methylnitronitrosoguanidine and Hyperplasia

Relatively short-term treatment (8 weeks) of rats with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in the drinking water (100 mg/l) was shown to adequately initiate gastric carcinogenesis when 10% NaCl was simultaneously administered in the diet. Utilizing this MNNG plus high salt diet as the initiation stage of a two-step protocol, it was also established that subsequent dietary administration of NaCl (10% of the diet) for 32 weeks tended to enhance tumor development in the glandular stomach. Similar tumor promoting activity was demonstrated for other mucosal damaging agents, such as potassium metabisulfite and formaldehyde. Biological changes of the gastric mucosa were examined after chronic administration or a single oral intubation of NaCl. Morphological lesions observed included diffuse mild erosions, atrophy of the glands, and hyperplasia of the foveolar epithelium when given 10% NaCl diet chronically. After a single oral intubation of NaCl, increased tritiated thymidine labeling index and ornithine decarboxylase (ODC) activity were observed in both pyloric and fundic mucosa. No remarkable effects of NaCl were observed on the forestomach or duodenal mucosa. These results suggest that NaCl exerts an enhancing effect at both initiation and promotion steps within the two stage model system of the gastric carcinogenesis, and that these effects of NaCl are possibly related to its mucosal damaging activity.

Topics: Animals; DNA; Gastric Mucosa; Histocytochemistry; Hyperplasia; Male; Methylnitronitrosoguanidine; Microscopy, Electron; Ornithine Decarboxylase; Rats; Sodium Chloride; Stomach Neoplasms

The early sequential development of gastric cancer was studied with experimental animals and examined with respect to what conclusions can be drawn for understanding carcinogenesis in man. After limited oral administration of N-methyl-N'nitro-N-nitrosoguanidine to 174 rats carcinomas developed in most cases directly from the otherwise unchanged mucosa through various successive stages of transformation, without passing through a benign-appearing proliferative or neoplastic epithelial lesion. Focal dysplasia grade I was the first recognizable change observed by light microscopy, followed by dysplasia grade II, and subsequently dysplasia grade III. In spite of very similar morphological characteristics, the experimentally induced dysplasias cannot be simply equated in their etiology and biological behavior with the dysplasias of the human stomach. Dysplasias of grade I and II commonly found in man are usually associated with a chronic gastritis; they are located in the upper third of the mucosa and are for the most part reversible. The experimental dysplasias occuring in the proliferative zone of an otherwise undisturbed mucosa must be considered potentially premalignant, as they are irreversible and develop progressively. This finding points out that in man dysplasias grade III within the regenerative zone of non-inflammatory mucosa should be considered particularly as possible precursors of gastric carcinomas.

Topics: Adenoma; Animals; Female; Gastric Mucosa; Hyperplasia; Methylnitronitrosoguanidine; Neoplasms, Experimental; Precancerous Conditions; Rats; Stomach Neoplasms; Time Factors

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

Topics: Adenocarcinoma; Animals; Carcinogenesis; Cell Proliferation; Gastric Mucosa; Hyperplasia; Leptin; Male; Methylnitronitrosoguanidine; Rats; Rats, Sprague-Dawley; Stomach; Stomach Neoplasms

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

In recent years, Chinese medicine has played an important role in the prognosis of gastric cancer. Precancerous lesions of gastric carcinoma (PLGC) is a class of gastric cancer which is closely related to the gastric mucosal pathology changes in the role of carcinogenic incentives, and plays key role in the progression of normal gastric mucosal cells into gastric cancerous cells. In current experiment, we explore the relationship between Chinese traditional medicine (Xiao Tan He Wei Decoction) and gastric cancer in the PLGC rat animal models and epithelial-mesenchymal transitioned GES-1 cells which were induced useing 1- Methyl-3-nitro-1-nitrosoguanidine (MNNG). PLGC rat model showed significant deterioration in the gastric mucosa with terrible growth rate in body weight and more atypical hyperplasia in gastric mucosa. MC cells, MNNG induced GES-1 cells which epithelial- mesenchymal-transition (EMT)-related proteins have a great change compare with normal GES-1 cells. The cells had characteristics of malignant cells including proliferation, invasion and metastasis ability. Our research founds that Xiao Tan He Wei Decoction could inhibit cell proliferation and increased apoptosis by increase the level of pro-apoptotic proteins like Bax and caspase-3 and decreased the level of anti-apoptotic protein Bcl-2, block the cells in G0/G1 phase simultaneously. Furthermore, Xiao Tan He Wei Decoction could inhibit nuclear factor kappa-light-chain-enhancer (NF-kB) activity and inhibit its transfer from the cytoplasm to the nucleus. However, when we incubated with NF-κB activator PMA, the effect of Xiao Tan He Wei Decoction was reversed. These results suggested that Xiao Tan He Wei Decoction could be used as a method for the treatment of gastric precancerous lesions, and possibly provide a theoretical basis for the clinical treatment of gastric cancer and gastric precancerous lesions.

Topics: Animals; Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Disease Models, Animal; Drugs, Chinese Herbal; Epithelial-Mesenchymal Transition; Humans; Hyperplasia; Methylnitronitrosoguanidine; NF-kappa B; Precancerous Conditions; Rats, Wistar; Stomach Neoplasms; Tetradecanoylphorbol Acetate

We investigated the delayed effects of neonatal exposure to 17α-ethynylestradiol (EE) on the female reproductive tract using Wistar Hannover GALAS rats. Female pups received single injections of EE (0, 0.02, 0.2, 2, 20, or 200 μg/kg) within 24h after birth and estrous cyclicity was observed until 10 months of age. All animals were treated at 9 weeks of age with the uterine carcinogen, N-ethyl-N'-nitro-N-nitrosoguanidine. Although the vaginal opening was not affected, abnormal cycles were significantly increased from 0.2 μg/kg. Persistent estrus was prominent and the incidence increased age- and dose-dependently. Severity of atypical hyperplasia of the uterus tended to increase from 2 μg/kg. In these groups, serum progesterone level was lowered relative to estradiol level. In conclusion, estrous cyclicity was a sensitive indicator reflecting delayed effects on the female reproductive tract. Early onset of anovulation leading to prolonged estrogen exposure might be a risk factor for uterine carcinogenesis.

Topics: Adenocarcinoma; Animals; Anovulation; Carcinogens; Estradiol; Estrogens; Estrous Cycle; Ethinyl Estradiol; Female; Hyperplasia; Mammary Glands, Animal; Methylnitronitrosoguanidine; Organ Size; Pregnancy; Prenatal Exposure Delayed Effects; Progesterone; Rats; Rats, Wistar; Uterine Neoplasms; Uterus; Vagina

Combined treatment with several phenolic antioxidants and sodium nitrite (NaNO(2)) has already shown to enhance rat forestomach carcinogenesis. In the present experiment, effects of green tea catechins (GTC) alone or in combination with NaNO(2) on gastric carcinogenesis were investigated in a rat two-stage carcinogenesis model. Groups of eight, 6-week-old F344 male rats were given 0.01%N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in their drinking water and 5% NaCl in the diet for 10 weeks for glandular stomach initiation and a single intragastric administration of 100 mg/kg/bodyweight of MNNG at week 9 for forestomach initiation. From week 11, they received either drinking water containing 0.2% NaNO(2) and a diet supplemented with 1% GTC in combination, each individual chemical alone or a basal diet until the end of week 42. In the forestomach, incidences and multiplicities of neoplastic lesions were clearly increased by the combined treatment, in spite of GTC alone suppressing the occurrence of papillomas. In a short-term experiment with similar protocol without MNNG pretreatment, a significant increase of 8-hydroxydeoxyguanosine (8-OHdG) levels in forestomach DNA occurred 24 h after the combined treatment, concomitant with erosion and inflammatory cell infiltration. In an in vitro study, electron spin resonance demonstrated hydroxyl radical formation after incubation of epigallocatechin gallate or epicatechin gallate with the NO generator, NOC-7. Thus, GTC alone showed a weak chemopreventive effect on forestomach carcinogenesis, but in the presence of NaNO(2) it exerted a promotive effect which might involve hydroxyl-radical-associated oxidative DNA damage. However, no influence was exerted in the glandular stomach.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Catechin; Deoxyguanosine; Disease Models, Animal; Epithelial Cells; Hyperplasia; Male; Methylnitronitrosoguanidine; Rats; Rats, Inbred F344; Stomach Neoplasms; Tea

The tumor suppressor BRCA1 contains multiple functional domains that interact with many proteins. After DNA damage, BRCA1 is phosphorylated by CHK2 at serine 988, followed by a change in its intracellular location. To study the functions of CHK2-dependent phosphorylation of BRCA1, we generated a mouse model carrying the mutation S971A (S971 in mouse Brca1 corresponds to S988 in human BRCA1) by gene targeting. Brca1(S971A/S971A) mice were born at the expected ratio without a developmental defect, unlike previously reported Brca1 mutant mice. However, Brca1(S971A/S971A) mice suffered a moderately increased risk of spontaneous tumor formation, with a majority of females developing uterus hyperplasia and ovarian abnormalities by 2 years of age. After treatment with DNA-damaging agents, Brca1(S971A/S971A) mice exhibited several abnormalities, including increased body weight, abnormal hair growth pattern, lymphoma, mammary tumors, and endometrial tumors. In addition, the onset of tumor formation became accelerated, and 80% of the mutant mice had developed tumors by 1 year of age. We demonstrated that the Brca1(S971A/S971A) cells displayed reduced ability to activate the G(2)/M cell cycle checkpoint upon gamma-irradiation and to stabilize p53 following N-methyl-N'-nitro-N-nitrosoguanidine treatment. These observations suggest that Chk2 phosphorylation of S971 is involved in Brca1 function in modulating the DNA damage response and repressing tumor formation.

Topics: Aging; Animals; BRCA1 Protein; Carcinogens; Cell Cycle; Cell Transformation, Neoplastic; Checkpoint Kinase 2; DNA Damage; Female; Gamma Rays; Hyperplasia; Mammary Glands, Animal; Methylnitronitrosoguanidine; Mice; Mutagenesis, Site-Directed; Mutation; Phenotype; Phosphorylation; Protein Serine-Threonine Kinases; Serine; Survival Rate; Uterus

The effects of sodium nitrite (NaNO2), in combination with one of three antioxidants, tert-butylhydroquinone (TBHQ), alpha-tocopherol (alpha-Toc) and propyl gallate (PG), on N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) stomach carcinogenesis were investigated in F344 rats. Groups of 15 male rats were treated with an intragastric dose of 150 mg/kg body weight of MNNG, and starting 1 week later, were treated with 0.5% TBHQ, 1% alpha-Toc, 1% PG or basal diet with or without 0.2% NaNO2 in their drinking water until they were killed at the end of week 36. Macroscopically, in MNNG-treated animals, combined administration of alpha-Toc or PG with NaNO2 significantly increased the areas and numbers of forestomach nodules as compared with the respective antioxidant alone values. Microscopically, in MNNG-treated animals, treatment with TBHQ significantly increased the incidence and multiplicity of forestomach papillomas as compared with basal diet alone value. Combined administration of alpha-Toc with NaNO2 significantly raised the multiplicity of forestomach papillomas, with a tendency to elevation in the incidence as compared with the group given alpha-Toc alone. Incidences of forestomach moderate and/or severe hyperplasias were significantly higher in the TBHQ or PG plus NaNO2 groups than in the single compound groups. In rats without MNNG treatment, combined treatment of antioxidants with NaNO2 significantly increased the incidences of mild or moderate hyperplasia. In the glandular stomach, although the incidence of atypical hyperplasia showed a non-significant tendency for decrease with TBHQ treatment, additional administration of NaNO2 caused significant increase. These results indicate that co-administration of NaNO2 with alpha-Toc, TBHQ or PG and particularly the first, promotes forestomach carcinogenesis. Concurrent alpha-Toc, TBHQ or PG treatment with NaNO2 is likely to induce forestomach tumors in the long term.

Topics: alpha-Tocopherol; Animals; Antioxidants; Body Weight; Carcinoma, Squamous Cell; Drug Combinations; Drug Interactions; Food Preservatives; Hydroquinones; Hyperplasia; Male; Methylnitronitrosoguanidine; Papilloma; Propyl Gallate; Rats; Rats, Inbred F344; Sodium Nitrite; Stomach Neoplasms

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 modifying effects of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), a mutagenic by-product in chlorinated water, on the development of glandular stomach cancers were investigated in Wistar rats. A total of 120 males, 6 weeks of age, were divided into six groups. After initiation with 100 ppm N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) solution and 5% NaCl diet for 8 weeks, 30 rats each in groups 1-3 were given MX in the drinking water at concentrations of 30, 10, or 0 ppm for the following 57 weeks. Ten animals each in groups 4-6 were administered the MX without prior carcinogen exposure. There were no statistical significant differences in final body weights between the groups. The incidences and multiplicities of adenocarcinomas in the glandular stomachs were significantly higher (P < 0.05) in the initiated 30 ppm MX group than those in the MNNG/NaCl group. The incidences of atypical hyperplasias in the glandular stomachs were also significantly increased (P < 0.05 or 0.01) by the MX treatments. With their multiplicity, the effects were clearly dose dependent. Interestingly, the 30 ppm MX alone itself induced atypical hyperplasias in the pylorus, although the incidences and severity were low. Moreover, MX showed a tendency to enhance the development of intrahepatic cholangiocellular tumors and thyroid follicular cell tumors in the MNNG-treated animals. The results of the present study thus indicate that MX exerts promoting effects when given during the postinitiation phase of two-stage glandular stomach carcinogenesis in rats.

Topics: Adenocarcinoma; Adenocarcinoma, Follicular; Adenoma, Bile Duct; Animals; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Body Weight; Carcinogens; Cholangiocarcinoma; Cocarcinogenesis; Fibrosis; Furans; Hyperplasia; Male; Methylnitronitrosoguanidine; Mutagens; Organ Size; Precancerous Conditions; Pylorus; Rats; Rats, Wistar; Stomach; Stomach Diseases; Stomach Neoplasms; Thyroid Neoplasms; Water Pollutants, Chemical

The morphology and evolution of epithelial lesions that developed at a gastrojejunal stoma due to reflux of duodenal contents were compared with MNNG-induced carcinomas in the pyloric mucosa of rats in a long term experiment. Random bred male Wistar rats were given MNNG in drinking water (100 mg/l) for 12 weeks and then one group was submitted to a gastrojejunal anastomosis at the greater curvature in the oxyntic mucosa. Untreated rats underwent either gastrojejunostomy or gastrotomy. The animals were killed at the 24th and 66th weeks of the experiment. The lesions obtained in the pyloric mucosa and in the mucosa of the gastrojejunal stoma were analyzed histologically using hematoxylin and eosin staining and immunohistochemistry for pepsinogen isoenzyme 1. Duodenal reflux induced proliferative lesions at the gastrojejunal junction that increased in incidence and size with time. Histologically they consisted of benign epithelial proliferation of gastric type. No evidence of malignant transformation within the gastric components of the proliferative lesions at the gastrojejunal stoma was observed even at the 66th week. Adenocarcinomas induced by MNNG in the pyloric mucosa increased in size during the experiment and were morphologically and histochemically distinct from the proliferative lesions at the gastrojejunal junction. In conclusion, proliferative lesions at the gastrojejunal stoma stimulated by duodenal reflux are biologically distinct from adenocarcinomas induced by MNNG in the pyloric mucosa. They do not seem to be precursor lesions of gastric carcinogenesis, as they do not undergo malignant transformation even after long-term, up to 66 weeks, follow-up.

Topics: Adenocarcinoma; Animals; Carcinogens; Cell Division; Duodenogastric Reflux; Gastric Mucosa; Hyperplasia; Male; Methylnitronitrosoguanidine; Pyloric Antrum; Rats; Rats, Wistar; Stomach Neoplasms; Surgical Stomas

The modifying effects of oltipraz on induction of glandular stomach carcinogenesis by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) were investigated in a total of 120 male 6-week-old Wistar rats, divided into six groups. Groups 1-3 (30 animals each) were given 100 p.p.m. MNNG in their drinking water for 10 weeks as an initiation treatment for gastric cancer induction and respectively fed diets supplemented with 0.04%, 0.02% and 0% oltipraz for 12 weeks, starting 1 week before and finishing 1 week after the carcinogen exposure. Groups 4-6 (10 animals each) were similarly treated without the application of MNNG. At the end of the 80th experimental week, all surviving animals were autopsied and examined histopathologically for the existence of gastric proliferative lesions. The incidence and multiplicity of adenocarcinomas were significantly (P < 0.01) lower in group 1 than in group 3. In addition, the multiplicity of atypical hyperplasias in the pyloric region was significantly (P < 0.05) decreased in group 1 as compared with the group 3 value. No gastric proliferative lesions were found in groups 4-6. In an additional short-term experiment, oltipraz significantly reduced cell proliferative activity (P < 0.01) and elevated glutathione levels (P < 0.05) in the glandular stomach mucosa of rats treated with MNNG. Thus our results clearly indicate that oltipraz can inhibit induction of proliferative glandular stomach lesions by MNNG in the rat.

Topics: Adenocarcinoma; Animals; Anticarcinogenic Agents; Hyperplasia; Male; Methylnitronitrosoguanidine; Pylorus; Pyrazines; Rats; Rats, Wistar; Stomach Neoplasms; Thiones; Thiophenes

The concept of hormesis (i.e., low-dose stimulation/high-dose inhibition) has been shown to be widely generalizable with respect to chemical class, animal model, gender, and biological end point. The public health implication of this lack of linearity in the low-dose area of the dose-response curve raises the question of whether low doses of carcinogens will reduce cancer risk. Articles relating to the process of carcinogenesis (i.e., initiation, promotion, tumor development, and progression) were obtained from a recently developed chemical hormesis database and evaluated for their evidence of hormesis. Numerous examples in well-designed studies indicate that U- or J-shaped dose-response relationships exist with respect to various biomarkers of carcinogenesis in different animal models of both sexes. Examples of such J-shaped dose-response relationships in each stage of the process of carcinogenesis were selected for detailed toxicological examination. These results have important implications for both the hazard assessment of carcinogens and cancer risk assessment procedures.

Topics: Animals; Caffeic Acids; Carcinogenicity Tests; Carcinogens; Cell Division; Dioxins; DNA Ligases; Dose-Response Relationship, Drug; Environmental Pollutants; Female; Humans; Hyperplasia; Keratinocytes; Kidney; Liver; Lung Neoplasms; Male; Mercury; Methylnitronitrosoguanidine; Neoplasms, Radiation-Induced; Phenobarbital; Polychlorinated Dibenzodioxins; Rats; Rats, Sprague-Dawley; Risk Assessment; Saccharin; Stomach; Testicular Neoplasms; Urinary Bladder; Urinary Bladder Neoplasms

The modifying effects of Chelidonium majis L. (Papaveraceae) herb extract (CH), an analgesic traditionally prescribed for gastric and duodenal ulcer patients, on gastric tumor development were studied in rats given N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Sixty-four male 6-week-old Wistar rats were used. Group 1 rats were initially given MNNG (200 mg/kg b.w.) by gavage at days 0 and 14 as well as saturated sodium chloride solution (S-NaCl, 1 ml per rat) every 3 days during weeks 0-3 (six times), and then placed on basal diet containing 0.1 or 0.2% CH for 16 weeks from week 4. Rats of Group 2 and 3 were treated with MNNG together with S-NaCl or saline (0.9% NaCl, 1 ml per rat), respectively, timed as in Group 1 but without further treatment. All surviving animals were killed at week 20 and histopathologically investigated. In the glandular stomach, the number of preneoplastic pepsinogen 1 altered pyloric glands (PAPGs) in the MNNG + S-NaCl-->CH (0.1%) group (Group 1) was significantly smaller than in the MNNG + S-NaCl group (Group 2) (P < 0.02). The incidences of forestomach neoplastic lesions (papillomas and squamous cell carcinomas) also showed a tendency to decrease with the CH treatment. The results thus indicate that CH exerts inhibitory effects on glandular stomach carcinogenesis in the rat, so that it may have potential as a chemopreventive agent for stomach cancer in man.

Topics: Animals; Anticarcinogenic Agents; Body Weight; Carcinogens; Cocarcinogenesis; Hyperplasia; Male; Methylnitronitrosoguanidine; Organ Size; Pepsinogens; Plant Extracts; Plants, Medicinal; Precancerous Conditions; Pyloric Antrum; Rats; Rats, Wistar; Saline Solution, Hypertonic; Stomach; Stomach Neoplasms

Current experimental models of pancreatic cancer either fail to reproduce the ductal phenotype or cause simultaneous cancers in other organs also. To develop an animal of pancreatic cancer that accurately mimics the human condition, we restricted carcinogenic exposure to the pancreas and specifically targeted ductal epithelial cells. Three different carcinogens were either implanted directly into the pancreas or infused into the pancreatic duct, with or without near-total pancreatectomy (as a means of inducing pancreatic ductal cell proliferation).. Groups of male Sprague-Dawley rats were exposed to varying doses of dimethylbenzanthracine (DMBA), methynitronitrosoguanidine, or ethylnitronitrosoguanidine either through direct implantation into the pancreas or infusion into the pancreatic duct. Near-total pancreatectomy was added in all groups except two DMBA implantation groups. Surviving rats were killed at 3, 6, 9, or 12 months, and the pancreata were evaluated histologically.. All three carcinogens caused pancreatic inflammation, ductal hyperplasia, atypia, and dysplasia beginning by 3 months and becoming more prominent at later time points. Only DMBA caused frequent invasive pancreatic ductal adenocarcinoma, which was first evident by 6 months. The prevalence of pancreatic cancer among DMBA-treated rats evaluated after 10 months was 39% (19 of 49). The addition of pancreatic resection did not enhance pancreatic cancer development.. Of the strategies tested, only direct implantation of DMBA into the rat pancreas frequently produces pancreatic cancer histologically similar to human ductal adenocarcinoma. The development of hyperplastic, atypical, and dysplastic changes preceding and accompanying carcinomas suggests that these lesions are preneoplastic. This model recapitulates the progression from normal to neoplastic epithelium and is likely to be useful for the study of morphologic and molecular mechanisms underlying the early stages of pancreatic carcinogenesis and for the investigation of novel diagnostic and therapeutic techniques.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinogens; Carcinoma, Ductal, Breast; Disease Models, Animal; Fibrosarcoma; Hyperplasia; Male; Methylnitronitrosoguanidine; Pancreatectomy; Pancreatic Ducts; Pancreatic Neoplasms; Rats; Rats, Sprague-Dawley; Sarcoma, Experimental

The modifying effects of 24R,25-dihydroxyvitamin D3 [24R,25(OH)2D3], a vitamin D3 derivative, on glandular stomach carcinogenesis were investigated in male Wistar rats by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and sodium chloride exposure during the postinitiation phase. A total of 130 male 6-week-old rats was divided into five groups. Groups 1-3 (consisting of 30 rats/group) were given MNNG in drinking water at a concentration of 100 ppm and were simultaneously fed a diet supplemented with 10% NaCl for 8 weeks. They were fed a diet containing either 5.0 ppm (group 1) or 2.5 ppm (group 2) 24R,25(OH)2D3 or were kept on the basal diet alone (group 3) for the following 57 weeks. Rats in groups 4 and 5 were given 24R,25(OH)2D3, as were animals in groups 1 and 3, but did not receive the MNNG + NaCl treatment. The total incidence of combined atypical hyperplasias and adenocarcinomas in the glandular stomachs was significantly lower in group 1 (24%) than in group 3 (70%; P < 0.01). The mean numbers of atypical hyperplasias or adenocarcinomas of the glandular stomachs in groups 1 (0.31) and 2 (0.66) were also significantly decreased (P < 0.01 and P < 0.05, respectively) as compared to the group 3 value (1.21). Thus, the development of cancerous and precancerous lesions in the glandular stomach was decreased by exposure to 24R,25(OH)2D3 in a dose-dependent manner. Urinary calcium levels were increased by this vitamin D3 derivative (in line with the applied dose) when assayed at 10, 30, and 62 weeks, regardless of the MNNG + NaCl treatment The present results clearly indicate that 24,25(OH)2D3 exerts chemopreventive effects, possibly by influencing calcium pharmacodynamics, when given during the postinitiation phase of glandular stomach carcinogenesis in rats.

Topics: 24,25-Dihydroxyvitamin D 3; Adenocarcinoma; Animals; Calcium; Carcinogens; Drug Screening Assays, Antitumor; Hyperplasia; Male; Methylnitronitrosoguanidine; Phosphorus; Precancerous Conditions; Rats; Rats, Wistar; Sodium Chloride; Stomach; Stomach Neoplasms

The susceptibility of pepsinogen-altered pyloric glands (PAPG) and neoplastic glandular stomach lesions induced by N-methyl-N-nitro-N-nitrosoguanidine (MNNG) and catechol or sodium cholate in Nagase analbuminemic rats (NAR) was compared to Sprague-Dawley rats (SD). Male NAR and SD rats were given a single dose of 80 mg/kg body weight of MNNG by gastric intubation and, 2 weeks later, fed basal diet containing 0.8% catechol or 0.3% sodium cholate for 18 weeks. The animals were killed at the end of week 20 or after maintenance on basal diet at week 60. The number of pepsinogen-altered pyloric glands at week 20 was significantly (P < 0.001) higher in NAR fed either catechol or sodium cholate compared with SD rats. At week 60, adenomatous hyperplasias and adenocarcinomas were observed in 7 (88%; P < 0.01) and 3 (38%; P < 0.01) of 8 NAR fed catechol and in 4 (22%) and 0 of 18 SD rats, respectively. The results show that the frequency of PAPG in NAR and SD rats is related to the susceptibility to glandular stomach carcinoma. PAPG is a useful endpoint lesion for evaluation of gastric carcinogenicity in a 20-week carcinogenicity test, and NAR are sensitive for glandular stomach carcinogenesis.

Topics: Adenocarcinoma; Animals; Carcinogens; Catechols; Cholic Acid; Cholic Acids; Gastric Mucosa; Hyperplasia; Male; Methylnitronitrosoguanidine; Pepsinogens; Pyloric Antrum; Rats; Rats, Mutant Strains; Rats, Sprague-Dawley; Serum Albumin; Species Specificity; Stomach Neoplasms

The effects of sodium arsenite (As) and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) on epithelia of human fetal trachea and bronchiolar epithelia of human fetal lung were studied by using organ-cultured explants. In epithelium of human fetal trachea, 34 microM MNNG induced hyperplasia, metaplasia, and dysplasia; 1 microM As induced hyperplasia; and 3-9 microM As induced hyperplasia and cellular atypia. In glandular epithelium of human fetal trachea, 34 microM MNNG induced hyperplasia and metaplasia; 1 microM As did not induce obvious changes; and 3-9 microM As induced hyperplasia and epidermoid metaplasia with nuclear atypia. In bronchiolar epithelium of human fetal lung, the induction of dysplasia was observed for 1 microM As. Arsenic-induced preneoplastic lesions support the conclusion of epidemiological studies that arsenic is carcinogenic to human lung.

Topics: Arsenites; Bronchi; Epithelium; Fetus; Humans; Hyperplasia; Lung; Lung Neoplasms; Methylnitronitrosoguanidine; Organ Culture Techniques; Precancerous Conditions; Sodium Compounds; Trachea; Tracheal Neoplasms

The modifying effects of caffeine ingestion on glandular stomach carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and sodium chloride (NaCl) were investigated in male Wistar rats. Animals were given a MNNG solution (100 ppm) as their drinking water and simultaneously fed a diet supplemented with 5% NaCl for 8 wk. They then received 0.25% caffeine solution (groups 1 and 3) or tap water (groups 2 and 4) as the drinking water, and were fed the NaCl diet (groups 1 and 2) or basal diet (groups 3 and 4) for the following 32 wk. Both caffeine and NaCl treatments exerted growth retardation effects, the suppression being stronger with caffeine than NaCl, and animals in group 1 (NaCl plus caffeine) showing the lowest body weight. The incidence of adenocarcinomas in the pylorus was significantly decreased in group 1 compared with the group 2 (NaCl) value (P < 0.05). The incidence of atypical hyperplasias in the fundus was also lower in group 1 than in group 2, although in both cases significantly higher (P < 0.05 and P < 0.01) than in group 4 (no treatment). These results were in good agreement with short-term assay findings whereby lipid peroxidation in the glandular stomach mucosa induced by 4% NaCl ingestion was inhibited by caffeine treatment. In group 3 (caffeine), caffeine intake by itself did not modulate glandular stomach tumour development. The results thus suggest that caffeine inhibits the gastric tumour promotion activity of NaCl in rats.

Topics: Adenocarcinoma; Animals; Biological Assay; Body Weight; Caffeine; Cell Division; Drug Interactions; Gastric Mucosa; Hyperplasia; Lipid Peroxidation; Male; Methylnitronitrosoguanidine; Precancerous Conditions; Rats; Rats, Wistar; Sodium Chloride; Stomach Neoplasms

A total of 130 female Donryu rats (10-week-old) were divided into two groups; 80 animals in the experimental group were given a single intra-uterine administration of 20 mg/kg N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) dissolved in polyethylene glycol (PEG) via the vagina without laparotomy, and 50 animals in the control group received PEG alone in the same manner. Small numbers of animals in both groups were killed at 3, 6, 9 and 12 months after ENNG treatment for sequential histological and endocrinological examination, and at 12.5 experimental months (15 months of age) all survivors were killed. At the termination, endometrial adenocarcinomas were present in 49% of the experimental group, compared to 0% in the control group. Severe endometrial hyperplasias were also found only in the experimental group and sequential histological examination showed first appearance of hyperplasia at 6 months and adenocarcinoma at 9 months. No tumors other than uterine carcinomas were induced by ENNG and the carcinogen treatment did not affect the endocrine environment of rats, persistent estrus appearing at 6 months after the start and increasing with age in both groups. The estradiol-17 beta:progesterone (E:P) ratio was also increased after 6 months, with further elevation at 12 months to about 8 times higher than the level at 6 months. These results indicate that an increased E:P ratio might act as a promoter of development of endometrial proliferative lesions initiated by ENNG in this rat strain. The study indicates that the present simple method using Donryu rats provides a good animal model for endometrial adenocarcinoma development in women.

Topics: Adenocarcinoma; Administration, Intravaginal; Animals; Carcinogens; Endometrial Neoplasms; Endometrium; Estradiol; Estrus; Female; Hyperplasia; Methylnitronitrosoguanidine; Progesterone; Rats; Rats, Inbred Strains; Time Factors

This study investigated the possible mechanism by which dichlorvos may have caused forestomach tumours in mice in a chronic corn oil gavage cancer bioassay [NTP (1989) Toxicology and carcinogenesis studies of dichlorvos in F344/N rats and B6C3F1 mice (gavage studies). National Toxicology Program Technical Report 342, NIH Publ. No 89-2598]. For this purpose, a method has been developed to assess the genotoxicity of irritant substances on mouse forestomach epithelium. Groups of five B6C3F1 mice were given a single oral dose of dichlorvos, the genotoxic forestomach carcinogen 1-methyl-3-nitro-1-nitrosoguanidine (MNNG) or the irritant, non-genotoxic forestomach carcinogen butylated hydroxyanisole (BHA). After periods of 2-48 h, three parameters were assessed: unscheduled DNA synthesis (UDS) by autoradiography of tissue sections, replicative DNA synthesis (RDS) also by autoradiography of incorporated [3H]thymidine, and histopathological changes, including hyperplasia. MNNG induced UDS but not RDS or hyperplasia in forestomach epithelium, consistent with its genotoxic mode of action. BHA and dichlorvos did not induce UDS, consistent with absence of genotoxic activity in the forestomach after in vivo exposure. In contrast, BHA and dichlorvos induced RDS and subsequent hyperplasia, which is likely to result from irritant damage. These data suggest that the chronic effects of dichlorvos on mouse forestomach epithelium in the oral gavage bioassay were mediated via enforced cell proliferation, rather than by a genotoxic mechanism.

Topics: Animals; Butylated Hydroxyanisole; Cell Division; Dichlorvos; DNA Damage; DNA Replication; Female; Hyperplasia; Male; Methylnitronitrosoguanidine; Mice; Stomach

The effects of combined treatment with NaNO2 and phenolic compounds on N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) stomach carcinogenesis were investigated in F344 rats. In the first experiment, groups of 15-20 male rats were treated with an intragastric dose of 150 mg/kg body weight of MNNG, and starting 1 wk later, were given 2.0% butylated hydroxyanisole, 0.8% catechol, 2.0% 3-methoxycatechol or basal diet either alone or in combination with 0.2% NaNO2 in the drinking water until they were killed at week 52. All three antioxidants significantly enhanced forestomach carcinogenesis without any effect of additional NaNO2 treatment. However, in the absence of MNNG pretreatment, the grade of forestomach hyperplasia in the catechol and 3-methoxycatechol groups was significantly increased by the combined treatment with NaNO2. In a second experiment, the combined effects of various phenolic compounds and NaNO2 on cell proliferation in the upper digestive tract were examined. Groups of 5 rats were given one of 24 phenolic compounds or basal diet either alone or in combination with 0.3% NaNO2 for 4 weeks and then killed. Particularly strong enhancing effects in terms of thickness of the forestomach mucosa were seen with t-butylhydroquinone (TBHQ), catechol, gallic acid, 1,2,4-benzenetriol, dl-3-(3,4-dihydroxyphenyl)-alanine and hydroquinone in combination with NaNO2. In the glandular stomach, similar enhancing effects were evident in 11 cases, and in the esophagus with phenol, TBHQ and gallic acid. These results demonstrate that NaNO2 can augment cell proliferation induced in the stomach epithelium by various phenolic compounds.

Topics: Animals; Butylated Hydroxyanisole; Carcinoma, Squamous Cell; Catechols; Cell Division; Hyperplasia; Male; Methylnitronitrosoguanidine; Phenols; Rats; Rats, Inbred F344; Sodium Nitrite; Stomach; Stomach Neoplasms

Effects of the dietary antioxidants alpha-tocopherol (alpha-Toc), t-butylhydroquinone (TBHQ), propyl gallate (PG) and butylated hydroxytoluene (BHT) were examined using a multi-organ carcinogenesis model. Groups of 20 F344 male rats were treated with a single intragastric administration of 100 mg/kg body weight N-methyl-N'-nitro-N-nitrosoguanidine, a single intragastric administration of 750 mg/kg body weight N-ethyl-N-hydroxyethylnitrosamine, two subcutaneous injections of 0.5 mg/kg body weight N-methylbenzyl-nitrosamine and four subcutaneous injections of 40 mg/kg body weight 1,2-dimethylhydrazine. At the same time the rats were given 0.1% N-dibutylnitrosamine for 4 weeks and then 0.1% 2,2'-dihydroxy-di-n-propylnitrosamine for 2 weeks in the drinking water, for a total carcinogen exposure period of 6 weeks. Starting 3 days thereafter the rats received 1% alpha-Toc, 1% TBHQ, 1% PG or 0.7% BHT in the diet, or basal diet alone. Further groups of 10-15 animals each were treated with antioxidant alone or basal diet alone as controls. Surviving animals were killed at the end of week 36. Histopathological examination showed that alpha-Toc increased the incidence of glandular stomach atypical foci but reduced the incidence and multiplicity of kidney atypical tubules. TBHQ significantly elevated the incidences of esophageal papillary or nodular (PN) hyperplasias and papillomas, as well as forestomach papillomas, but significantly decreased the multiplicity of colon adenocarcinomas. PG was only effective in reducing the multiplicity of kidney atypical tubules. BHT enhanced the development of thyroid hyperplasias, but strongly reduced the incidence and multiplicity of colon adenocarcinomas. This compound was also associated with lowered incidence and multiplicity of renal cell tumors. None of the agents studied was unequivocal in exerting either positive or negative influence.

Topics: 1,2-Dimethylhydrazine; Animals; Anticarcinogenic Agents; Antioxidants; Butylated Hydroxytoluene; Carcinogens; Colon; Colonic Neoplasms; Dimethylhydrazines; Gastrointestinal Neoplasms; Hydroquinones; Hyperplasia; Kidney; Kidney Neoplasms; Male; Methylnitronitrosoguanidine; Neoplasms, Experimental; Nitrosamines; Organ Size; Precancerous Conditions; Propyl Gallate; Rats; Rats, Inbred F344; Vitamin E

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 methylation patterns of the rat pepsinogen 1 (Pg1) gene in preneoplastic and neoplastic stomach lesions induced by genotoxic N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) or the non-genotoxic carcinogen catechol were investigated. Male WKY/Ncrj rats were given MNNG in their drinking water (50 mg/l) for 30 weeks or 0.8% catechol throughout the experiment (60 weeks). MNNG induced Pg1 altered pyloric glands (PAPG), adenomatous hyperplasias and well-differentiated adenocarcinomas. Catechol also induced PAPG and adenomatous hyperplasias although cancers did not develop. Adenomatous hyperplasias and adenocarcinomas all consisted of gastric type cells resembling surface mucous cells or pyloric gland cells with little or no Pg1 expression. In MNNG-induced stomach cancers generally lacking Pg1, altered Pg1 gene methylation was observed with both CCGG and GCGC sites being methylated more than normal pyloric mucosa. MNNG or catechol-induced adenomatous hyperplasias also demonstrated essentially the same methylation changes in the CCGG, but not in the GCGC sites. In the mucosa containing PAPG in groups treated with MNNG or catechol the methylation patterns of the Pg1 gene were quite similar to those of normal pyloric mucosa, although the CCGG sites tended to demonstrate slightly increased methylation. The results suggest that the altered methylation of the Pg1 gene observed in stomach cancers is acquired early in the carcinogenic process and progressive methylation changes occur with tumor development.

Topics: Adenocarcinoma; Animals; Catechols; DNA; Gastric Mucosa; Hyperplasia; Male; Methylation; Methylnitronitrosoguanidine; Pepsinogens; Precancerous Conditions; Rats; Rats, Inbred WKY; Stomach; Stomach Neoplasms

Short-term assays in vivo have suggested that hickory smoke condensate (HSC), a food flavouring, might have tumour-initiating and/or promoting activities in the glandular stomach of the rat. In the present study, the modifying effects of HSC on glandular stomach carcinogenesis after initiation with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and sodium chloride (MNNG salt) were investigated in male Wistar rats. Animals were given MNNG solution (100 ppm) as drinking water and simultaneously fed the diet supplemented with 5% sodium chloride for 8 wk. Matched negative controls received neither MNNG nor sodium chloride. Rats were then fed a basal diet and given HSC solution (1 or 3%) or tap water for the following 32 wk. During the experimental period, treatment with MNNG salt and administration of HSC both brought about growth retardation although the final body weight of rats was comparable between groups. Only two rats treated with MNNG salt followed by 1% HSC developed adenocarcinoma of the stomach. HSC treatment appeared to increase the number of rats with preneoplastic hyperplasias and/or adenocarcinomas in both the fundic and pyloric mucosa, although not to a statistically significant extent. HSC administration significantly increased malondialdehyde levels in the urine and gastric mucosa, the former in a dose-dependent manner. The results suggest that HSC has little, if any, promoting effect on two-stage glandular stomach carcinogenesis in rats when given during the post-initiation phase. However, the tumour co-initiating effects of HSC require further clarification.

Topics: Adenocarcinoma; Animals; Diet; Drinking; Flavoring Agents; Gastric Mucosa; Hyperplasia; Male; Malondialdehyde; Methylnitronitrosoguanidine; Precancerous Conditions; Rats; Rats, Wistar; Smoke; Sodium Chloride; Stomach Neoplasms; Weight Gain; Wood

Promotion effects of the o-dihydroxybenzene derivatives, protocatechuic acid (PCA), dopamine hydrochloride (DAH), dl-dopa and caffeic acid on forestomach and glandular stomach carcinogenesis were investigated in rats pretreated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Groups of 20 male F344 rats were given a single intragastric administration of 150 mg/kg body wt MNNG and starting 1 week later than received diet containing 1.5% PCA, 1.5% DAH, 1.5% dl-dopa or 1% caffeic acid or basal diet alone for 51 weeks and then killed. Other groups of 10-15 rats were given PCA, DAH, dl-dopa or basal diet alone without the MNNG pretreatment. On histological assessment, the incidences of forestomach papillomas and squamous cell carcinomas were significantly enhanced in the group treated with caffeic acid (95 and 100%) as compared with the control values (35 and 10%). Although the incidence was not different, the number of papillomas per rat in the group given DAH (0.79 +/- 0.79) was also significantly increased (0.35 +/- 0.49). PCA and dl-dopa treatments did not modify the development of neoplastic lesions in the forestomach epithelium to any significant extent. None of the four chemicals enhanced glandular stomach carcinogenesis. The results thus demonstrated that whereas caffeic acid and DAH respectively, exert strong and weak promotion activity for rat forestomach carcinogenesis this promotion potential is not shared by all dihydroxybenzene derivatives. An influence of substituents in the para position in addition to the o-dihydroxy moiety is indicated.

Topics: Adenocarcinoma; Animals; Body Weight; Caffeic Acids; Carcinogens; Carcinoma, Squamous Cell; Dihydroxyphenylalanine; Dopamine; Drug Synergism; Epithelium; Hydroxybenzoates; Hyperplasia; Leiomyosarcoma; Male; Methylnitronitrosoguanidine; Papilloma; Rats; Rats, Inbred F344; Stomach; Stomach Neoplasms

Hickory-smoke condensate (HSC) is a popular food flavouring in the USA. Available data have suggested that this food additive has tumour-initiating/promoting potential. Accordingly, a commercial HSC has been investigated for its capacity to promote tumours in the rat glandular stomach using pepsinogen 1 (Pg 1)-altered pyloric glands (PAPG) as the marker of preneoplastic lesions. The development of PAPG initiated by a single intragastric administration of N-methyl-N'-nitroso-N-nitrosoguanidine was significantly increased by feeding rats a diet containing 5% HSC; no effect was observed with lower doses (1.25 or 2.5%) of HSC. The results suggest that HSC has weak tumour-promoting potential in the rat glandular stomach.

Topics: Animals; Atrophy; Food Additives; Gastric Mucosa; Hyperplasia; Immunoenzyme Techniques; Male; Methylnitronitrosoguanidine; Pepsinogens; Pyloric Antrum; Rats; Rats, Inbred WKY; Smoke; Stomach Neoplasms; Wood

The mechanisms of reversibility of basal cell hyperplasia in the rat forestomach were investigated. Male F344 rats were given an initial single gastric intubation of N-methyl-N'-nitro-N-nitorosoguanidine and then received 2% butylated hydroxyanisole in the diet from the third week to the 26th week. Rats were killed at weeks 26 and 46 after return to basal diet and their forestomachs were removed. Bromouracil deoxyriboside (BUdR) was administered as a single i.p. injection 1 h before death or by osmotic minipump (120 micrograms/h) continuously for 7 days before death. Additional animals were maintained for 2 or 4 weeks after removal of osmotic minipumps to allow assessment of the fate of proliferating populations. In each case BUdR-labeled cells were demonstrated by immunohistochemistry by immunohistochemistry. At week 26, hyperplastic changes were more pronounced than at week 46. Squamous cells above basal cell hyperplasias were strongly labeled even 4 weeks after cessation of continuous BUdR Three-dimensional reconstruction of persisting basal cell hyperplasias showed almost all basal cells limited to a thin sheet in direct contact with the squamous cell layer, occasional separate islands demonstrating differentiation to squamous cells and formation of epidermal cysts. The results thus showed that the mechanism of reversibility of basal cell hyperplasia involves differentiation of basal cells to squamous cells.

Topics: Animals; Bromodeoxyuridine; Butylated Hydroxyanisole; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Cell Differentiation; Cell Transformation, Neoplastic; Gastric Mucosa; Hyperplasia; Image Processing, Computer-Assisted; Male; Methylnitronitrosoguanidine; Rats; Rats, Inbred F344; Stomach; Stomach Neoplasms

The effects of vaso-active intestinal peptide (VIP) on gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) were investigated in Wistar rats given VIP every other day for 27 weeks after oral administration of MNNG for 25 weeks. In week 52, administration of VIP caused a significant increase in the incidence of gastric cancers, but did not influence their histological appearance. VIP significantly increased the labeling indices of the antral mucosa. Our findings indicate that VIP enhances gastric carcinogenesis, and that this effect may be related to its effect in increasing cell proliferation of the antral epithelial cells.

Topics: Animals; Drug Synergism; Gastric Juice; Gastrins; Hyperplasia; Male; Methylnitronitrosoguanidine; Rats; Rats, Inbred Strains; Stomach; Stomach Neoplasms; Vasoactive Intestinal Peptide

The effects of calcium chloride on glandular stomach carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and sodium chloride were investigated in male outbred Wistar rats. Animals were given MNNG solution (100 p.p.m.) as drinking water and simultaneously fed a diet supplemented with 5% sodium chloride for 8 weeks. Matched negative controls received neither MNNG nor sodium chloride. Rats were then fed basal diet and given calcium chloride solution (1 or 0.2%) or tap water for the following 52 weeks. The incidences and multiplicities of preneoplastic hyperplasias in the glandular stomachs of rats given MNNG/sodium chloride followed by 1 and 0.2% calcium chloride were significantly lower than those in rats given MNNG/sodium chloride alone. The inhibitory effects of calcium were exerted in a dose-dependent manner. Calcium treatment also showed a tendency to inhibit the development of gastric adenocarcinomas although this was not statistically significant. Rats without carcinogen treatment had neither carcinomas nor preneoplastic hyperplasias in the glandular stomach. Calcium intake also significantly reduced the levels of malondialdehyde, a measure of lipid peroxidation, in the gastric mucosa and urine, the former in a dose-dependent manner. Thus, calcium chloride exerted inhibitory effects when given during the post-initiation phase of two-stage glandular stomach carcinogenesis in rats.

Topics: Animals; Antineoplastic Agents; Calcium Chloride; Carcinogens; Gastric Mucosa; Hyperplasia; Male; Methylnitronitrosoguanidine; Precancerous Conditions; Rats; Rats, Inbred Strains; Sodium Chloride; Stomach Neoplasms

Cell kinetics of reversible and persistent forestomach lesions induced by the genotoxic agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and/or the nongenotoxic antioxidant butylated hydroxyanisole (BHA) was investigated. A total of 184 male F344 rats were divided into four groups: Group 1 given an initial single gastric intubation of MNNG received 2% BHA diet from the third wk to the 26th wk and then basal diet; Group 2 receiving 2% BHA without MNNG initiation; Group 3 given MNNG alone; and Group 4 serving as a nontreated control. Rats were sequentially sacrificed at 6, 16, 26, 30, and 46 wk. Bromodeoxyuridine was administered either as a single i.p. injection (100 mg/kg of body weight) 1 h before killing or continuously via an osmotic minipump (120 micrograms/h) for 1, 3, or 7 days prior to sacrifice, in each case labeled cells being detected by immunohistochemistry. Squamous cell hyperplasia (SCH) and basal cell hyperplasia (BCH), each characterized by different phenotypic keratin expression, were induced in Groups 1 to 3. After withdrawal of BHA, rapid regression of SCH and extremely slow regression of BCH were observed. Papillomas and squamous cell carcinomas developed irreversibly in Group 1 and 3, BHA significantly (P less than 0.01) enhancing the incidence of SCC in Group 1. Flash and continuous bromodeoxyuridine labeling revealed SCH to consist of cells of high mitotic activity and short life span, whereas BCH consisted of cells with low mitotic activity and long life span. In addition, highly labeled areas were observed in SCH after cessation of BHA feeding in Group 1 without regression, and similar lesions were also evident in Group 3. The results suggest that rapid regression of SCH and slow regression of BCH reflect different cell kinetic patterns and that highly labeled areas after release from stimulating agents might be preneoplastic changes related to cancer development.

Topics: Animals; Butylated Hydroxyanisole; DNA; Epithelium; Hyperplasia; Immunoenzyme Techniques; Keratins; Male; Methylnitronitrosoguanidine; Precancerous Conditions; Rats; Rats, Inbred F344; Stomach; Stomach Neoplasms; Time Factors

Dietary habits have been causally implicated in gastric carcinogenesis, whereas minor dietary items may also play a part. Wasabi is a popular pungent spice in Japanese meals. In this study the effect of wasabi on N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced gastric carcinogenesis was studied in rats. Wistar WKY male rats received drinking water containing 50 micrograms/ml of MNNG or tap water alone and a basal diet (PCE-2) or PCE-2 containing 10% (wt/wt) of wasabi powder for 40 weeks. Thus, three groups were completed as MNNG + PCE-2 (n = 30), MNNG + wasabi (n = 30), and tap water + wasabi (n = 30). At autopsy, nine rats (30%) had seven glandular stomach tumors (2 adenocarcinomas, 2 adenomatous polyps, and 3 adenomatous glandular hyperplasias) and three duodenal adenocarcinomas in the MNNG + PCE-2 group, whereas in the MNNG + wasabi group, two rats (7%) had one forestomach epidermoid cyst and one duodenal carcinosarcoma (corrected chi 2 = 4.63, p less than 0.05 for incidences of glandular stomach tumors between 2 groups). In addition, two rats had microscopic atypical glands in the MNNG + PCE-2 group. There was no tumor in the tap water + wasabi group. These results indicated that glandular stomach carcinogenesis induced by MNNG was suppressed by the administration of wasabi.

Topics: Adenocarcinoma; Animals; Condiments; Diet; Duodenal Neoplasms; Gastric Mucosa; Hyperplasia; Japan; Male; Methylnitronitrosoguanidine; Plants, Edible; Polyps; Rats; Rats, Inbred WKY; Stomach Neoplasms; Water

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

To assess the temporal changes of the pancreatic duct following the administration of N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) in two dogs, serial pancreatography was performed. They received intraductal administration of a total of 595 and 500 mg ENNG in each one, over the periods of 12 and 13.5 months, respectively. In one dog, sequential changes of the main duct were observed, a small round filling defect developed a circumferential defect and became a severe stenosis associated with proximal dilatation of the duct. While no gross tumors were macroscopically detected at autopsy, continuous lesions with features of hyperplasia, atypical hyperplasia, and cancerous change of duct epithelial cells were microscopically seen. In the other one, a small round filling defect was detected by pancreatography, which was histopathologically hyperplasia of pancreatic duct, rather than cancerous cells. The present dog model for induction of pancreatic duct carcinomas appears useful for elucidating clinico-pathological changes occurring during cancer development.

Topics: Adenocarcinoma; Animals; Carcinogens; Dogs; Epithelium; Hyperplasia; Male; Methylnitronitrosoguanidine; Pancreatic Ducts; Pancreatic Neoplasms; Radiography

Topics: Adenoma; Animals; Antioxidants; Butylated Hydroxyanisole; Carcinoma; Cell Division; Epithelium; Female; Hyperplasia; Lipid Peroxidation; Male; Methylnitronitrosoguanidine; Papilloma; Rats; Rats, Inbred F344; Stomach; Stomach Neoplasms

The combined effects of low doses of promoters or carcinogens on two-stage forestomach carcinogenesis were examined in rats pretreated with N-methyl-N'-nitro-N-nitrosoguanidine. Groups of 15 rats were given a single 150 mg/kg body weight intragastric dose of N-methyl-N'-nitro-N-nitrosoguanidine. Starting 1 week later they were fed a diet containing low doses of known forestomach promoters/carcinogens (0.5% caffeic acid, 0.2% catechol, 0.5% butylated hydroxyanisole, or 0.25% 2-tert-butyl-4-methylphenol), alone or in combination, or basal diet without antioxidant supplement for 35 weeks. Histopathological examination revealed the incidences of forestomach squamous cell carcinomas in animals treated with N-methyl-N'-nitro-N-nitrosoguanidine followed by caffeic acid, catechol, butylated hydroxyanisole, 2-tert-butyl-4-methylphenol, and basal diet to be 27, 20, 13, 13, and 7%, respectively, whereas the incidence increased to 80% by the combined treatment with these four chemicals. The present results thus show that although the low doses of individual promoters/carcinogens did not have significant promoting activity, their combination exerted a strong enhancing influence on rat forestomach carcinogenesis. The findings indicate the importance of summation and synergism at a low dose for agents present in the human environment.

Topics: Animals; Butylated Hydroxyanisole; Butylated Hydroxytoluene; Hyperplasia; Male; Methylnitronitrosoguanidine; Premedication; Rats; Stomach; Stomach Neoplasms

The modifying effects of para-methoxyphenol (PMP) second stage treatment on N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-initiated rat forestomach carcinogenesis were investigated. Groups of 15 6 week old male F344 rats were given a single intragastric administration of 150 mg/kg body wt MNNG and starting 1 week later were administered powdered diet containing 2.0, 1.0, 0.5, 0.25 or 0% PMP until they were killed at week 52. PMP caused epithelial damage and hyperplasia in a dose-dependent manner in the forestomach epithelium, but nevertheless was not associated with any increase in the incidence of either papillomas or squamous cell carcinomas. The results thus clearly indicated that stimulation of cell proliferation does not necessarily correlate with promotion in the second stage of two-stage forestomach carcinogenesis.

Topics: Animals; Anisoles; Carcinogenicity Tests; Carcinoma; Cell Division; Hyperplasia; Male; Methylnitronitrosoguanidine; Muscle, Smooth; Organ Size; Papilloma; Rats; Rats, Inbred F344; Stomach; Stomach Neoplasms

The reversibility of butylated hydroxyanisole (BHA)-induced hamster forestomach hyperplasia was examined histopathologically. Groups of 10-15 male Syrian golden hamsters were treated with 2% BHA, for 12, 24 or 48 weeks and in each case then placed on basal diet until termination of the experiment at week 72, or treated with 2% BHA continuously for 72 weeks. Although sequential sampling revealed that BHA-induced hyperplasia reverted after cessation of antioxidant treatment, dysplastic lesions such as squamous cell dysplasia and basal cell dysplasia persisted and tended to increase with time on BHA. Basal cell dysplasia was observed in some hamsters later than squamous cell dysplasia, i.e. those treated with BHA for 24 weeks or more and killed up to 48 weeks later. Whereas the increase in labeling index evident in areas of hyperplasia during treatment returned to control level after cessation, this was not the case for the dysplastic lesions which continued to demonstrate elevated proliferation. The results thus suggest that basal cell dysplasia, including regions of squamous cell dysplasia, may be of particular importance as a precursor pre-neoplastic lesion.

Topics: Animals; Butylated Hydroxyanisole; Cricetinae; Hyperplasia; Male; Mesocricetus; Methylnitronitrosoguanidine; Precancerous Conditions; Stomach; Stomach Neoplasms; Uracil; Urinary Bladder

Modifying effects of resorcinol, hydroquinone, p-tert-butylcatechol (PTBC), p-methylcatechol (PMC), and o-methylcatechol on N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced forestomach and glandular stomach carcinogenesis were investigated in F344 rats. Groups of 15 to 16 male 6-wk-old animals were given a single intragastric administration of 150 mg/kg of body weight of MNNG and starting 1 wk later were administered powdered diet containing 0.8% resorcinol, 0.8% hydroquinone, 1.5% PTBC, 1.5% o-methylcatechol, 1.5% PMC, or basal diet alone for 51 wk. Additional groups of 10 to 15 rats each were treated with the phenolic compounds or received basal diet without prior carcinogen exposure. Histological examination after sacrifice at Wk 52 revealed that squamous cell carcinoma development in the forestomachs of rats treated with MNNG followed by PTBC (75%, P less than 0.001) or MNNG followed by PMC (100%, P less than 0.001) was significantly greater than in animals receiving MNNG alone (20%). Treatment with PMC alone also resulted in a 40% yield of papilloma. In the glandular stomach, incidences of adenomatous hyperplasias in rats treated with MNNG followed by PTBC (31.3%, P less than 0.05) or PMC (100%, P less than 0.001) and the incidence of adenocarcinomas in rats treated with MNNG followed by PMC (100%, P less than 0.001) were significantly higher than in controls. In addition, PMC alone induced a 100% yield of adenomatous hyperplasias and 6.7% of adenocarcinomas. Thus, the results demonstrated that PTBC and PMC treatment significantly enhances forestomach and glandular stomach carcinogenesis and that PMC itself may possess weak carcinogenic potential in these organs. The ortho-position appears to be important for this dihydroxybenzene activity.

Topics: Adenocarcinoma; Adenoma; Animals; Hyperplasia; Male; Methylnitronitrosoguanidine; Phenols; Rats; Rats, Inbred F344; Stomach; Stomach Neoplasms; Structure-Activity Relationship

Glyoxal and methylglyoxal were tested for tumor-promoting potential in a two-stage stomach carcinogenesis model. Male outbred Wistar rats were initially given N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in the drinking water (100 mg/l) along with a 10% sodium chloride dietary supplement for 8 weeks. Thereafter, they were returned to basal diet and maintained on drinking water containing no addition or either 0.5% glyoxal or 0.25% methylglyoxal for 32 weeks and then killed for necropsy and histological examination at week 40. Glyoxal treatment significantly increased the incidence of adenocarcinomas in the pylorus of the glandular stomach of rats pretreated with MNNG and sodium chloride. Furthermore, although methylglyoxal did not enhance the development of adenocarcinomas, the incidence of hyperplasias in the pylorus was significantly increased. The results indicate that glyoxal exerts tumor promoting activity on rat glandular stomach carcinogenesis and that methylglyoxal might also have promoting potential.

Topics: Aldehydes; Animals; Body Weight; Glyoxal; Hyperplasia; Male; Methylnitronitrosoguanidine; Pyruvaldehyde; Rats; Rats, Inbred Strains; Reference Values; Stomach; Stomach Neoplasms

DNA repair response to N-methyl-N'-nitro-N-nitrosoguadine (MNNG) was examined in an organ culture of hyperplastic urinary bladder epithelium, induced by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in male F344 rats. Organ cultures of urinary bladders obtained from rats given a solution of 0.05% BBN for 4-12 weeks, were processed and exposed to MNNG (10(-3)M). The DNA repair response was estimated by autoradiographic analysis of unscheduled DNA synthesis (UDS). In general, hyperplastic cells of the urinary bladder induced by BBN showed lower UDS levels than those of non-hyperplastic cells. The reduction of DNA repair response to MNNG was more prominent in advanced hyperplastic cells with longer BBN treatment than in early appearing hyperplastic cells with shorter BBN treatment.

Topics: Animals; Butylhydroxybutylnitrosamine; Carcinogens; DNA Repair; Hyperplasia; Male; Methylnitronitrosoguanidine; Organ Culture Techniques; Rats; Rats, Inbred F344; Urinary Bladder

The experiments carried on 107 rats have shown that the sensitivity of the epithelium of experimental adenomatous diverticuli of the stomach to the action of N-methyl-N'-nitro-N-nitrosoguanidine is lower than that of the gland epithelium of the organ.

Topics: Adenocarcinoma; Animals; Diverticulum, Stomach; Epithelium; Female; Foreign Bodies; Gastric Mucosa; Hyperplasia; Methylnitronitrosoguanidine; Microscopy, Electron; Rats; Stomach; Stomach Neoplasms

The effects of combined administration of cimetidine and tetragastrin on gastric acid secretion, the labeling index of the gastric mucosa, and the incidence of gastric adenocarcinomas induced by N-methyl-N'-nitro-N-nitrosoguanidine were investigated in inbred Wistar rats. Prolonged administration of tetragastrin in depot form after treatment with N-methyl-N'-nitro-N-nitrosoguanidine resulted in a significant increase in gastric acid secretion, a significant decrease in the labeling index of the antral mucosa, and a significant decrease in the incidence of adenocarcinomas of the glandular stomach. Administration of cimetidine at 20 mg, but not 10 mg, per kg body weight with tetragastrin significantly reduced the gastric acid secretion induced by tetragastrin alone but did not influence the labeling index of the antral mucosa or the inhibitory effect of tetragastrin on gastric carcinogenesis. These findings indicate that gastric acid secretion has no influence on the development of gastric adenocarcinomas and that the inhibitory effect of tetragastrin on gastric carcinogenesis may be related to its effect in decreasing proliferation of cells in the antral mucosa.

Topics: Adenocarcinoma; Animals; Cimetidine; DNA; Gastric Acid; Gastric Mucosa; Gastrins; Hyperplasia; Male; Methylnitronitrosoguanidine; Rats; Rats, Inbred Strains; Stomach Neoplasms; Tetragastrin

Sequential changes of numbers of pepsinogen 1 (Pg 1)-decreased pyloric glands (PDPG) detected by immunohistochemistry and of the incidence of gastric carcinomas were examined in five different strains of rats treated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG;CAS:70-25-7). Male SD (Crj:CD), WKY (WKY/NCrj), Lewis (LEW/Crj), Wistar (Crj:Wistar) and F344 (F344/DuCrj) rats (40 per strain), were given drinking water containing 100 micrograms/ml MNNG for 30 weeks and then normal tap water, and were killed at week 10, 30 and 50 of the experiment. Adenocarcinomas of the glandular stomach were found in nine of 15 SD rats (60%), in eight of 12 WKY rats (67%), in eight of 15 Lewis rats (53%), in three of 13 Wistar rats (23%) and in one of 18 F344 rats (6%) at week 50. These incidences of carcinomas in SD, WKY and Lewis were significantly higher (P less than 0.01) than that in F344 rats. From week 10, the numbers of PDPG in SD, WKY and Lewis rats were significantly greater (P less than 0.01) than that in F344 rats. From week 30, the numbers of PDPG in Wistar rats were also significantly greater (P less than 0.05-0.01) than that of F344. The susceptibility of rats to induction of gastric carcinoma by MNNG correlated with the susceptibility to induction of PDPG by MNNG in each strain, suggesting that induction of PDPG is a preneoplastic change in chemical gastric carcinogenesis.

Topics: Animals; Gastric Mucosa; Hyperplasia; Immunohistochemistry; Intestinal Neoplasms; Male; Methylnitronitrosoguanidine; Pepsinogens; Precancerous Conditions; Pylorus; Rats; Rats, Inbred Strains; Species Specificity; Stomach Neoplasms

After administration of N-methyl-N'-nitro-N-nitrosoguanidine for 15 weeks, the effects of bilateral, anterior and posterior vagotomy on the incidence, number and location of gastric adenocarcinomas, gastric acid secretion and cell proliferation of the gastric mucosa were investigated in inbred Wistar rats. Bilateral or anterior vagotomy, but not posterior vagotomy, significantly increased the incidence and number of adenocarcinomas at experimental week 52. In sham-operated control rats and rats subjected to bilateral vagotomy, there was no significant difference between the incidence or number of gastric tumors in the anterior and posterior walls. After anterior and posterior vagal denervation, however, there were significantly more gastric cancers on the denervated side than on the other. Bilateral and unilateral vagotomy resulted in significantly reduced gastric acid secretion by experimental weeks 25 and 52. Bilateral vagotomy significantly increased the labelling indices of both the fundic and antral mucosa at both times, but did not cause any significant difference between those of the anterior and posterior wall. Anterior or posterior vagotomy resulted in a significant increase in the labelling indices of both the fundic and antral mucosa on the denervated side. These findings indicate that the vagal nerve exerts a trophic action on the gastric mucosa, and that the promoting effect of vagotomy on gastric carcinogenesis may be related to its effect in increasing proliferation of cells in the antral mucosa.

Topics: Animals; Gastric Acid; Gastric Mucosa; Gastrins; Hyperplasia; Male; Methylnitronitrosoguanidine; Rats; Rats, Inbred Strains; Stomach Neoplasms; Vagotomy

N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was given to 3 groups of rats with the drinking water for 32 weeks in different doses: 25, 50 and 100 micrograms/ml. After 50 weeks the induced tumours of the stomach and the upper small intestine were investigated. Most tumours were well differentiated adenocarcinomas or adenomatous-hyperplastic lesions with focal adenocarcinoma. After low MNNG-concentration (25 micrograms/ml) only adenomatous hyperplastic lesions with focal adenocarcinoma were found. A tumour development in connection with intestinal metaplasia was detectable exclusively in two rats of the group receiving 50 micrograms MNNG/ml. The frequency of gastric tumours shows a relatively low peak (3.3 tumours/10 animals) after administering a medium MNNG-concentration (50 micrograms/ml) and a little decrease of the frequency after higher MNNG-concentration, as opposed to the approximately linear dose-related increase of the tumour frequency in the upper small intestine. The highest tumour induction rate was found in the upper small intestine after 100 micrograms MNNG/ml (5.6 tumours/10 rats). It can be concluded that the mucosa of the upper small intestine possesses a greater susceptibility to the carcinogenic effect of MNNG than the glandular stomach of the rat.

Topics: Adenocarcinoma; Administration, Oral; Animals; Cell Transformation, Neoplastic; Dose-Response Relationship, Drug; Hyperplasia; Intestinal Neoplasms; Intestine, Small; Male; Methylnitronitrosoguanidine; Neoplasm Invasiveness; Rats; Rats, Inbred Strains; Stomach; Stomach Neoplasms

The effects of combined administration of propranolol and tetragastrin on gastric acid secretion and the incidence and histological types of gastric adenocarcinomas induced by N-methyl-N'-nitro-N-nitrosoguanidine were investigated in inbred Wistar rats. Prolonged administration of tetragastrin, 1 but not 0.2 mg/kg body weight in depot form after treatment with N-methyl-N'-nitro-N-nitrosoguanidine significantly reduced the incidence of adenocarcinoma of the glandular stomach. The adenocarcinomas that did develop in rats treated with the higher dose of tetragastrin had high mucin-producing activity and showed little or no typical glandular structure. A combination of propranolol (2 mg/kg) and tetragastrin (1 mg/kg) did not influence the inhibitory effect of gastrin on gastric carcinogenesis. However, concomitant administration of propranolol (2 mg/kg) and tetragastrin (0.2 mg/kg) caused a significant increase in gastric acid secretion and a reduction in the incidence of gastric carcinomas. With this treatment, the incidence of adenocarcinoma was similar to that of treatment with tetragastrin (1 mg/kg). Histological examinations showed that like the cancers in control rats, the adenocarcinomas induced in these rats were all highly differentiated.

Topics: Adenocarcinoma; Animals; Drug Synergism; Gastric Acid; Gastric Mucosa; Gastrins; Hyperplasia; Male; Methylnitronitrosoguanidine; Propranolol; Rats; Rats, Inbred Strains; Stomach Neoplasms; Tetragastrin

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

Sequential histologic changes of the stomach during carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG; CAS: 70-25-7) were studied in susceptible ACI and resistant BUF strain rats. Rats were given MNNG at a concentration of 83 micrograms/ml in their drinking water for 32 weeks and then tap water and were sacrificed sequentially between weeks 1 and 57. In ACI rats, erosions, regenerative changes, focal and slightly atypical changes, and diffuse and severe atypical changes were observed sequentially in the pyloric region during the period of MNNG administration, where adenocarcinomas were observed after the cessation of MNNG treatment. In BUF rats, the main histologic changes induced by MNNG were erosions and hyperplasia of the glandular portion of pyloric glands at the margin of erosions. After the cessation of MNNG treatment, the hyperplasia of the pyloric glands subsided and was followed by atrophy of these glands. The results suggested that the responses of the gastric mucosa to MNNG in ACI and BUF rats were qualitatively different.

Topics: Adenocarcinoma; Animals; Gastric Mucosa; Hyperplasia; Male; Methylnitronitrosoguanidine; Pylorus; Rats; Rats, Inbred ACI; Rats, Inbred BUF; Regeneration; Stomach Neoplasms

Juvenile medaka were exposed to N-methyl-N'-nitro-N-nitrosoguanidine in water under static renewal conditions for 28 days. Two groups of 134 fish each were pulsed 3 times weekly at nominal concentrations of 1.0 and 0.5 mg/liter with N-methyl-N'-nitro-N-nitrosoguanidine dissolved in dimethylformamide. A third group of 134 fish was exposed to the solvent control, 0.01% dimethylformamide in water. Following the 28-day exposure, and during the recovery period, fish were sampled at intervals of approximately 0, 3, 6, and 9 months and examined grossly. Selected tissues were evaluated microscopically. Many tumor types developed in both N-methyl-N'-nitro-N-nitrosoguanidine exposure groups, but only the gill lesions will be discussed. Approximately 50% of the fish in both treatment groups died from gill damage in the second to third month of the recovery period. More than 90% of the surviving treated fish displayed gill lesions, which progressed from mild epithelial hyperplasia of gill filaments at 0-months recovery to epitheliomatous hyperplasia at 3 months and advanced to a more focal nodular appearance of gill filaments at 6 months. Eight to 9 months after the treatment period, at least four fish displayed branchial blastomas. The control fish had no gill lesions. Chemically induced gill tumors have not been previously observed in fish. Even gill tumors of unknown origin are very rare.

Topics: Animals; Disease Models, Animal; Fish Diseases; Fishes; Gills; Hyperplasia; Methylnitronitrosoguanidine; Neoplasms; Time Factors

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

The carcinogenic or cocarcinogenic effects of bile or bile acid on stomach carcinogenesis were investigated in inbred W rats. Bile or bile acid was introduced into the stomach by choledochogastrostomy or with food after the administration of N-methyl-N'-nitro-N-nitrosoguanidine [(MNNG) CAS: 70-25-7; 1-methyl-3-nitro-1-nitrosoguanidine] in drinking water. The animals that received MNNG and bile or sodium taurocholate (CAS: 145-42-6; N-choloyltaurine sodium salt) had a significantly higher incidence of hyperplastic and neoplastic lesions in the stomach mucosa than did the relevant MNNG-treated controls. The result suggested an enhancing effect of bile and sodium taurocholate in stomach tumorigenesis.

Topics: Animals; Bile; Carcinogens; Drug Synergism; Hyperplasia; Male; Methylnitronitrosoguanidine; Rats; Rats, Inbred Strains; Stomach; Stomach Neoplasms; Taurocholic Acid

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

Serial autoradiographic studies were made in wistar-rats during oral administration of N-methyl-N'-nitroso-guanidine (MNNG). Between the 4th and the 40th week 16 rats were killed at intervals. During the first period of the experiment we observed a foveolar hyperplasia of the mucosa of the glandular stomach. Later we found adenomatous hyperplasia but finally severe mucosal dysplasiae, which were looked upon as precursors of cancer. In the course of the 40th weeks investigation period no cancer was induced. In the antral mucosa the labelling index was higher than in the other parts of the glandular stomach. On the lesser curvature the proliferation rate was higher than on the greater curvature, or in comparison with the anterior and the posterior wall of the stomach. Furthermore the severe mucosal dysplasiae showed a higher labelling index than the adjacent area or the corresponding part of the lesser curvature.

Topics: Animals; Gastric Mucosa; Hyperplasia; Methylnitronitrosoguanidine; Precancerous Conditions; Rats; Rats, Inbred Strains; Stomach; Stomach Neoplasms; Time Factors

This study examined the effects of N-methyl-N'-nitro-N-nitrosoguanidine (M.N.N.G.) on the oral mucosa of Wistar rats. The rats were born from dams treated by i.p. injections of M.N.N.G. during gestation. Each pregnant rat of a first group received a total dose of 39.60 mg/kg of M.N.N.G. administered throughout the gestation period. Each pregnant rat of a second group received a total dose of 82.50 mg/kg of M.N.N.G. by i.p. injections during the first ten days of gestation. In the progeny of dams from both groups, the morphology of the gingiva was modified. The lingual gingiva from the lower jaw was most impaired. The epithelium always displayed hyperplasia: acanthosis, papillomatosis and hyperkeratosis. These results indicate a pathogenic effect of M.N.N.G. on lingual, mandibular gingiva. This effect was slight but permanent and irreversible. No carcinogenic effect was noticed on the oral mucosa. Similarities between the lesions described in this work and human epithelial dysfunction makes this experimental model interesting.

Topics: Animals; Female; Gingiva; Hyperplasia; Maternal-Fetal Exchange; Methylnitronitrosoguanidine; Microscopy, Electron; Mouth Mucosa; Pregnancy; Rats; Rats, Inbred Strains

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.

Topics: Aged; Animals; Female; Gastric Mucosa; Humans; Hyperplasia; Male; Methylnitronitrosoguanidine; Middle Aged; Neoplasm Invasiveness; Rats; Rats, Inbred Strains; Stomach Neoplasms

Two experiments were undertaken to induce uterine cancer in rats by intrauterine administration of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in a total of 120 inbred female ACI rats, 5 weeks old. In Experiment I, 55 rats were divided into 3 groups and given a single injection of MNNG 50 mg (Group 1) or 100 mg (Group 2)/kg body weight emulsified in olive oil or olive oil alone (Group 3) into the uterine canals after the laparotomy. Uterine corpus tumors including endometrial adenocarcinomas were developed in 35.3% (Group 1) and 16.7% (Group 2) of the effective animals. Endometrial adenomatous hyperplasia which was considered to be a precancerous lesion, was observed in a few rats of Group 2. No tumors nor hyperplastic lesions were seen in the control group. (The incidence of tumors in the uterine corpus was significantly higher in the animals of Group 1 or 2 than in those of Group 3 (P less than 0.05]. In Experiment II, 65 rats were divided into 4 groups and treated as follows; Group 1: Rats were given intravaginal detention of absorbent cottons dipped with 0.5 mg of MNNG dissolved in 0.2 ml of olive oil for a week. The treatment was repeated 20 times once every two weeks. Group 2: Animals were treated by intravaginal detention of cottons containing 10% acetic acid or MNNG in alternate weeks 5 times each, and then the detention of MNNG-cottons 15 times every other week. Group 3: Rats were given the absorbent cottons containing olive oil alone 20 times biweekly.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenocarcinoma; Administration, Topical; Animals; Carcinoma, Squamous Cell; Endometrium; Female; Hyperplasia; Methylnitronitrosoguanidine; Rats; Uterine Cervical Neoplasms; Uterine Neoplasms; Vaginal Neoplasms

Topics: Animals; Bile; Gastritis; Hyperplasia; Methylnitronitrosoguanidine; Rats; Rats, Inbred Strains; Stomach

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Cell Division; Dose-Response Relationship, Drug; Hyperplasia; Methylnitronitrosoguanidine; Mice; Mice, Inbred Strains; Phorbols; Rats; Rats, Inbred F344; Skin; Skin Neoplasms; Species Specificity; Tetradecanoylphorbol Acetate

The inductions of hyperplastic liver nodules (HN) by four carcinogens were examined by their administration continuously and repeatedly by intragastric (i.g.), intraperitoneal (i.p.), intravenous (i.v.) and/or subcutaneous (s.c.) injections before (initiation stage) or after (promotion stage) exposure to N-2-fluorenylacetamide (2-FAA) in male F344 rats. Diethylnitrosamine (DEN), a water-soluble hepatocarcinogen, and 3'-methyl-4-dimethylaminobenzene (3'-Me-DAB), a water-insoluble hepatocarcinogen, markedly increased development of HN when administered by any route in both stages. However, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), a water-soluble non-hepatocarcinogen, and benzo[a]pyrene (B[a]P), a water-insoluble non-hepatocarcinogen, increased HN slightly by all or some of the routes of application only in the initiation stage. The influence of the administration route was more evident with water-insoluble compounds in the promotion stage and with non-hepatocarcinogens in the initiation stage.

Topics: 2-Acetylaminofluorene; Animals; Carcinogens; Diethylnitrosamine; Hyperplasia; Liver; Male; Methyldimethylaminoazobenzene; Methylnitronitrosoguanidine; Organ Specificity; Rats

Aryl hydrocarbon hydroxylase (AHH) was present in explant cultures of human prostate obtained from surgery of benign prostatic hyperplasia and was inducible by benz[a]anthracene (BA). The induction of AHH ranged from 14- to 150-fold when compared with control values and 10-fold variation of AHH inducibility among individuals was observed. Epithelial cells grown from human prostate tissue also contained measurable AHH activity and AHH was inducible by BA and 7,12-dimethylbenz[a]anthracene (DMBA). Inducibility of AHH by BA ranged from 2- to 63-fold. The inducibility of AHH by DMBA was always less than that by BA. In cells treated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), there were no changes in AHH activity. These findings support the view that the human prostate is susceptible to environmental polycyclic hydrocarbon carcinogens and that environmental and occupational factors might contribute to the etiology of human prostatic carcinoma.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Adenocarcinoma; Adult; Aryl Hydrocarbon Hydroxylases; Cells, Cultured; Culture Techniques; Enzyme Induction; Humans; Hyperplasia; Male; Methylnitronitrosoguanidine; Prostate; Prostatic Neoplasms

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

The suitability of using coloscopy as a diagnostic method is investigated with respect to colonic carcinomas induced locally by the administration of N-nitrosoacetoxymethyl-methylamine, N-methyl-N-nitrosourea, and methylnitro-nitrosoguanidine, or systemically by subcutaneous injection of 1,2-dimethylhydrazine in Sprague-Dawley rats. The endoscopic diagnostic examination proved to be clearly superior to methods of animal inspection, palpation, investigation for occult blood and exploratory laparotomy which have so far been employed in animal experiments with small rodents. The relevance of this method is discussed for the early detection of chemically induced colonic tumors, and the observation of tumor development under experimental cytostatic therapy.

Topics: Adenocarcinoma; Animals; Carcinogens; Colon; Colonic Neoplasms; Colonoscopy; Dimethylnitrosamine; Evaluation Studies as Topic; Hyperplasia; Intestinal Polyps; Male; Methylamines; Methylnitronitrosoguanidine; Methylnitrosourea; Rats

Rats of non-pure strain were allowed to drink N-Methyl-N-Nitro-N-Nitroso-guanidine (MNNG) solution (200-250 micrograms per milliliter) ad libitum. After 14 months, in addition to MNNG, each of them was fed with 1 ml of saturated NaCl solution once a week. During a period of 18 months, there were 5 cases of gastric adenocarcinoma and 2 cases of adenocarcinoma of the duodenum among 18 experimental rats. Besides, there were a few cases of papilloma of the fore-stomach and carcinoma of the lung. In 17 control rats, no tumors of the gastro-intestinal tract were seen. Microscopic examination of the mucosa of the pyloric gland region of the stomach in the experimental rats showed that the deep epithelial cells of the gastric pit exhibited a marked degree of proliferation and a malignant change had started in these cells. Electron microscopic observation of these epithelial cells revealed that the the proliferating cells showed only increased nucleocytoplasmic ratio, while those with atypical hyperplasia showed that the form of the nucleus and the changes in the basement membrane and intercellular junctions were somewhat similar to those of malignant cells. It is believed that increase in concentration of the carcinogens and prolongation of the time of contact with them may induce malignant tumors in the insensitive animal.

Topics: Adenocarcinoma; Animals; Epithelium; Gastric Mucosa; Hyperplasia; Methylnitronitrosoguanidine; Microscopy, Electron; Neoplasms, Experimental; Pylorus; Rats; Stomach Neoplasms

Malignant transformation of rat stomach was studied after oral administration of MNNG. The lesions were investigated with cytomorphological and histochemical methods, while the alkaline phosphatase (ALP) isoenzyme pattern was investigated by means of gel electrophoresis. Hyperdiploid-aneuploid DNA values were observed in dysplasias, as well as in carcinomas. The liver type ALP isoenzyme could be detected in intact and regenerative gastric mucosa. It also occurred in atypical hyperplasia and carcinoma. Placental type ALP isoenzyme was absent in all intact or regenerating gastric mucosa, but present in atypical hyperplasias and carcinomas. It can be concluded that DNA aneuploidy and the presence of placental type ALP are indicative of malignant transformations. The MNNG-induced adenomatous hyperplasia associated with atypia behaved like cancer and can thus be regarded as an obligatory preneoplastic lesion.

Topics: Adenoma; Animals; Carcinoma; Hyperplasia; Methylnitronitrosoguanidine; Precancerous Conditions; Rats; Stomach; Stomach Neoplasms; Time Factors

The effect of administration of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) at a dose level of 83 mg/liter in the drinking water was followed in the pyloric mucosae of male noninbred Wistar rats. Autoradiographic studies were done on animals killed after 10, 15, 26, and 36 weeks of treatment. In the normal-appearing mucosae of the rats treated with MNNG for 10 weeks, the number of epithelial cells per pit column was significantly increased over that in control rats. Simultaneously, a shift in the major zone of epithelial cell proliferation was noted in the treated rats. Along with the formation of a longer pit in MNNG-treated rats, the greatest number of DNA-synthesizing cells was displaced from the middle third of the pit in a downward direction toward the muscularis mucosa. In addition, at this early experimental time period, pits lined with more immature, cuboidal, mucus-depleted cells were recognizable. These pits not only had higher labeling indices than normal-appearing pits of the same animals but also expressed a dual nature with increased proliferative activity extending either upward to the luminal surface or further in a downward direction. Focal areas of cellular atypism were present by week 10 of treatment with a threefold to sevenfold greater DNA synthesis activity than that found in the normal-appearing mucosa of the same animal. A wide range of values in proliferative activity was found not only among invasive pyloric tumors within the same animal but also within different areas of the same tumor. The mechanism for the formation of adenomas and invasive adenocarcinomas is believed to be related to the dual character of the hyperplastic pits described.

Topics: Animals; Autoradiography; DNA; DNA, Neoplasm; Epithelium; Gastric Mucosa; Hyperplasia; Kinetics; Male; Methylnitronitrosoguanidine; Neoplasm Invasiveness; Pyloric Antrum; Rats; Stomach Neoplasms; Time Factors

Topics: Animals; Atrophy; Autoradiography; Gastrectomy; Gastric Mucosa; Histocytochemistry; Hyperplasia; Male; Methylnitronitrosoguanidine; Postoperative Complications; Rats; Stomach Neoplasms; Time Factors

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

In 189 rats N-methyl-N'-nitro-N-nitrosoguanidine or 1,2-dimethylhydrazine (DMH) was given in order to induce colonic tumours. The tumour induction was followed by double contrast examination. At 894 examinations 196 adenomatous tumours were revealed. Autopsy and microscopy revealed 214 macroscopic and 53 microscopic benign or malignant adenomatous tumours. Metastases were found in 17 per cent in the DMH group. The relationship between adenomas and carcinomas is also evaluated.

Topics: Adenocarcinoma; Adenoma; Animals; Carcinogens; Colon; Colonic Neoplasms; Dimethylhydrazines; Female; Hyperplasia; Injections; Injections, Intravenous; Injections, Subcutaneous; Intestinal Mucosa; Male; Methylnitronitrosoguanidine; Neoplasm Metastasis; Neoplasms, Experimental; Radiography; Rats; Rectum; Time Factors

The antihyperplastic activity of beta-retinoic acid (RA) and nine synthetic analogues (retinoids) was examined in organ cultures of mouse prostate made hyperplastic by treatment with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). After 8 or 10 days, when most explants developed hyperplasia, the carcinogen was withdrawn and explants were incubated in control medium and medium containing different concentrations of a retinoid. The antimitotic activity of retinoids was compared with that of RA. Different retinoids produced variable degrees of mitotic inhibition in the hyperplastic prostate epithelium. The methylketo cyclopentenyl and 1-methoxyethyl cyclopentenyl analogues of RA were at least 50-fold more active than RA in reversing MNNG-induced hyperplasia. The trimethylmethoxyphenyl analogue of RA and retinyl methyl ether were significantly more active than RA. Three analogues, N-acetyiretinylamine, retinal acetyl hydrazone, and retinal oxime, were as active as RA. The chlorotrimethylphenyl analogue showed less activity than RA, and alpha-retinyl acetate was completely devoid of mitotic inhibitory activity.

Topics: Cell Division; Epithelium; Hyperplasia; Male; Methylnitronitrosoguanidine; Neoplasms, Experimental; Organ Culture Techniques; Precancerous Conditions; Prostate; Prostatic Neoplasms; Structure-Activity Relationship; Tretinoin; Vitamin A

In an effort to establish a test system to examine the carcinogenic potential of chemicals, mouse prostate explants were maintained as organ cultures and the effects of carcinogenic and noncarcinogenic compounds were examined at various intervals after treatment. The degree of hyperplasia produced by a compound was determined by the colcemid metaphase arrest technique. Extensive hyperplasia of the prostatic epithelium occurred at 8 days after treatment with 3-methylcholanthrene, the 11-12 epoxide of methylcholanthrene, benzo(a)pyrene and N-methyl-N-nitro-N-nitrosoguanidine. At 12 days most carcinogen-treated explants were anaplastic. The noncarcinogenic compounds, pyrene and phenanthrene, did not produce a mitotic stimulatory effect on the epithelium of the explants. The data suggest that the organ culture system of mouse prostate may be employed as a test system to obtain preliminary information regarding the cardinogenicity of a compound.

Topics: Anaplasia; Animals; Benzopyrenes; Carcinogens; Epithelium; Ethers, Cyclic; Hyperplasia; Male; Methylcholanthrene; Methylnitronitrosoguanidine; Mice; Mitosis; Organ Culture Techniques; Phenanthrenes; Prostate; Pyrenes

Experimental carcinomas in the glandular stomach of rats were induced by oral administration of MNNG (M-methyl-N'-nitro-N-nitrosoguanidin) for 35 weeks or ENNG (N-ethyl-N'-nitro-N-nitrosoguanidin) for 20 weeks. Rats were killed at different times after beginning of carcinogen treatment and tissue specimens were prepared for histologic investigation. Particular interest was placed on the development of tumors and on pathological findings possibly contributing to early diagnosis of stomach cancer. During the development of tumors, several dysplastic reactions were observed in the antral mucosa. They could be classified into 4 groups: One was regenerative hyperplasia (1) that meant irregular glandular proliferations without cell atypism at the margin of erosions and ulcers. This lesion was mainly found 1-9 weeks after administration of MNNG. In glandular hyperplasia (2) either crypts or glands were extended and mucosal layers were thickened. No signs of cell atypism were observed. This lesion was mainly found 12-17 weeks after administration of MNNG. Dysplasia (3) was combined with considerable structural modifications and cellular atypism. However, this lesion was limited to the mucosal layer. Neoplastic changes (4) were characterized by marked cellular atypism and extension to tunica submucosa and tunica serosa. Some tumors showed the histological patterns of benign tumors, but most of them were adenocarcinomas. In some cases metastases into pancreas, liver and lymph nodes and in one case into the 12th rib were observed. No particular enzyme patterns were found by histochemistry.

Topics: Animals; Gastric Mucosa; Hyperplasia; Male; Methylnitronitrosoguanidine; Neoplasm Metastasis; Neoplasms, Experimental; Nitrosoguanidines; Precancerous Conditions; Rats; Stomach Neoplasms

The effect of beta-retinoic acid (RA) on carcinogen-induced hyperplasia was studied in organ cultures of mouse prostate gland. 3-Methylcholanthrene (MCA), requiring metabolic activation, or N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), not requiring activation, were used to induce hyperplastic changes. Treatment of cultures with MCA or MNNG stimulated cell proliferation and caused the alveolar epithelium to become hyperplastic. The development of this hyperplasia was inhibited when RA was added simultaneously with MCA or MNNG. However, RA had no significant effect on cell proliferation in untreated control cultures. Elimination of carcinogen from the hyperplastic cultures after 8 days of treatment did not reverse hyperplasia of the alveolar epithelium. When the withdrawal of MCA or MNNG was followed by treatment of the cultures with RA, hyperplasia was markedly reversed within 96 hours. Thus RA actively inhibited and reversed the effect of MCA and MNNG, two carcinogens that may have different mechanisms of action.

Topics: Animals; Cell Division; Epithelial Cells; Epithelium; Hyperplasia; Male; Methylcholanthrene; Methylnitronitrosoguanidine; Mice; Organ Culture Techniques; Prostate; Prostatic Diseases; Time Factors; Tretinoin; Vitamin A

Topics: Adenocarcinoma; Animals; Carcinoid Tumor; Carcinoma, Hepatocellular; Carcinoma, Squamous Cell; Duodenal Neoplasms; Female; Hyperplasia; Liver Neoplasms; Male; Methylnitronitrosoguanidine; Neoplasms, Experimental; Nitrosoguanidines; Papilloma; Rats; Rodent Diseases; Stomach Neoplasms

Topics: Adenocarcinoma; Administration, Oral; Animals; Carcinogens; Disease Progression; Hyperplasia; Male; Methylnitronitrosoguanidine; Rats; Rats, Wistar; Stomach Neoplasms; Time Factors; Water