methylnitronitrosoguanidine and Esophageal-Neoplasms

The present survey deals with requirements the experimental-oncological models used in morphogenetic investigations should meet. Data on ways of inducing tumours of various organs the most suited for such investigations are presented. The available at present literature comprises data on different variants of morphogenesis of tumours; in a number of cases malignant neoplasms can develop against the background of an unchanged structure without previous alterations. Because of a contradictory character of the literature reports on morphogenesis of tumours, further investigations into the morphodynamics of the process of cancerogenesis are needed; at present, this may be successfully implemented if adequate models of the majority of tumour diseases in man are available. These studies are of importance for better understanding of pathogenesis or tumour growth and for ascertaining the concept of precancer changes.

Topics: 2-Acetylaminofluorene; 9,10-Dimethyl-1,2-benzanthracene; Aflatoxins; Animals; Azoxymethane; Benzopyrenes; Brain Neoplasms; Carcinogens; Cricetinae; Dimethylhydrazines; Dogs; Esophageal Neoplasms; Ethionine; Ethylnitrosourea; Female; Hematopoietic System; Intestinal Neoplasms; Liver Neoplasms; Lung Neoplasms; Male; Mammary Neoplasms, Experimental; Methylnitronitrosoguanidine; Methylnitrosourea; Mice; Neoplasms, Experimental; Nitrosamines; Nitroso Compounds; Nitrosoguanidines; o-Aminoazotoluene; p-Dimethylaminoazobenzene; Precancerous Conditions; Rats; Skin Neoplasms; Stomach Neoplasms; Urinary Bladder Neoplasms

Studies have shown that environmental carcinogens exerted an important function in the high incidence of esophageal cancer (EC). Nitrosamines have been identified as important environmental carcinogens for EC. This study aimed to investigate the metabolic disturbances and new key toxicological markers in the malignant transformation process of normal esophageal epithelial cells (Het-1A) induced by MNNG (N-methyl-N'-nitro-N-nitrosoguanidine). Untargeted metabolomic and lipidomic profiling analysis by using ultra-high-performance liquid chromatography coupled with mass spectrometry (UHPLC-MS) were applied to explore the metabolic network alterations of Het-1A cells. The metabolomic results showed that significant alterations were observed in metabolic signatures between different generations (P5, P15, P25, P35) and the control cell group (P0). A total of 48 differential endogenous metabolites were screened and identified, mainly containing fatty acids, amino acids, and nucleotides. The differential metabolites were predominantly linked to the pathway of biosynthesis of unsaturated fatty acids metabolism. The cell lipidomic profiling revealed that the most differential lipids contained fatty acids (FAs), phosphatidylcholines (PC), phosphatidylethanolamines (PE), and phosphatidylserines (PS). The enrichment of the lipidomic pathway also confirmed that the lipid metabolism of biosynthesis of unsaturated fatty acids was the significant variation during the cell malignant transformation. Furthermore, we detected the expression of the upstream regulatory enzymes related to the unsaturated fatty acids to explore the regulation mechanism. The expression of stearoyl-CoA desaturase (SCD), ELOVL fatty acid elongase 1 (ELOVL1) promoted, and fatty acid desaturase 1 (FADS1) inhibited the key fatty acids of unsaturated fatty acids metabolism compared to the control cell group. Overall, our results revealed that lipid fatty acid metabolism was involved in the malignant transformation of Het-1A cells induced by MNNG and deepened the awareness of the carcinogenic mechanism of environmental exposure pollutants.

Topics: Carcinogens, Environmental; Cell Transformation, Neoplastic; Esophageal Neoplasms; Fatty Acids; Fatty Acids, Unsaturated; Humans; Metabolomics; Methylnitronitrosoguanidine

We examined the role of DNA methyltransferase 1 (DNMT1) in

Topics: Animals; Carcinogens; Cell Line; Cell Transformation, Neoplastic; DNA (Cytosine-5-)-Methyltransferase 1; Epithelial Cells; Esophageal Neoplasms; Esophagus; Female; Humans; Methylnitronitrosoguanidine; Mice, Inbred BALB C; Mice, Nude

In the current study, we examined the protective effect of hydroferrate fluid MRN-100 against the carcinogen methylnitronitrosoguanidine (MNNG)-induced gastric and esophageal cancer in rats. MRN-100 is an iron-based compound composed of bivalent and trivalent ferrates. At 33 weeks post treatment with MNNG, rats were killed and examined for the histopathology of esophagus and stomach; liver, spleen, and total body weight; and antioxidant levels in the blood and stomach tissues. Results showed that 17/20 (85%) gastroesophageal tissues from carcinogen MNNG-treated rats developed dysplasia and cancer, as compared to 8/20 (40%) rats treated with MNNG plus MRN-100. In addition, MRN-100 exerted an antioxidant effect in both the blood and stomach tissues by increasing levels of GSH, antioxidant enzymes SOD, CAT, and GPx, and total antioxidant capacity (TAC) level. This was accompanied by a reduction in the total free-radical and malondialdehyde levels. Furthermore, MRN-100 protected against body and organ weight loss. Thus, MRN-100 exhibited significant cancer chemopreventive activity by protecting tissues against oxidative damage in rats, which may suggest its effectiveness as an adjuvant for the treatment of gastric/esophageal carcinoma.

Topics: Animals; Esophageal Neoplasms; Free Radicals; Iron; Methylnitronitrosoguanidine; Organ Size; Oxidation-Reduction; Oxidative Stress; Protective Agents; Rats, Wistar; Stomach Neoplasms

The effect of ethanol (EtOH) on esophageal cell proliferation and the development of esophageal cancers induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in shrews were investigated. Sequential histological examination was done, and cell proliferation was assessed by BrdU labeling. At 5 weeks of age, animals were given tap water, 2% EtOH, 50 ppm MNNG, or 50 ppm MNNG plus 2%, 5% or 10% EtOH in the drinking water. Administration of 10% and 5% EtOH simultaneously with MNNG caused death in 40% (10/25) within 4 days and in 20% (6/30) within 7 days respectively, whereas other treatment were well tolerated with no sudden deaths. Administration of 2% EtOH for 30 weeks caused a 2-fold increase, and that of MNNG caused a 4.5-fold increase in the proliferation index of the basal cells of the esophagus compared with control shrews, and MNNG plus 2% EtOH caused a 5.5-fold increase. In MNNG-treated shrews, with or without 2% EtOH administration, sequential histological examination of esophageal tissue revealed a similar change; dysplasia appeared at 30 weeks of age, squamous cell carcinoma occurred at 35 weeks of age, and the depth of invasion extended to adventitia at 45 weeks of age. These finding indicate that treatment with 2% EtOH promoted the proliferation of esophageal basal cells but did not alter the tumor induction period and did not have tumor-promoting activity. EtOH per se was not carcinogenic; no tumors were seen in shrews not administered MNNG.

Topics: Animals; Carcinogens; Cell Division; Cocarcinogenesis; Disease Models, Animal; Esophageal Neoplasms; Esophagus; Ethanol; Female; Methylnitronitrosoguanidine; Shrews

The distribution of keratins in N-methyl-N'-nitro-N-nitrosoguanidine-induced oesophageal carcinomas in shrews was tested immunohistochemically, using a panel of seven different monoclonal antibodies. The studies were done on methacarn-fixed paraffin-embedded tissue, using the labelled streptavidin biotin method, and the relationship between morphological characteristics and keratin reaction patterns in carcinomas was analysed and compared with that in adjacent "normal" oesophageal epithelium. In the normal oesophageal epithelia, KL1, AE1, AE3, CK8.12, and CK4.62 stained suprabasal cells, 312C8-1 reacted to basal cells, and KS-1A3 labelled all epithelial cells. In squamous cell carcinomas, almost all the cancer cells were labelled strongly by 312C8-1 and weakly by KS-1A3, while a few cells in the centres of the keratinized foci were stained by KL1, AE1, AE3, CK8.12, and CK4.62. Like human oesophageal carcinomas, shrew oesophageal carcinomas maintain expression of human keratin 14, as determined by 312C8-1. The expression of human keratin 13, as determined by KS-1A3, was down-regulated.

Topics: Animals; Antibodies, Monoclonal; Carcinoma, Squamous Cell; Esophageal Neoplasms; Female; Immunohistochemistry; Keratins; Methylnitronitrosoguanidine; Shrews

The histological changes occurring in the esophageal mucosa of shrews (Suncus murinus) after N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) treatment were investigated sequentially. Six-week-old female shrews were given a 50 micrograms/ml MNNG solution as drinking water for 30 weeks, and 5 selected at random were killed at 10 and 20 weeks of age, and thereafter at 5-week intervals until 45 weeks of age. Controls were killed at 45 weeks of age. The MNNG-induced esophageal lesion in shrews began from basal cell hyperplasia at 20 weeks of age, followed by dysplasia occurring at 25 weeks of age, then progressed toward intraepithelial carcinoma to invasive squamous cell carcinoma at 35 weeks of age. Apparent sequential dysplasia-carcinoma transition was seen. Papillomas were seen from 25 weeks of age but there was no evidence of papilloma-carcinoma sequence. Five MNNG-untreated shrews killed at the end of the experiment were free of esophageal tumors.

Topics: Animals; Carcinoma in Situ; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Disease Models, Animal; Esophageal Neoplasms; Female; Immunoenzyme Techniques; Methylnitronitrosoguanidine; Papilloma; Shrews

Female 6-week-old shrews were given a solution of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) at a concentration of 50 micrograms/ml or 100 micrograms/ml in the drinking water. All 11 shrews receiving 100 micrograms/ml MNNG died 8-13 days after the beginning of carcinogen administration and 6 of the 20 shrews receiving 50 micrograms/ml MNNG died after 10-54 days. When animals were between 43 and 54 weeks of age, multiple esophageal lesions were evoked in all 14 that had received 50 micrograms/ml MNNG for 30 weeks. All shrews developed a protruding, ulcerative, or superficial type of squamous-cell carcinoma of the esophagus, accompanied by papillomas. Local invasion was seen in squamous-cell carcinoma but no distant metastasis was noted. None of the 5 control shrews developed any esophageal abnormality. No gastric adenocarcinoma, intestinal sarcoma, or other tumors were induced with MNNG. It can be concluded that MNNG has a carcinogenic effect on shrew esophageal epithelium.

Topics: Animals; Carcinoma, Squamous Cell; Disease Models, Animal; Esophageal Neoplasms; Female; Methylnitronitrosoguanidine; Papilloma; Shrews

The effects of butylated hydroxyanisole (BHA) pretreatment on subsequent low dose N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) or N,N-dibutylnitrosamine (DBN) treatment on forestomach or esophageal carcinogenesis were investigated in male F344 rats. Groups of animals were pretreated with 2% BHA or basal diet alone for 24 weeks and then were given 20 mg/kg body wt MNNG once every 2 weeks, 0.025% DBN in drinking water continuously or basal diet alone for the subsequent 24 weeks. Further groups of rats were similarly treated with BHA or basal diet alone for 24 weeks, placed on basal diet for the next 24 weeks and then treated with MNNG, DBN or basal diet alone for the subsequent 24 weeks. Animals were killed 48 or 72 weeks after the beginning of the experiment. Histopathological examination showed that the incidence of forestomach tumors was not significantly affected by the BHA pretreatment in the MNNG-treated groups. On the other hand, the incidence of esophageal squamous cell carcinomas was lower in the group pretreated with BHA followed by DBN than in that treated with basal diet followed by DBN (48 week experiment). There was no significant difference in esophageal tumor incidence in the 72 week experiment. The results thus indicate that continuous treatment with 2% BHA for 24 weeks does not exert initiating activity on forestomach and esophageal epithelia.

Topics: Animals; Body Weight; Butylated Hydroxyanisole; Carcinogens; Carcinoma, Squamous Cell; Esophageal Neoplasms; Esophagus; Hyperplasia; Male; Methylnitronitrosoguanidine; Nitrosamines; Organ Size; Papilloma; Rats; Rats, Inbred F344; Stomach; Stomach Neoplasms

In order to establish an effective method to induce selectively experimental dog esophageal carcinoma, we compared the restricted oral administration of N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) with projecting spout with the ad libitum oral administration of it. Five dogs were given a solution of ENNG at a concentration of 50mg/l with restricted oral administration with projecting spout for 52 weeks. In all of them, elevated type of esophageal lesions were endoscopically observed soon after the cessation of the ENNG administration. Histological examination revealed that besides the multiple squamous cell carcinomas of the esophagus, various degrees of dysplasias were seen. Two dogs had metastasizes to the regional lymph nodes and one dog had metastatic lesions in the lung. Gastric carcinomas were also seen in four dogs. Another five dogs were given ad libitum the same concentration of ENNG solution. Gastric carcinomas were induced in four dogs, but esophageal carcinomas were seen in small lesions in two dogs. The restricted oral administration of ENNG with projecting spout is a reliable method for the selective induction of esophageal carcinoma in dog.

Topics: Administration, Oral; Animals; Carcinogens; Carcinoma, Squamous Cell; Dogs; Esophageal Neoplasms; Female; Male; Methylnitronitrosoguanidine; Papilloma; Stomach Neoplasms

Topics: Adenocarcinoma; Animals; Carcinoma, Squamous Cell; Dogs; Dose-Response Relationship, Drug; Esophageal Neoplasms; Male; Methylnitronitrosoguanidine; Stomach Neoplasms

Topics: Adult; Cell Transformation, Neoplastic; Cells, Cultured; Esophageal Neoplasms; Fibroblasts; Humans; Methylnitronitrosoguanidine; Middle Aged

In order to obtain a reliable experimental model simulating human esophageal cancer, endoscopic and histopathological studies were undertaken in the esophageal cancer produced in the beagle dog. Thirty-seven dogs had been given a solution of N-Ethyl-N'-nitro-N-nitrosoguanidine (ENNG) at a concentration of 150 micrograms/ml for 3-9 months. Follow-up studies included serial endoscopy and biopsy, and almost all animals were eventually sacrificed for histological examination. The results were as follows: Squamous cell carcinoma was observed in 5 out of 22 female dogs, while none in male dogs at all. For the induction of squamous cell carcinoma in the esophagus, administration in the condition of 150 micrograms/ml (75mg/day) for 6-9 months was most suitable. Almost all of esophageal lesions were protruding and well-differentiated squamous cell carcinoma with invasion of the submucosa. The stages of hyperplasia, dysplasia and squamous cell carcinoma in the esophagus were chronologically followed. Carcinoma had been observed in the stomach about 4 months prior to the appearance of esophageal carcinoma. This experimental model was proved to be useful for studies on histogenesis of human esophageal cancer both light and electron microscopically.

Topics: Animals; Carcinoma, Squamous Cell; Dogs; Esophageal Neoplasms; Female; Male; Methylnitronitrosoguanidine; Microscopy, Electron; Sex Factors; Stomach Neoplasms

An endoscopical study of chronological change during the carcinogenetic process of cancer of the esophagus induced by N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) in 16 male beagle dogs was performed to clarity whether or not precancerous lesions exist in the esophagus. Redness was first observed in the mucosa in the lower and/or middle portions of the esophagus. A small nodule developed in the redness, followed by a nodule. The nodule then developed into a flat polyp which finally developed into lesions such as an elevated lesions, protrusions or elevations with depressions. Histologically, esophagitis or acanthosis in the redness and acanthosis were found in most of the small nodules. With regard to the nodules, papillomatosis was observed in half of the lesions, while either acanthosis or atypical epithelial proliferation were found in most of the flat polyps. Almost all the elevated or protruding lesions were found to be carcinoma.

Topics: Animals; Biopsy; Carcinogens; Cell Transformation, Neoplastic; Dogs; Esophageal Neoplasms; Esophagoscopy; Esophagus; Male; Methylnitronitrosoguanidine

Following chronic oral administration of hot water and N-methyl-N'-Nitro-N-nitrosoguanidine (MNNG), 4 of 30 Wistar rats developed sarcoma of the esophagus. 6 animals had tumors of the stomach, the liver and in the jejunum. One malignant tumor of the mediastinum was observed. The relatively short tumor induction time may be caused by the combined action of thermal injury and subsequently administered carcinogen. Organotropy of MNNG is changed and malignancies not only developed in the glandular stomach but also at the site of thermal injury to the esophagus.

Topics: Adenocarcinoma; Administration, Oral; Animals; Burns; Colonic Neoplasms; Esophageal Neoplasms; Female; Male; Methylnitronitrosoguanidine; Rats; Rats, Inbred Strains; Sarcoma; Stomach Neoplasms

Chronic administration of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in the drinking water causes a high incidence of carcinomas of the glandular stomach in rats. Following a single oral dose of [14C-methyl]MNNG (80 p.p.m.; 2.5 mg/kg), the extent of DNA methylation in the glandular stomach was 9 and 20 times higher than that in the forestomach and oesophagus, respectively. The autoradiographic distribution of tissue-bound radioactivity within the glandular stomach of BONN/WIST rats coincides with strain-specific tumor location at the small curvature. Following intragastric administration of [14C-methyl]MNNG, alkylation levels in forestomach and glandular stomach were twice as high as those observed after oral exposure via the drinking water, whereas duodenal DNA showed a much lower extent of methylation. The regional differences in DNA alkylation correlated with tissue-specific variations in the concentration of cellular thiols which are known to accelerate the heterolytic decomposition of MNNG. When [14C-methyl]MNNG was given intragastrically together with the thiol-blocking agent, N-ethylmaleimide, covalent binding of the 14C-radioactivity to forestomach, glandular stomach and duodenum was almost completely abolished. This indicates that the preferential induction of glandular stomach tumors by MNNG relies on high concentrations of cellular thiols in the target tissue.

Topics: Animals; Carbon Radioisotopes; Duodenal Neoplasms; Esophageal Neoplasms; Ethylmaleimide; Female; Gastrointestinal Neoplasms; Jejunal Neoplasms; Liver Neoplasms; Methylnitronitrosoguanidine; Neoplasms, Experimental; Rats; Rats, Inbred Strains; Stomach Neoplasms

Topics: Animals; Carcinogens; Carcinoma, Squamous Cell; Dogs; Epithelium; Esophageal Neoplasms; Male; Methylnitronitrosoguanidine; Neoplasms, Experimental

Topics: Animals; Carcinoma, Squamous Cell; Dogs; Esophageal Neoplasms; Male; Methylnitronitrosoguanidine

Early changes in the esophageal mucosa of dogs induced by N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) were studied. Seven one-year-old beagle dogs were given a solution of 250 micrograms ENNG/ml to drink ad libitum for 4 months. Three different kinds of lesions (10 erosive carcinomas, 4 slightly elevated microcarcinomas and 19 leukoplakias) were recognized. These three kinds of lesions were not located adjacent to one another, and were surrounded by almost normal stratified squamous epithelium. The foci of the carcinomas revealed an abrupt transition to normal epithelium and were considered to have arisen abruptly from normal esophageal epithelium. The histogenesis of squamous cell carcinomas of the esophagus in dogs may differ from that in man.

Topics: Animals; Carcinoma; Carcinoma, Squamous Cell; Dogs; Esophageal Neoplasms; Leukoplakia; Male; Methylnitronitrosoguanidine; Neoplasms, Experimental

Neoplastic transformation of primary fibroblast culture derived from esophagus tissue of a 52-year old male esophageal cancer patient was induced by chemical carcinogen (N-methyl-N'-nitro-N-nitrosoguanidine, MNNG) treatment. The transformed cells showed the biological and morphological properties characteristic of malignant cells, such as loss of contact inhibition, unlimited growth in vitro, aneuploidy, agglutinability by concanavalin A, formation of microvilli on the cell surface, growth on solid agar medium and tumor (fibrosarcoma) formation after heterotransplantation into immunosuppressed newborn mice.

Topics: Aneuploidy; Animals; Cell Division; Cell Transformation, Neoplastic; Cells, Cultured; Concanavalin A; Disease Susceptibility; Esophageal Neoplasms; Esophagus; Fibroblasts; Fibrosarcoma; Humans; Male; Methylnitronitrosoguanidine; Mice; Middle Aged; Neoplasm Transplantation

A recent epidemiological survey in China showed that there is a regional distribution of esophageal cancer and a correlation between mortality for this cancer and environmental factors, especially the consumption of pickled vegetables. A series of experimental studies with pickled vegetable extract were done using different in vitro biological systems. The results showed that pickled vegetable extract induced 6-thioguanine-resistant mutants in V79 cells and increased sister chromatid exchanges in the same cells and in Syrian hamster embryo cells. Pickled vegetables extract induced transformed foci in Syrian hamster embryo cells and in 3-methylcholanthrene initiated C3H/10T1/2 cells. The mutagenic, transforming and promoting activities of pickled vegetable extract seen in vitro conform with in vivo results and provide evidence for the presence of a mutagen and/or a carcinogen in pickled vegetable extract. A possible role of pickled vegetables consumption in the etiology of esophageal cancer is discussed.

Topics: Animals; Cell Transformation, Neoplastic; Cells, Cultured; China; Cricetinae; Cricetulus; Drug Resistance; Esophageal Neoplasms; Fibroblasts; Food Preservation; Food Preservatives; Male; Mesocricetus; Methylnitronitrosoguanidine; Mice; Mice, Inbred C3H; Mutagenesis; Mutagenicity Tests; Rats; Rats, Wistar; Sister Chromatid Exchange; Spices; Thioguanine; Vegetables

Three 6-month-old male beagle dogs were given a solution of 150 microng N-ethyl-N'-nitrosoguanidine (ENNG)/ml to drink ad libitum for 9 months. They all developed esophageal squamous cell carcinomas and gastric adenocarcinomas. The stomach adenocarcinomas were mostly in the antrum along the lesser curvature and were either well differentiated or poorly differentiated, with or without signet ring cells. The well-differentiated adenocarcinomas metastasized to the liver, and the poorly differentiated ones metastasized to the lymph nodes. The gastric mucosa in the antrum was atrophic, and the muscularis mucosae was fibrotic. Esophageal lesions were multicentric moderately differentiated squamous cell carcinomas, and they developed without diffuse hyperplastic changes of the epithelium. One dog with a large ulcerated carcinoma of the esophagus had metastases in the lung, liver, peritoneum, and abdominal lymph nodes. One dog also had a hemangiosarcoma with hepatic metastasis and spindle cell sarcoma in the stomach and duodenum, respectively.

Topics: Adenocarcinoma; Administration, Oral; Animals; Carcinoma, Squamous Cell; Dogs; Esophageal Neoplasms; Male; Methylnitronitrosoguanidine; Neoplasm Metastasis; Neoplasms, Experimental; Neoplasms, Multiple Primary; Stomach Neoplasms

Topics: Animals; Azoxymethane; Benz(a)Anthracenes; Colonic Neoplasms; Cricetinae; Dogs; Duodenal Neoplasms; Esophageal Neoplasms; Gastrointestinal Neoplasms; Guinea Pigs; Methylnitronitrosoguanidine; Mice; Neoplasms, Experimental; Nitrites; Nitrosamines; Nitrosoguanidines; Pancreatic Neoplasms; Rabbits; Rats; Stomach Neoplasms