reported by other authors after control capsule implantation but developed in some rats after implantation of a carcinogen-containing one, the results of the present investigation may be interpreted as an experimental proof of the carcinogenicity of arsenic which was previously assumed on epidemiologic evidence.     

The effect of vagotomy on carcinogenesis in the glandular stomach of rats, induced by N-methyl-N'-nitro-N-nitrosoguanidine

The effect of hydrochlorhydria caused by vagotomy on carcinogenesis in the glandular stomach of male rats was studied. Group A (35 rats): After N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) 80 mg/l solution was orally administered during the first 15 weeks of life, vagotomy was performed. Group B (35 rats): After the oral administration of MNNG 80 mg/l solution during the first 15 weeks of life, laparotomy was done. Group C (10 rats): As the control, vagotomy was undertaken at the 15th week of life. Group D (10 rats): As the control, laparotomy was done at the same time. At the 52nd week, all surviving rats were autopsied, and gastrin cell counts and body weight were ascertained. The incidence of adenocarcinoma was 62% in Group A, 32% in Group B (p less than 0.05) and nil in Group C and D. These results strongly support the view that the hypochlorhydria plays the role of a promoting factor in producing gastric carcinoma.     

Induction of stomach tumors in rats by N-methyl-N-nitroso-N1-nitroguanidine]

N-methyl-N-nitroso-N'-nitroguanidine was administered as drinking water to Wistar strain and non-inbred male rats in the dosage of 100 mKg/ml for 7 months, Adenocarcinomas of the stomach were produced in about 70% of rats. The first tumors in the glandular stomach were noticed in 10-12.5 months. Studies of the kinetics of morphological changes indicated that MNNG induced a damage to the mucous membrane, subsequent regenerative hyperplasia, adenomatous hyperplasia with cellular and structural atypism, atrophy, pylorization of the mucosa and development of gastric adenocarcinomas.     

Chemoprevention of glandular stomach carcinogenesis through duodenogastric reflux in rats by a COX-2 inhibitor

Duodenogastric reflux (DGR) causes glandular stomach carcinogenesis in rats without carcinogens. We aimed to investigate how this carcinogenesis might be prevented by a selective COX-2 inhibitor, meloxicam. A series of 188 Fisher 344 rats underwent a surgical DGR procedure and were divided into 2 groups. One group was given commercial chow (control group), and the other an experimental chow containing meloxicam [0.3 mg/kg bw/day] (meloxicam group). The animals were sequentially sacrificed at weeks 20, 30, 40, 50 and 60 after surgery. The stomachs were removed and examined for the presence of carcinoma, incidence of reflux-induced morphologic changes, COX-2 expression and its activity. Adenocarcinoma in the glandular stomach developed in 7 of 21 animals (33%) in the control group at week 60, but none of 20 (0%) in the meloxicam group (p < 0.01). Moreover, reflux-induced gastritis was definitely alleviated in the meloxicam group compared with the control group. COX-2 immunoreactivity was predominantly detected in stromal cells such as macrophages and fibroblasts. Compared with nonsurgical rats, RNA expression of COX-2 in the mucosa increased, reaching peak at an early phase of week 20 in both groups (p < 0.005). Expression of microsomal prostaglandin E synthase-1 was lower in the meloxicam group than in the control group. PGE(2) production was significantly suppressed throughout the experiment in the meloxicam group compared with the control group (p < 0.01). Gastric carcinogenesis via duodenal reflux was mediated by the COX-2 pathway in rats. Administration of meloxicam prevented this carcinogenesis by suppressing the inflammatory process.     

Induction of adenocarcinomas in the glandular stomach of BALB/c mice treated with N-methyl-N-nitrosourea.

Male 6-week-old BALB/c strain animals (groups 1 and 2) received 10 weekly intragastric intubations of 0.5 mg/mouse of N-methyl-N-nitrosourea. At week 11 the forestomachs were resected in group 1 but not group 2. Although many animals in group 2 died due to development of squamous cell carcinomas in the forestomach, development of cancers in the glandular stomach was quite similar in both groups. Well-differentiated adenocarcinomas in groups 1 and 2 were found at low incidence at week 20, rising to 100% at week 40, with two lesions metastasizing to the lymph nodes. Four poorly differentiated adenocarcinomas and 5 signet ring cell carcinomas were also found in 27 glandular stomach tumor-bearing animals.     

Chemopreventive effects of curcumin on glandular stomach carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine and sodium chloride in rats

The modifying effects of pure curcumin on glandular stomach carcinogenesis were investigated during the post-initiation phase in male Wistar rats treated with N-methyl-N'-nitro-N-nitrosoguanisine (MNNG) and sodium chloride. A total of 110 male 6-week-old rats were divided into four groups. Groups 1-3 (consisting of 30 rats/group) were given MNNG in their drinking water at a concentration of 100 ppm and simultaneously fed a diet supplemented with 5% NaCl for 8 weeks. They were then fed a diet containing either 0.2% (group 1) or 0.05% (group 2) pure curcumin or kept on a basal diet alone (group 3) for 55 weeks. The rats of the curcumin-treated groups (groups 1 and 2) were then switched to the basal diet for the following 4 weeks before sacrifice. Group 4 (20 rats) served as a non-treatment control. The total incidence of combined atypical hyperplasias and adenocarcinomas in the glandular stomachs was rather lower in groups 1 (93%) and 2 (90%) than in group 3 (100%), albeit without statistical significance. However, the mean number of atypical hyperplasias or adenocarcinomas of the glandular stomachs in group 1 (4.70) was significantly less than the value of group 3 (7.17) (p<0.05). Thus, the development of cancerous and precancerous lesions in the glandular stomach was decreased by exposure to pure curcumin. The present results indicate that the compound exerts chemopreventive effects, when given during the post-initiation phase of glandular stomach carcinogenesis in rats.     

Human stomach cancer bearing similarity to experimentally induced stomach cancer in rats

A periodical and histological study on the histogenesis of experimental stomach carcinoma induced by N-methyl-N'-nitro-N-nitrosoguanidine in rats suggested that cancer progression occurred from the submucosal focus under the condition of existing adenomatous hyperplasia. This carcinoma manifested particular atypia, combined hyperplasia of the smooth muscle, indistinct borderline from the surrounding normal mucosa. These were considered to be specific histological findings in experimental carcinoma. In 3 of 273 gastrectomized patients with gastric carcinoma the same histological findings were obtained as in experimental gastric carcinoma; 35 patients had submucosal heterotopic glands similar to the experimentally induced rat foci or adenomatous hyperplasias seen in the experimental carcinoma. These results suggest the same histogenesis for human stomach cancer and the experimental carcinoma.