methylnitronitrosoguanidine and Metaplasia

Helicobacter pylori (Hp) was concluded to be 'a definite carcinogen' by WHO/IARC in 1994. We have demonstrated that Hp infection enhances chemical carcinogen-induced stomach carcinogenesis in Mongolian gerbils (MGs) using N-methyl-N'-nitro-N-nitrosoguanidine or N-methyl-N-nitrosourea. Not only well-differentiated but also poorly differentiated and signet ring cell types of cancers are observed, mimicking the human case. Eradication of Hp was found to be effective of preventing enhancing effects. Hp infection alone, without chemical carcinogens, caused submucosal proliferating lesions, but not gastric carcinomas, in contrast to reports that Hp infection alone may act on a complete carcinogen. Precise pathological assessment is required to solve this controversy. Here we demonstrate alleviation of Hp induced gastric lesions with eradication in MGs.

Topics: Animals; Disease Models, Animal; Gastric Mucosa; Gerbillinae; Helicobacter Infections; Helicobacter pylori; Humans; Metaplasia; Methylnitronitrosoguanidine; Methylnitrosourea; Stomach Neoplasms

Gastric cancer is a very typical cancer related to life styles, including nutrition and dietary conditions. Cigarette smoking has also been pointed out as an enhancing factor in gastric cancer development. Improvement of dietary conditions, regular dietary habits including lower salt, nitrite and nitrite intake and balanced nutritious food may be factors suppressing the incidence of gastric cancer. At the same time, advances in technology for early diagnosis and early surgical treatment have elevated the cure rate of gastric cancers. From both primary and secondary cancer prevention aspects, gastric cancer is now a conquerable disease.

Topics: Animals; Diet; Humans; Male; Metaplasia; Methylnitronitrosoguanidine; Mutagens; Rats; Rats, Inbred Strains; Risk Factors; Stomach; Stomach Neoplasms

Intestinal metaplasia of the stomach is classified into two types, complete and incomplete, by enzymatical, mucin histochemical and histological differences. Complete type resembles the small intestine while incomplete type does not. But, even complete type differs from the small intestine from the point of cytological observations. Vascular structures of the metaplastic mucosa are different from those in the mucosae of stomach, small and large intestines. Focal intestinal metaplasia can be induced in rats by a gastric carcinogen, N-propyl-N'-nitro-N-nitrosoguanidine or regeneration after ulceration with 0.5 NaOH. There is no solid evidence that intestinal metaplasia is a precancerous change of the stomach. However, the patients with extensive intestinal metaplasia of the stomach belong to the high risk group for the gastric cancer. Therefore, careful follow-up studies are needed for these patients using endoscopy by dye-staining method.

Topics: Animals; Epithelium; Gastric Mucosa; Humans; Metaplasia; Methylnitronitrosoguanidine; Middle Aged; Precancerous Conditions; Rats; Stomach Neoplasms

Chi006Eese herbal medicine Weifuchun Tablets (WFC) approved by the State Food and Drug Administration in 1982 has been widely used in treating a variety of chronic stomach disorders including Chronic atrophic gastritis (CAG) and Gastric precancerous lesions in China clinically. This study aimed to investigate the efficacy and potential mechanism of WFC in treating Gastric intestinal metaplasia (GIM) and Gastric dysplasia (GDys).. Rat GIM and GDys established by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) combined with hot paste, ethanol injury, and intermittent fasting were intervened by WFC. Body weight, histopathology, pH of gastric acid, pepsin activity, intestinal metaplasia index and inflammation were detected. Rat bone marrow derived macrophages (BMDMs) pretreated with WFC were stimulated by LPS. Inflammatory factors and the nuclear factor-kappa B (NF-κB) pathway were assessed. GES-1 cells pretreated by WFC were stimulated by MNNG and TNF-α, intestinal metaplasia index, the NF-κB pathway and interaction between P65 and CDX2 were detected.. WFC improved rat body weight, histopathology, pH value of gastric acid, activity of gastric pepsin, intestinal metaplasia (CDX2), inflammation (IL-1β, IL-6 and TNF-α), macrophage aggregation (CD68) in gastric mucosa in rat GIM and GDys. WFC inhibited inflammation (IL-1β and TNF-α) by inactivating the NF-κB pathway. WFC reduced the expression of CDX2 by inhibiting the binding of CDX2 promoter TSS upstream region with p65.. WFC blocked GIM and GDys associated with inflammation by regulating the NF-κB pathway.

Topics: Animals; Gastric Mucosa; Hyperplasia; Inflammation; Metaplasia; Methylnitronitrosoguanidine; NF-kappa B; Pepsin A; Precancerous Conditions; Rats; Stomach Neoplasms; Tumor Necrosis Factor-alpha

Gastric Cancer is one of the most common types of cancer. And the occurrence of gastric carcinoma is an evolutionary histopathological stage. As a result, further research of GPL, which is a borderline of gastric cancer, is indispensable for preventing the formation and development of gastric carcinoma. Several studies have demonstrated a correlation between the expression of autophagy, apoptosis and Gastric cancer (GC). However, the effects of autophagy and apoptosis on human gastric cancer progression, particularly on gastric precancerous lesions (GPL), have not totally been investigated. At present, Astragaloside IV(AS-IV) is a saponin purified from Astragalus membranaceous Bge, a traditional Chinese herb that has been widely used for more than 2000 y in the treatment of cancer, cardiovascular and immune disorders. This study was designed to investigate the mechanism of AS-IV protecting gastric mucosa in N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced GPL rats. The lesions of GIM and GED were significantly ameliorated compared with the model rats, especially crowded tubular glandular and back-to-back tubular structure, which were the dangerous borderline between GPL and GC. Western Blot analysis showed that the ratio of Bcl-2/Bax and the protein expression of Bcl-XL, p53, Beclin1, p62, ATG5 and ATG12 were decreased and the level of Caspase3 was increased in the group of AS-IV compared with the model group; RT-PCR analysis showed that the gene expression Ambra1, Beclin1, ATG5, LC3 and p62 were decreased in the group of AS-IV compared with the model group. This research manifested that the occurrence of gastric cancer was preceded by a prolonged precancerous stage, which could be ameliorated by the AS-IV. Meanwhile, the mild and moderate stage of precancerous lesions is similar with gastric adenocarcinoma in critical biological processes, including inflammation, cell proliferation, differentiation. But this lesion is very different from cancer, because it does not appear obvious invasion and malignant lesions in this pathologic stag. Further, AS-IV could regulate p53 expression to activate the Ambra1/Beclin1 complex in GPL, and it will protect the gastric mucosal injury, prevent and cure gastric mucosal atrophy, intestinal metaplasia and atypical hyperplastic lesions. It provided a potential therapeutic strategy in reversing intestinal metaplasia and dysplasia of gastric precancerous lesions and protecting the gastric mucosa in GPL rats.

Topics: Adenocarcinoma; Animals; Apoptosis; Cell Differentiation; Cell Proliferation; Gastric Mucosa; Hyperplasia; Metaplasia; Methylnitronitrosoguanidine; Precancerous Conditions; Protective Agents; Rats; Rats, Sprague-Dawley; Saponins; Stomach; Stomach Neoplasms; Triterpenes

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

Gastric cancer results from a combination of Helicobacter pylori (H pylori) infection, exposure to dietary carcinogens, and predisposing genetic make-up. Because the role of these factors in gastric carcinogenesis cannot be determined readily in human beings, the present study examined the role of an oral carcinogen and H pylori infection in rhesus monkeys.. Gastroscopies were performed in 23 monkeys assigned to 4 groups: controls; nitrosating carcinogen ethyl-nitro-nitrosoguanidine administration alone; inoculation of a virulent H pylori strain alone (H); and ethyl-nitro-nitrosoguanidine in combination with H pylori (EH). Follow-up gastroscopies and biopsies were performed at 3-month intervals for 5 years for pathologic and molecular studies.. Postinoculation, H and EH groups showed persistent infection and antral gastritis. Starting at 2 and 5 years, respectively, gastric intestinal metaplasia and intraepithelial neoplasia developed in 3 EH monkeys but in no other groups. Transcriptional analysis of biopsy specimens at 5 years revealed group-specific expression profiles, with striking changes in EH monkeys, plus a neoplasia-specific expression profile characterized by changes in multiple cancer-associated genes. Importantly, this neoplastic profile was evident in nonneoplastic mucosa, suggesting that the identified genes may represent markers preceding cancer.. Gastric intraglandular neoplasia is induced in primates when H pylori infection is associated with consumption of a carcinogen similar to the nitrosamines found in pickled vegetables, suggesting that H pylori and the carcinogen synergistically induce gastric neoplasia in primates.

Topics: Animals; Biopsy; Carcinogens; Carcinoma in Situ; Cell Transformation, Neoplastic; Cluster Analysis; Diet; Disease Models, Animal; Disease Progression; DNA Repair; Female; Gastritis; Gastroscopy; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Helicobacter Infections; Helicobacter pylori; Macaca mulatta; Male; Metaplasia; Methylnitronitrosoguanidine; Oligonucleotide Array Sequence Analysis; Precancerous Conditions; Stomach Neoplasms; Time Factors

To observe the development and progression of intestinal metaplasia (IM) in dog's stomach and expression of tumor-related proteins in gastric mucosa lesions.. IM animal model was induced in stomach of Beagle dog by combining treatment of oral administration of N-methyl-N'-nito-N-nitrosoguanidine (MNNG) and ranitidine (R) with X-ray irradiation to the target organ. Expression of APC, p53, K-ras and bcl-2 gene proteins in animal gastric mucosa lesions were determined with immunohistochemical method.. IM animal model was successfully induced and the dynamic pathological changes were observed by means of this model. It was confirmed that the progression from normal epithelial cells to IM cells may require several stages, including superficial gastritis, chronic atrophic gastritis, slight focal IM and moderate or severe IM. Aberrant bcl-2 protein can be detected in the atrophic mucosa epithelium and the abnormal expression of APC, K-ras and bcl-2 can be found in IM of mucosa.. IM model in stomach of Beagle dog can be successfully induced by our method (MNNG + R + X-ray). The progression from normal to IM in dog resembles that of human being and the expression of tumor-related proteins (APC, bcl-2, K-ras) may play a role in the malignant transformation of IM.

Topics: Adenomatous Polyposis Coli Protein; Animals; Dogs; Gastric Mucosa; Immunohistochemistry; Male; Metaplasia; Methylnitronitrosoguanidine; Precancerous Conditions; Proto-Oncogene Proteins c-bcl-2; Stomach Neoplasms; Tumor Suppressor Protein p53

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

Formation of a comedo, an impaction of horny cells in sebaceous follicles, entails a metaplastic change in the differentiation patterns of the follicular epithelium. Since metaplasia is a requisite early stage in carcinogenesis, we postulated that carcinogens might be comedogenic. The rabbit ear was used to assay the comedogenic potentialities of an array of known tumorigens. Complete carcinogens and some tumor promotors were invariably strongly comedogenic at concentrations of 1.0% and below. Comedogenic chemicals commonly found in skin care products usually required concentrations of 40% and greater to induce comedones which were small in comparison to carcinogen induced comedones. We suggest that the rabbit ear model might be an easy and reliable way to screen for carcinogenicity.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Benz(a)Anthracenes; Carcinogens; Coal Tar; Ear; Lanolin; Male; Metaplasia; Methylnitronitrosoguanidine; Rabbits; Sebum; Skin; Skin Care

A polyclonal antibody against rat intestinal-type alkaline phosphatase (I-ALP) was generated and proven to be applicable immunohistochemically to paraffin-embedded sections. Expression of I-ALP in normal tissues, intestinal metaplasia and stomach tumors induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was then investigated in five different strains of rats. Male SD (Crj:CD), Lewis (LEW/Crj), WKY (WKY/NCrj), Wistar (Crj:Wistar) and F344 (F344/DuCrj) animals were given drinking water containing 100 micrograms/ml of MNNG for 30 weeks and were killed at week 50. Among the 5 strains, stomach adenocarcinomas were found most frequently in the SD case. The susceptibility of rats to induction of stomach carcinoma did not correlate with the development of intestinal metaplasias in each strain. Histochemical staining for mucin demonstrated all stomach tumors (adenomatous hyperplasias and well-differentiated adenocarcinomas) to consist mainly of gastric type cells (pyloric gland cell and surface mucous cell types), with intestinal-type tumor cells (goblet cell and intestinal absorptive cell types) being only occasional findings. Immunohistochemically, I-ALP was strongly positive on the striated cell borders of small intestinal absorptive cells of the villus and on brush borders of epithelial cells of kidney proximal tubules. I-ALP was also detected in the normal stomach, limited to the striated cell borders of absorptive cells of the upper one-fourth of intestinal metaplastic glands. I-ALP may thus be a useful marker for stomach tumor cells of intestinal absorptive cell type, indicative of maturation and differentiation. No stomach tumors consisting mainly of intestinal-type cells were found, and therefore there was no suggestion of any derivation from intestinal metaplasias.

Topics: Adenocarcinoma; Adenoma; Alkaline Phosphatase; Animals; Immunoenzyme Techniques; Intestines; Male; Metaplasia; Methylnitronitrosoguanidine; Mucins; Rats; Rats, Inbred Strains; Rats, Sprague-Dawley; Rats, Wistar; Stomach Neoplasms

Tracheas were excised from fetal Syrian golden hamsters on the 15th day of gestation. Tracheal explants were cultured in vitro and exposed to different dose-levels of well known carcinogens. We chose two nitroso compounds, N-Methyl-N-nitro-N-nitrosoguanidine (MNNG) and Diethylnitrosamine (DEN) and two aromatic amines, Aminofluorene (AF) and Acetylaminofluorene (AAF). The tracheal explants were treated for 24 h in vitro, then the carcinogens were washed off and the tracheas were kept for 21, 28 or 35 days in culture. After fixation tracheal explants were transversely cut with serial section techniques and scored for morphological changes of the epithelium by light microscopy. Most of the control explants completed differentiation and had a normal morphology at the end of the in vitro culture period. Occasionally we found a decrease of the number of ciliated cells and some areas with squamous metaplasia in the respiratory epithelium. Carcinogen treatment with nitroso compounds led to a significant increase of the morphologic changes of the epithelium. These effects were especially obvious after DEN treatment. Morphologic changes of the epithelium such as metaplasia and hyperplasia were discussed as carcinogen-related events. In vitro exposure with aromatic amines did not induce marked metaplastic or hyperplastic changes in the respiratory epithelium of tracheal explants.

Topics: Animals; Cricetinae; Diethylnitrosamine; Hyperplasia; Mesocricetus; Metaplasia; Methylnitronitrosoguanidine; Trachea

The effects of As2O3, MNNG and B(a)P on epithelia of human fetal tracheae and rat tracheae in organ culture were studied. In human fetal trachea, a small dose of arsenic (1 mumol As) induced hyperplasia of the epithelium; 3-9 mumol As induced hyperplasia and cellular atypia in the epithelium, and hyperplasia and squamous metaplasia in the adenoepithelium. Similar effects were not observed in rat tracheae. MNNG and B(a)P induced hyperplasia, squamous metaplasia and dysplasia in human fetal tracheal and rat tracheal epithelia respectively, and MNNG also induced hyperplasia and squamous metaplasia in human fetal tracheal adenoepithelium. The data suggest that 1) arsenic may be carcinogenic to the human respiratory tract but not to the rat; and 2) human tissues in organ culture are very useful for detecting carcinogens and for studying carcinogenesis.

Topics: Animals; Arsenic; Arsenic Trioxide; Arsenicals; Benzo(a)pyrene; Carcinogens; Epithelium; Fetus; Humans; Metaplasia; Methylnitronitrosoguanidine; Organ Culture Techniques; Oxides; Precancerous Conditions; Rats; Trachea; Tracheal Neoplasms

Intestinal metaplasia (IM) in the glandular stomach of male Wistar rats induced by oral administration of N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) and/or intubation of 0.1N sodium hydroxide (NaOH) was studied as follows. Experiment I, sequential study: Rats in group I were given 100 micrograms/ml ENNG in drinking water for 12 weeks. Rats in group II were given 5 ml of 0.1N NaOH by gastric intubation once a week for 12 weeks. Group III control rats were given tap water. Rats were killed from week 1 until week 69 sequentially. IM was first found at week 26 in group I and at week 58 in groups II and III, its incidence being significantly higher in group I than in the other two groups (P less than 0.01), but without any difference between group II and group III. Experiment II, two-stage carcinogenesis: Rats in groups I and II were treated in the same way as in experiment I, while rats in group III were given 100 micrograms/ml ENNG for 12 weeks, followed by 0.1N NaOH once a week for 12 weeks intragastrically. All rats were killed at week 56. The numbers of metaplastic glands in groups I and III were higher than in group II. Gastric carcinomas were induced in all groups of rats treated with ENNG. The results of these two experiments show that IM is effectively induced by a carcinogen but is not enhanced by regeneration induced by alkaline treatment.

Topics: Aging; Animals; Carcinogens; Carcinoma; Gastric Mucosa; Male; Metaplasia; Methylnitronitrosoguanidine; Precancerous Conditions; Rats; Rats, Inbred Strains; Regeneration; Sodium Hydroxide; Stomach Neoplasms

N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was given to 3 groups of male Wistar rats in different doses of 25 micrograms/ml, 50 micrograms/ml and 100 micrograms/ml with their drinking water for 32 weeks. After 50 weeks the antrum region of the stomach was investigated by serial sections. All animals showed tubules with metaplastic intestinal epithelium. The different values of metaplastic glands in the antrum region of the stomach were 187 (25 micrograms MNNG), 76 (50 micrograms MNNG) and 51 (100 micrograms MNNG). They indicate an inverse relationship of the frequency of intestinal metaplasia and the MNNG dose. As opposed to this dose-response pattern, cytotoxic alterations, regenerative hyperplastic lesions and tumours of the stomach are more frequent after medium of high MNNG doses. It is therefore suggested that the induction of intestinal metaplasia is a specific effect of the carcinogen mainly in the low dose range.

Topics: Animals; Dose-Response Relationship, Drug; Intestinal Diseases; Intestine, Small; Male; Metaplasia; Methylnitronitrosoguanidine; Pyloric Antrum; Rats; Rats, Inbred Strains; Stomach Diseases

N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and N-propyl-N'-nitro-N-nitrosoguanidine (PNNG) were administered to male F344 rats at a single dose of 200 mg/kg by gavage and the animals were observed for 110 weeks. The results revealed that PNNG was a weaker carcinogen for the stomach than MNNG under these conditions. After MNNG, the mortality of animals was higher and their average survival time was shorter than after PNNG. Neoplasms were induced in both the forestomach and glandular stomach by both agents. The incidence of forestomach tumors was high: 85% with MNNG, 64% with PNNG, but with PNNG a greater proportion of the forestomach neoplasms were benign. The incidence of neoplasms of the glandular stomach was 18% with PNNG as compared to 65% with MNNG. Intestinal metaplasia appeared in the glandular stomach after exposure to either MNNG or PNNG. There was also a high incidence in untreated control rats. Most glandular stomach neoplasms were composed of both gastric-type and intestinal-type epithelial elements. Only 3 cases of adenocarcinomas were composed solely of intestinal-type cells. These findings suggest that intestinal metaplasia may not necessarily be a preneoplastic stage.

Topics: Animals; Gastric Mucosa; Hyperplasia; Male; Metaplasia; Methylnitronitrosoguanidine; Precancerous Conditions; Rats; Rats, Inbred F344; Stomach Neoplasms

Topics: Adenocarcinoma, Mucinous; Animals; Disease Models, Animal; Dogs; Female; Gastric Mucosa; Male; Metaplasia; Methylnitronitrosoguanidine; Stomach Neoplasms

The influence of x-radiation and N-methyl-N'-nitro-N-nitrosoguanidine [(MNNG) CAS: 70-25-7] on intestinal metaplasia and gastric tumorigenesis was examined in 5-week-old male Crj:CD(SD) rats. The animals were treated either with two 10-Gy fractions of x-rays separated by 3 days for a total of 20 Gy to the gastric region and/or with MNNG orally for 4 months. Simultaneous treatment with x-rays and MNNG (group II) and MNNG only (group IV) induced gastric tumors in the majority of the animals. Sequential treatment with x-radiation and MNNG, either x-ray 2 months prior to MNNG (group I) or MNNG 2 months prior to x-ray (group III), resulted in a lower incidence of gastric tumors as compared with the incidence after treatment with MNNG alone. The frequencies of intestinal metaplasia in the x-irradiated groups (groups I and V) were significantly higher than those in group II, III, or IV. The incidence of intestinal metaplasia and of gastric tumor was inversely proportional. These results indicate that intestinal metaplasia does not play a role in the induction of gastric tumors by MNNG.

Topics: Animals; Cocarcinogenesis; Gastric Mucosa; Male; Metaplasia; Methylnitronitrosoguanidine; Precancerous Conditions; Rats; Rats, Inbred Strains; Regression Analysis; Stomach Neoplasms

Syrian golden hamster pancreatic organ explants were treated with either methylnitrosourea (MNU) or N-methyl-N-nitroso-N'-nitroguanidine (MNNG). In control explants treated with only dimethylsulfoxide, there was evidence of autophagy and crinophagy in acinar cells. Carcinogen-exposed explants showed increased numbers of autophagic and crinophagic vacuoles. In long-term cultured explants there was an increase in the number of ducts over zero time control tissues. Eosinophilic cells similar to hepatocyte-like cells were seen in 90% of the carcinogen-treated explant experiments and in 45% of the controls. Nitrosamine exposure did not induce an increase in the overall amount of necrosis measured morphometrically. Nitrosamine exposure in vitro appears to lead to a sequence of events that follow carcinogen metabolism by the acinar cells. The changes that follow include altered cell morphology and toxic cell injury evidenced by autophagic and crinophagic processes, regeneration of ductal appearing cells, the appearance of hepatocyte-like cells and an overall increase in the amount of ductal metaplasia. Within some of these ductal foci, several ductules show atypical features.

Topics: Animals; Cell Transformation, Neoplastic; Cricetinae; Mesocricetus; Metaplasia; Methylnitronitrosoguanidine; Methylnitrosourea; Nitrosourea Compounds; Organ Culture Techniques; Pancreas; Pancreatic Neoplasms; Phenotype

On the basis of paradoxical concanavalin A (Con A) staining, the tendency of tumor cells of gastric phenotype to shift to intestinal phenotype and the stability of the latter phenotype in stomach tumors of different sizes were examined quantitatively with an image processor. Phenotypic expression of tumors of the small intestine was also studied. One hundred male Wistar rats were given N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) at 50 micrograms/ml in their drinking water for 20 weeks (group 1). Twenty male F344 rats were given methylnitrosourea (MNU) at a dose of 50 mg/kg ip twice a week for 2 weeks (group 2). Rats in group 1 were killed in week 50 of the experiment and rats in group 2 were killed in week 25. In group 1, the percentage areas of intestinal-type cells in small, medium and large adenocarcinoma of the stomach were 0.5, 2.7 and 6.6%, the differences between these values being significant (P less than 0.05-0.01). Intestinal phenotypic expression of tumor cells of the stomach is stable and the proportion of intestinal-type cells in adenocarcinomas of the stomach is higher in the larger tumors. Adenomatous hyperplasias and adenocarcinomas of the small intestine in groups 1 and 2 were all composed entirely of cells of the intestinal type. These results suggested that intestinal-type cells in adenocarcinoma of the stomach did not originate from intestinal metaplasias but from gastric-type cells in stomach adenocarcinomas.

Topics: Adenocarcinoma; Animals; Gastric Mucosa; Hyperplasia; Intestinal Neoplasms; Intestines; Male; Metaplasia; Methylnitronitrosoguanidine; Methylnitrosourea; Nitrosourea Compounds; Phenotype; Rats; Rats, Inbred Strains; Stomach Neoplasms

Promoting activities of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), and NaCl and of combinations of these antioxidants with NaCl on gastric carcinogenesis initiated by N-methyl-N'-nitro-N-nitrosoguanidine [(MNNG) (CAS: 70-25-7; 1-methyl-3-nitro-1-nitrosoguanidine] were investigated in male inbred F344 rats. Animals, 6-week old, were given an intragastric administration of MNNG at 150 mg/kg body weight by gastric tube and 1 week later were placed on a diet containing BHA (0.5%), BHT (1.0%), NaCl (5.0%), BHA (0.5%) plus NaCl (5%), or BHT (1.0%) plus NaCl (5.0%) for 51 weeks. Control rats received no further treatment after MNNG administration. A single intragastric application of MNNG to rats induced multiple epithelial tumors of the forestomach and a few epithelial tumors of the glandular stomach after 52 weeks. Squamous cell carcinomas of the forestomach were seen in 2 of 18 effective rats (11.1%) in the control groups, and the incidences in the groups receiving the subsequent treatment were 45.0% with BHA, 15.8% with BHT, 30% with NaCl, 70% with BHA plus NaCl, and 52.9% with BHT plus NaCl. Differences in the incidences of squamous cell carcinoma between the controls and groups given BHA, BHA plus NaCl, and BHT plus NaCl were statistically significant. NaCl given alone after MNNG administration also significantly increased the incidence of papillomas in the forestomach. Incidences of glandular stomach tumors, adenomas and carcinomas were not affected by any of the subsequent treatments. No tumors of the stomach developed in the groups given BHA, BHT, and NaCl without MNNG pretreatment. Thus the present experiment revealed that BHA and NaCl but not BHT exert promoting activity on MNNG-induced forestomach carcinogenesis in rats and that, when BHA and BHT were given with NaCl, promotion was more marked, suggesting a synergistic effect on tumor promotion.

Topics: Animals; Anisoles; Body Weight; Butylated Hydroxyanisole; Butylated Hydroxytoluene; Male; Metaplasia; Methylnitronitrosoguanidine; Rats; Rats, Inbred F344; Sodium Chloride; Stomach; Stomach Neoplasms

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

Topics: Adenocarcinoma; Animals; Intestines; Isoenzymes; Male; Metaplasia; Methylnitronitrosoguanidine; Models, Biological; Pepsinogens; Pylorus; Rats; Rats, Inbred Strains; Stomach Neoplasms

Topics: Adenocarcinoma, Papillary; Animals; Carcinoma, Intraductal, Noninfiltrating; Cricetinae; Gallbladder Neoplasms; Intestines; Male; Mesocricetus; Metaplasia; Methylnitronitrosoguanidine; Neoplasms, Experimental

To elucidate the developmental process of the intestinal metaplasia of the stomach, PNNG was orally administered to dogs and the sequential endoscopic examination was performed by using the methylene blue staining method. In the early period of the drug administration dogs showed the findings of erosive gastritis at the antral portion. In the 42nd experimental week, a clearly stained lesion was observed at the gastric angle. The histological findings of the biopsy specimens from the stained lesion showed the elongation of the foveolar epithelium and goblet cell-like mucous cells. Apparently stained lesion was observed at the antral portion in the 128th week. The close-up endoscopic appearance was very similar to that of stained intestinal metaplasia seen in the human stomach. The endoscopic methylene blue staining method as performed in the experimental dogs could provide useful results in the observation of minute lesions especially intestinal metaplasia in human stomach. This experiment, and further studies, may help to elucidate the pathogenesis of the gastric carcinoma in humans.

Topics: Animals; Carcinogens; Dogs; Endoscopy; Gastric Mucosa; Male; Metaplasia; Methylene Blue; Methylnitronitrosoguanidine; Staining and Labeling; Stomach; Stomach Diseases

CD/CRJ rats were subjected to localized X-irradiation of the stomach and given N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in the drinking water. Rats given MNNG alone and non-treated rats were used as controls. Upon sacrifice at 15 months after the initial MNNG administration, intestinal metaplasia was observed; the histology was of complete type and the incidence was 100% in rats treated with X-rays and MNNG, whereas in rats treated with MNNG alone the intestinal metaplasia was of incomplete type and its incidence was 80%. However, the incidence of gastric cancer in rats treated with MNNG alone was 25%.

Topics: Adenocarcinoma; Administration, Oral; Animals; Metaplasia; Methylnitronitrosoguanidine; Neoplasms, Radiation-Induced; Rats; Stomach; Stomach Neoplasms; Thymidine

Intestinal metaplasia and carcinoma of the stomach were produced in Wistar strain rats by oral administration of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Alkaline phosphatase (AlP) isoenzymes of tissues from intestinal metaplastic mucosa and carcinoma of the stomach were studied. The ALP activity from all carcinoma tissues was several times higher than that of the surrounding gastric mucosa, and two of the tissues has over 100 times higher activity. An AlP zymogram from carcinoma tissues of the stomach showed one broad active band on 5% polyacrylamide-gel disc electrophoresis. This band was separated into 2 sharp active bands after treatment with neuraminidase: A-band (Rf = 19%) and B-band (Rf = 32%). From the enzymological and immunological study, B-band had properties similar to those of AlP isoenzyme from the intestinal metaplastic mucosa of the stomach, as well as intestinal AlP isoenzyme, while A-band had different ones. Anm AlP zymogram from glandular mucosa of the stomach showed 2 types of active band (A and B band) after treatment with neuraminidase, which were identical with those appearing in carcinoma tissues. The properties of AlP isoenzyme from the intestinal metaplastic mucosa of rat stomach induced by MNNG were similar to those of humans, and the carcinoma tissues of rat stomach were suspected of producing high amounts of AlP, especially the intestinal-type AlP isoenzyme.

Topics: Alkaline Phosphatase; Animals; Female; Gastric Mucosa; Intestines; Isoenzymes; Metaplasia; Methylnitronitrosoguanidine; Neoplasms, Experimental; Rats; Stomach Neoplasms

Topics: Adenocarcinoma; Animals; Intestines; Male; Metaplasia; Methylnitronitrosoguanidine; Neoplasms, Experimental; Precancerous Conditions; Rats; Stomach Neoplasms

PNNG, the propyl derivative of MNNG, was administered to Wistar rats by a concentration of 59.5 micrograms/ml in the drinking water for 4, 8, and 12 months and the rats were killed in the 15th month. Intestinal metaplasia was induced in the glandular stomachs of 25%, 75%, and 83% of the rats treated with PNNG for 4, 8, and 12 months, respectively. Metaplastic glands were found in the pyloric region, especially near the pyloric ring. These glands contained goblet cells and columnar cells with striated borders. No tumors were found in the stomach of rats after 4-months treatment, but adenomas were found after 8-months treatment, and both adenomas and adenocarcinomas after 12-months treatment.

Topics: Adenocarcinoma; Animals; Intestinal Mucosa; Male; Metaplasia; Methylnitronitrosoguanidine; Rats; Stomach Neoplasms

Topics: Animals; Male; Metaplasia; Methylnitronitrosoguanidine; Neoplasms, Experimental; Nitrosoguanidines; Rats; Stomach; Stomach Neoplasms

Topics: Alkaline Phosphatase; Animals; Electrophoresis, Polyacrylamide Gel; Female; Gastric Mucosa; Isoenzymes; Male; Metaplasia; Methylnitronitrosoguanidine; Neoplasms, Experimental; Rats; Stomach Neoplasms

N-Methyl-N'-nitro-N-nitrosoguanidine (MNNG) was administered orally to male Wistar rats at a concentration of 83 microgram/ml in the drinking water for 2, 4, 5, and 7 months; the rats were killed at about month 15. Intestinal metaplasia was found in the stomachs of 80-100% of the rats treated with MNNG for 4 or more months, of 37.5% treated with MNNG for 2 months, and of 10% of the controls. Metaplastic glands, composed of goblet cells and columnar cells with striated borders, were found in the pyloric region. Paneth's cells were found at the bottom of metaplastic glands in a rat treated with MNNG for 4 months. The incidence of well-differentiated adenocarcinomas of the stomach was 63-90% in rats treated with MNNG for 4 or more months and 25% in those treated with MNNG for 2 months.

Topics: Adenocarcinoma; Animals; Intestines; Male; Metaplasia; Methylnitronitrosoguanidine; Neoplasms, Experimental; Precancerous Conditions; Pylorus; Rats; Stomach Neoplasms; Time Factors