methylnitronitrosoguanidine and Stomach-Ulcer

Exposure to mild stress by chemicals and radiation causes DNA damage and leads to acquired stress resistance. Although the linear no-threshold (LNT) model of safety assessment assumes risk from any dose, evidence from radiological research demonstrates a conflicting hormetic phenomenon known as the hormesis effect. However, the mechanisms underlying radiation hormesis have not yet been clarified, and little is known about the effects of low doses of chemical carcinogens. We analyzed the efficacy of pretreatment with low doses of the alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) on the subsequent induction of cell transformation and gastric ulceration by high-dose MNNG. We used an in vitro Balb/3T3 A31-1-1 cell transformation test and monitored the formation of gastric ulcers in 5-week-old male ICR mice that were administered MNNG in drinking water. The treatment concentrations of MNNG were determined by the cell survival rate and past reports. For low-dose in vitro and in vivo experiments, MNNG was used at 0.028 μM, and 2.8 μg/mL, respectively. The frequency of cell transformation induced by 10 μm MNNG was decreased by low-dose MNNG pretreatment to levels similar to that of spontaneous transformation. In addition, reactive oxygen species (ROS) and mutation frequencies induced by 10 μm MNNG were decreased by low-dose MNNG pretreatment. Importantly, low-dose MNNG pretreatment had no effect on cell proliferation. In vivo studies showed that the number of gastric ulcers induced by 1 mg/mL MNNG decreased after low-dose MNNG pretreatment. These data indicate that low-dose pretreatment with carcinogens may play a beneficial role in the prevention of chemical toxicity under specified conditions.

Topics: Alkylating Agents; Animals; Dose-Response Relationship, Drug; Hormesis; Male; Methylnitronitrosoguanidine; Mice; Mice, Inbred ICR; Oxidative Stress; Stomach Ulcer; Treatment Outcome

Doublecortin and calcium/calmodulin-dependent protein kinase-like-1 (DCAMKL1) is a candidate marker for progenitor cells in the gastrointestinal mucosa. Lineage cells in the gastric mucosa are derived from progenitor cells, but this process can be altered after injury. Therefore, we explored DCAMKL1 expression under pathological conditions.. An immunohistochemical analysis was performed in rat stomach with acute superficial injury, chronic ulcer, intestinal metaplasia and dysplasia.. DCAMKL1 was exclusively expressed in immature quiescent cells in the isthmus of normal fundic glands, where putative progenitor cells are thought to reside. DCAMKL1-positive cells and proliferating cells shed into the lumen after superficial injury and re-appeared during the regenerative process, mainly in the superficial mucosa. In the marginal mucosa around the active ulcer, parietal and chief cells diminished, foveolar hyperplasia was evident, and trefoil factor family 2 (TFF2)/spasmolytic polypeptide-expressing metaplasia (SPEM) emerged at the gland base. DCAMKL1 cells re-emerged in the deep mucosa juxtaposed with SPEM and proliferating cells. In the healing ulcer, the TFF2 cell population expanded and seemed to redifferentiate to chief cells, while proliferating cells and DCAMKL1 cells appeared above and below the TFF2 cells to promote healing. SPEM appeared and PCNA cells increased in the intestinalized mucosa, and DCAMKL1 was expressed in the proximity of the PCNA cells in the deep mucosa. DCAMKL1, PCNA and TFF2 were expressed in different dysplastic cells lining dilated glands near SPEM.. The ultrastructural appearance of DCAMKL1-positive cells and the expression patterns of DCAMKL1 in normal and pathological states indicate that the cells belong to a progenitor cell population. DCAMKL1 expression is closely associated with TFF2/SPEM cells after injury. DCAMKL1 cells repopulate close to proliferating, hyperplastic, metaplastic and dysplastic cells, and the progenitor zone shifts according to the pathological circumstances.

Topics: Acetic Acid; Animals; Biomarkers; Cell Proliferation; Disease Models, Animal; Doublecortin Protein; Doublecortin-Like Kinases; Gastric Mucosa; Intestinal Diseases; Male; Metaplasia; Methylnitronitrosoguanidine; Protein Serine-Threonine Kinases; Rats; Rats, Wistar; Regeneration; Stem Cells; Stomach; Stomach Diseases; Stomach Ulcer; Trefoil Factor-2

Helicobacter pylori (Hp) is thought to be a stomach carcinogen from epidemiological findings. To determine the effects of infection with the bacteria on experimental carcinogenesis, a study of the glandular stomach of Mongolian gerbils (MGs) was performed. Male MGs were treated with N-methyl-N'-nitro-N-nitrosoguanidine followed by inoculation with Hp or infected with Hp followed by N-methyl-N'-nitro-N-nitrosoguanidine administration. Animals were killed at week 50, and their excised stomachs underwent microbiological and histopathological examinations. In addition, a serological investigation was performed. The incidences of adenocarcinomas were significantly higher in animals treated with 60 or 300 p.p.m. N-methyl-N'-nitro-N-nitrosoguanidine for 10 weeks followed by Hp inoculation or Hp followed by 20 p.p.m. N-methyl-N'-nitro-N-nitrosoguanidine for 30 weeks than in the respective controls. Moreover, tumour-bearing animals had higher titres of anti-Hp antibodies than tumour-free animals. Of interest was the finding that a dose of 100 p.p.m. N-methyl-N'-nitro-N-nitrosoguanidine given to infected gerbils eradicated the Hp in about half the animals, with a concomitant reduction in the promoting effect. No tumours were found in animals infected with Hp without N-methyl-N'-nitro-N-nitrosoguanidine or non-treated gerbils. Hp infection enhances glandular stomach carcinogenesis in MGs treated with N-methyl-N'-nitro-N-nitrosoguanidine. Animals with high titres of anti-Hp antibodies are at greatest risk of developing neoplasms.

Topics: Adenocarcinoma; Animals; Antibodies, Bacterial; Carcinogens; Cell Differentiation; Cocarcinogenesis; Drug Administration Schedule; Edema; Gastric Mucosa; Gastritis; Gastrointestinal Hemorrhage; Gerbillinae; Helicobacter Infections; Helicobacter pylori; Hyperplasia; Male; Metaplasia; Methylnitronitrosoguanidine; Precancerous Conditions; Specific Pathogen-Free Organisms; Stomach Neoplasms; Stomach Ulcer; Time Factors

The data obtained did not prove the stimulating effect of experimental chronic ulcer on the induced carcinogenesis of the stomach in the rat. It is shown that some surgical procedures followed by a gastroduodenal reflux enhance the gastric carcinogenesis while the procedures without such a reflux do not reveal any modifying effect on stomach cancer. The results of this study together with data from literature may have some relevance to the treatment procedures of patients with gastric ulcers.

Topics: Animals; Carcinoma; Chronic Disease; Duodenogastric Reflux; Male; Methylnitronitrosoguanidine; Postgastrectomy Syndromes; Rats; Stomach Neoplasms; Stomach Ulcer; Time Factors

The purpose of this experiment was to determine whether chronic gastric ulcers in the rat are predisposed to tumor formation when exposed to a usually noncarcinogenic dose of the carcinogen, N-Methyl-N'-nitro-N-nitrosoguanidine (MNNG). Two groups of rats were prepared; one subjected to a standard ulcer-producing operation, the other as control. Both groups were given oral MNNG (100 mg/liter as drinking water) for 12 weeks, the carcinogen was then stopped and replaced with tap water, and the experiment terminated at 52 weeks. Results showed that a low dose of carcinogen (200 mg) did not induce tumor formation in any of the normal rats. In the presence of a chronic gastric ulcer, only intestinal metaplasia and hyperplastic glandular nodules were observed, but there were no gastric tumors. It is concluded that the presence of a chronic gastric ulcer did not increase the likelihood of gastric tumor formation in rats treated with a noncarcinogenic dose of the carcinogen MNNG.

Topics: Animals; Carcinogens; Female; Gastric Acid; Gastrins; Liver; Methylnitronitrosoguanidine; Rats; Rats, Inbred Strains; Stomach; Stomach Neoplasms; Stomach Ulcer

Microspectrophotometric measurement of the DNA content of cell nuclei was performed on the lesions (including atypical glands) in gastric carcinogenesis of 15 male beagle dogs, which had been induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). The distribution patterns of DNA content were classified into three types: normal, subnormal, and abnormal. The histograms of the distribution in normal and regenerative glands were a normal type and subnormal type, respectively, while adenocarcinoma showed an abnormal distribution type. In atypical glands, the distribution patterns in autopsy cases were subnormal and abnormal types. When sequential endoscopic observation of the angulus of the stomach in dog No. 3 was carried out, atypical glands were found in an ulcer in the early stage of MNNG administration and a precancerous lesion in the late stage after termination of MNNG. The atypical glands in the early stage were of the subnormal type, while the atypical glands in the late stage were of the abnormal type. According to the results, these two types-subnormal and abnormal - of distribution of DNA content on the atypical glands may be related to regeneration and subsequent development of cancer, respectively.

Topics: Adenocarcinoma; Animals; Biopsy; DNA, Neoplasm; Dogs; Gastric Mucosa; Male; Methylnitronitrosoguanidine; Regeneration; Stomach Neoplasms; Stomach Ulcer

The susceptibility of healed, experimental gastric ulcers to chemical carcinogenesis was investigated. Slowly healing gastric ulcers were induced by the acetic acid method in the fundic and pyloric gastric mucosae of inbred male Wistar rats. N-Methyl-N'-nitro-N-nitrosoguanidine (MNNG) was administered in drinking water at a concentration of 50 mg/liter for 360 days after ulcer induction. Twenty-eight adenomatous hyperplasias and six-adenocarcinomas developed in the pyloric mucosae of rats, including five cases of adenomatous hyperplasia which developed in the periphery of the healed ulcer. In contrast, only one adenomatous lesion was found in the regenerated mucosa of the healed pyloric ulcer. No neoplasm was observed in the healed fundic ulcer area. The results demonstrated an increased incidence of neoplasms in the peripheral area of the healed pyloric ulcer and a decreased incidence of neoplasms in the regenerated mucosa within the healed pyloric ulcer scar, although these differences were not statistically significant in comparison with the intact pyloric mucosae of the MNNG-treated rats. Histoautoradiographs of the gastric mucosae demonstrated increased labeling indices in the healed ulcer periphery of the pyloric mucosa and decreased labeling indices in the regenerated mucosa within the healed pyloric ulcer scar of MNNG-treated rats, which might be related to the differential susceptibility of the two regions to gastric carcinogenesis. Intestinal metaplasia preferentially developed near the pyloroduodenal junction in MNNG-treated rats but was not localized in control rats. In the fundic ulcer scar area, an unusual squamous cell metaplasia was observed in one rat.

Topics: Animals; Cell Division; Disease Susceptibility; Gastric Mucosa; Male; Methylnitronitrosoguanidine; Pyloric Antrum; Rats; Rats, Inbred Strains; Stomach Neoplasms; Stomach Ulcer; Wound Healing

Topics: Adenocarcinoma; Animals; Cell Transformation, Neoplastic; Gastric Fundus; Male; Methylnitronitrosoguanidine; Rats; Rats, Inbred Strains; Stomach Neoplasms; Stomach Ulcer

The effect of reflux of the duodenal contents on the development of gastric stump carcinoma induced in male rats was studied. Two gastro-jejunal anastomoses were made in the resected stomach of 28 rats and about half of the rats were also given a single dose of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Well-differentiated adenocarcinomas developed in the resected stomachs with and without MNNG administration at incidences of 40% in the former and 23% in the latter. All the carcinomas were localized in the vicinity of the gastro-jejunal anastomosis, at which the proximal jejunal segment was drained. Several mucosal changes were found predominantly in the fundic mucosa surrounding the anastomosis, i.e., ulcer, foveolar hyperplasia, intestinal metaplasia and atypical hyperplasia. On the other hand, there was little mucosal change surrounding the gastro-jejunal anastomosis of the distal jejunal segment. These findings suggest a direct correlation between the exposure of mucosa of the anastomotic region to the duodenal contents and the development of adenocarcinoma.

Topics: Adenocarcinoma; Animals; Gastric Mucosa; Hyperplasia; Jejunum; Male; Metaplasia; Methylnitronitrosoguanidine; Rats; Rats, Inbred Strains; Stomach; Stomach Neoplasms; Stomach Ulcer

The effect of ulcers on the development of gastric tumors by N-methyl-N'-nitro-N-nitrosoguanidine in (MNNG) was studied in male Wistar rats. Ulcers were produced by the application of a steel rod, 5 mm in diameter and frozen at -78 degrees C, to the serosal surface of the forestomach, fundus, pylorus, or proximal duodenum. The existence of the ulcers at these areas was confirmed 1 week later in a preliminary experiment. Experimental groups were given MNNG in their drinking water at a concentration of 100 micrograms/ml for 16 weeks beginning 7 days after the ulcers developed. Administration of MNNG after ulceration resulted in a relative increase in the tumor incidences at each ulcer site, especially the proximal duodenum, which suggested that regenerating cells in the duodenum were the most susceptible cells among the cells of the four sites. The increase in tumor incidence following ulceration may be due to exposure of MNNG to a greater number of regenerating cells during the renewal process that seem to be more responsive to carcinogenic influences that normal cells.

Topics: Adenocarcinoma; Animals; Duodenal Neoplasms; Duodenal Ulcer; Gastric Mucosa; Male; Methylnitronitrosoguanidine; Papilloma; Rats; Stomach Neoplasms; Stomach Ulcer

The effect of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) on gastroduodenal epithelial proliferation p]rior to the development of frank neoplasia was studied in inbred LEW rats with or without gastric ulcers. The rats received either MNNG (100 gm/liter) in the drinking water or plain water. After 4 weeks, some rats in the MNNG-treated and control groups were given injections of tritiated thymidine and killed 1 hour later. In other rats, either an ulcer of the fundic mucosa was formed by a suction biopsy tube at laparotomy or a sham operation was performed. At 2 and 4 weeks after the operation, these rats were given injections of tritiated thymidine and killed 1 hour later. Sections of fundus, antrum, and duodenum were prepared for light autoradiography. MNNG treatment stimulated gastroduodenal epithelial proliferation, expanded the proliferative zone (PZ), and in the duodenum caused marked villus blunting and elongation of the crypts. No additional effect of the fundic ulcer or sham operation on gastroduodenal proliferation could be determined. The MNNG-induced expansion of the PZ occurred in a downward direction. Thus theories of carcinogenesis should include not only the expansion of the PZ toward the mucosal surface but also the possibility of expansion of the PZ toward the base of the mucosa.

Topics: Animals; Duodenum; Epithelium; Gastric Mucosa; Hyperplasia; Intestinal Mucosa; Male; Methylnitronitrosoguanidine; Precancerous Conditions; Rats; Rats, Inbred Lew; Stomach; Stomach Ulcer

Topics: Adenocarcinoma; Animals; Gastrectomy; Gastric Juice; Gastrins; Intestinal Polyps; Male; Methylnitronitrosoguanidine; Neoplasms, Experimental; Rats; Stomach Neoplasms; Stomach Ulcer

Serial studies by endoscopy and biopsy were made in a Beagle dog during and after oral administration of N-methyl-N'-nitro-N-nitroguanidine (MNNG). Between the 23rd and the 45th week of observation erosions and ulcers appeared at the angulus of the stomach and turned into ulcer scar. A depression with atypical glands was seen in the ulcer scar of the posterior wall of the angulus at the 94th week. It developed elevated margins at the 102nd week, when a well differentiated adenocarcinoma was found histopathologically. Ulceration and reepithelialization were observed in the early carcinoma. The carcinoma progressed into a larger one of Borrmann's type 2 at the 115th week and further into its type 3 at the 181st week. A second carcinoma with signet ring cell carcinoma developed in the anterior wall of the angulus. The two carcinomas fused and formed a single lesion. At autopsy in the 216th week the carcinoma invaded the serosa, and metastasis to regional lymph nodes was observed.

Topics: Adenocarcinoma; Animals; Biopsy; Carcinoma; Dogs; Gastroscopy; Jejunal Neoplasms; Methylnitronitrosoguanidine; Neoplasms, Experimental; Sarcoma, Experimental; Stomach; Stomach Neoplasms; Stomach Ulcer

Topics: Animals; Chronic Disease; Female; Methylnitronitrosoguanidine; Rats; Stomach Neoplasms; Stomach Ulcer

Differences in susceptibility to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) of fundic mucosa in various states of regeneration after induction of ulcer with iodoacetamide were examined histologically in male Wistar rats. Iodoacetamide was given to rats in their drinking water, before (Group 1), with (Group 2), or after (Group 3) MNNG. Atypical hyperplasia in the renewed mucosa and pyloric gland metaplasia were observed on the ulcers in Group 1 in higher incidence than in Groups 2 and 3. In addition, adenocarcinoma developed in the ulcer of 2 of 17 effective animals in Group 1. These observations suggest that the mucosa showing pyloric gland metaplasia is more susceptible to MNNG than the young rapidly regenerating mucosa at the margin of ulcers.

Topics: Adenocarcinoma; Adenoma; Animals; Gastric Mucosa; Hyperplasia; Iodoacetamide; Male; Methylnitronitrosoguanidine; Neoplasms, Experimental; Precancerous Conditions; Rats; Regeneration; Stomach Neoplasms; Stomach Ulcer

Fifteen male Beagle dogs received N-methyl-N-nitro-N-nitrosoguanidine (MNNG), 50 or 83 microgram/ml, in drinking water for 35 to 63 weeks. Broad superficial erosion and ulceration were observed in the angulus of the antrum and the anterior or posterior wall of the fundus during MNNG administration. After the discontinuation of MNNG administration, the erosions and ulcers healed rapidly, resulting in mucosal atrophy and scarring of the ulcer. In two dogs new depressions with atypical glands were observed by endoscopy and biopsy of the ulcer scars of the angulus, which became carcinomatous lesions at about the 100th week. Necropsy revealed 5 other carcinomas in the fundus of 5 additional dogs. One lesion was located in the ulcer scar and the other 4 in the areas of the mucosal atrophy. The possible relationship between carcinoma and the associated lesions was discussed.

Topics: Animals; Biopsy; Dogs; Endoscopy; Male; Methylnitronitrosoguanidine; Neoplasms, Experimental; Precancerous Conditions; Stomach Neoplasms; Stomach Ulcer; Time Factors

Topics: Animals; Disease Models, Animal; Methylnitronitrosoguanidine; Neoplasms, Experimental; Rats; Stomach Neoplasms; Stomach Ulcer

This study was undertaken to determine the effect of ulcer induced by iodoacetamide on the development of gastric carcinoma by N-methyl-N'-nitro-N-nitrosoguanidine in male Wistar rats. Fifty-six of the 62 ulcers induced by IAM were located in the fundic gland area along the limiting ridge. The incidence of fundic carcinoma was 16% in the groups treated with IAM and MNNG, while no fundic carcinoma was found in the group treated with MNNG alone. This difference was statistically significant. All the carcinomas in the fundic gland area were confined within the ulcer itself or its scar tissue, produced by IAM. These findings indicate that if an ulcer is present, carcinoma develops even in the fundic mucosa which is, if intact, resistant to the carcinogenic stimulation of MNNG. It was concluded that gastric ulcer predisposes the development of gastric carcinoma.

Topics: Adenocarcinoma; Adenoma; Animals; Cell Transformation, Neoplastic; Drug Synergism; Iodoacetamide; Iodoacetates; Male; Methylnitronitrosoguanidine; Neoplasms, Experimental; Rats; Stomach; Stomach Neoplasms; Stomach Ulcer

Topics: Animals; Iodoacetamide; Male; Methylnitronitrosoguanidine; Precancerous Conditions; Rats; Stomach Neoplasms; Stomach Ulcer

The effect of ulcers induced by iodoacetamine on the development of gastric tumors by N-methyl-N'-nitro-N-nitrosoguanidine was studied in male Wistar rats. The ulcerative lesions induced by iodoacetamide were confined symmetrically to the fundic region along the limiting ridge in the stomach and the pyloric region was unaffected. Animals treated with iodoacetamide and N-methyl-N'-nitro-N-nitrosoguanidine produced a high incidence of tumors including adenocarcinoma in the fundic region. The incidence of tumors in the pyloric region in the control group was 80% but there were no tumors in the fundic region. The tumors in the fundic region were most frequently found in the same areas that ulcers had previously been induced. These findings suggest that ulceration and regeneration of the mucosa are important factors in gastric carcinogenesis induced in rats by N-methyl-N'-nitro-N-nitrosoguanidine.

Topics: Adenocarcinoma; Adenoma; Animals; Gastric Mucosa; Iodoacetamide; Iodoacetates; Male; Methylnitronitrosoguanidine; Neoplasms, Experimental; Nitrosoguanidines; Pylorus; Rats; Sarcoma; Stomach Neoplasms; Stomach Ulcer