Induction of esophageal carcinogenesis by diethylnitrosamine and assessment of the promoting effect of ethanol and N-nitrosonornicotine: experimental model in mice (original) (raw)
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Journal of Cancer Research and Clinical Oncology, 1996
The effect of ethanol (EtOH) on esophageal cell proliferation and the development of esophageal cancers induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in shrews were investigated. Sequential histological examination was done, and cell proliferation was assessed by BrdU labeling. At 5 weeks of age, animals were given tap water, 2% EtOH, 50 ppm MNNG, or 50 ppm MNNG plus 2%, 5% or 10% EtOH in the drinking water. Administration of 10% and 5% EtOH simultaneously with MNNG caused death in 40% (10/25) within 4 days and in 20% (6/30) within 7 days respectively, whereas other treatments were well tolerated with no sudden deaths. Administration of 2% EtOH for 30 weeks caused a 2-fold increase, and that of MNNG caused a 4.5-fold increase in the proliferation index of the basal cells of the esophagus compared with control shrews, and MNNG plus 2% EtOH caused a 5.5-fold increase. In MNNGtreated shrews, with or without 2% EtOH administration, sequential histological examination of esophageal tissue revealed a similar change; dysplasia appeared at 30 weeks of age, squamous cell carcinoma occurred at 35 weeks of age, and the depth of invasion extended to adventitia at 45 weeks of age. These finding indicate that treatment with 2% EtOH promoted the proliferation of esophageal basal cells but did not alter the tumor induction period and did not have tumor-pro-moting activity. EtOH per se was not carcinogenic; no tumors were seen in shrews not administered MNNG.
Experimental esophageal carcinogenesis: technical standardization and results
Diseases of the Esophagus, 2002
The aim of this research was to determine the occurrence of epidermoid carcinoma of the esophagus induced by diethylnitrosamine (DEN) in Wistar rats. DEN was administered (250-300 g) in drinking water (10 mg ⁄ kg body weight) to four groups of rats for 72 h ⁄ week, for a duration of 90, 120, 150, or 200 days (groups T90, T120, T150, and T200). Ten animals whose drinking water did not contain DEN constituted the control group. All rats were sacrificed and their esophaguses studied macro-and microscopically. The control group did not exhibit either carcinomas or preneoplasic lesions. The T120 and T200 groups presented, respectively, 47 and 58 in situ carcinomas; 1 and 20 submucosal carcinomas (P < 0.05); 4 and 17 microinvasive carcinomas (P < 0.05); 4 and 11 advanced carcinomas (P < 0.05); and 1 and 1 cases of benign hyperplasia. Pulmonary and liver carcinomas were also found in the T200 group. The majority of advanced macroscopic lesions in the T200 group were polypoid, exophytic, and not microscopically invasive in the esophageal wall. This research confirms the effectiveness of the DEN in bringing about carcinogenesis in the Wistar rat esophagus and also shows that the lesions are dosage dependent.
Cancer Research, 2003
Perillyl alcohol (POH) is a monoterpene found in lavender, spearmint, and cherries. Phase I clinical trials with this agent have shown a favorable toxicity profile and preliminary data indicate some chemotherapeutic efficacy in advanced cancers. Animal studies have demonstrated the ability of POH to inhibit tumorigenesis in the mammary gland, liver, and pancreas. Although the precise mechanism of action is unclear, POH has been shown to inhibit the farnesylation of small G-proteins, including Ras, up-regulate the mannose-6-phosphate receptor, and induce apoptosis. Previous studies in our laboratory using the rat model of squamous cell carcinoma of the esophagus have shown that a specific Ha-ras codon 12 mutation is important for tumor promotion and progression. Given the limited toxicity of POH in humans, its proven efficacy in several animal models and its potential to inhibit Ha-ras farnesylation, we conducted an animal study to evaluate the efficacy of POH as a chemopreventive agent for squamous cell carcinoma of the esophagus. Male Fischer-344 rats were treated s.c. with 0.25 mg/kg b.w. of N-nitrosomethylbenzylamine three times a week for 5 weeks. Three days after the final carcinogen dose, they were started either on control diet or diets containing 0.5 or 1.0% POH. At 25 weeks, the animals were sacrificed, and esophageal tumors were counted. Animals fed either dose of POH showed a significant increase in dysplasia when compared with controls (P < 0.05) and a nonsignificant trend toward increased tumor multiplicity. Additionally, 1.0% POH did not affect Ras membrane localization. These data indicate that POH has a weakly promoting effect early in nitrosamine-induced esophageal tumorigenesis and suggest that POH may not be an effective chemopreventive agent for esophageal cancer in humans.
Mouse Model of Diethylnitrosamine-Induced Gastric Cancer
Journal of Surgical Research, 2008
Background. Nitrosamines are associated with the potential to induce cancer in the digestive tract. Ethanol has also been shown to enhance the effects of nitrosamine-induced carcinogenesis. The aim of this study was to investigate a murine model of the prevalence and types of epithelial lesions induced in the stomach by diethylnitrosamine (DEN), and to evaluate the influence of ethanol and N=-nitrosonornicotine (NNN) as promoters of gastric carcinogenesis.
South African Medical Journal, 2015
Squamous cell carcinoma (SCC) of the oesophagus dominates the oesophageal cancer landscape in the Middle East, Africa, Asia and parts of Europe. The global incidence rates are highest in Northern China, South Africa (SA), Turkey and Iran. In the USA, black people have a five times higher incidence than whites. [1] SCC of the oesophagus is common among black South Africans. [2] From 1912 to 1927, no case of SCC of the oesophagus was recorded in the files of the South African Institute for Medical Research. [2] The tumour started to appear in small numbers in the 1930s, reached a peak in the 1980s and then started to decline, so that today the numbers are one-fifth of what they were at their highest. Based on the premise that a carcinogen exerts its tumorigenic effect for approximately 30-40 years for a tumour to manifest, a cause was sought dating from 30 years prior to the 1930s when the tumour first appeared. Among various potential causes considered, a dietary change emerged as a potentially significant factor. [2] A major dietary alteration at the turn of the 20th century was the change of the staple diet of black Africans from sorghum to maize. This is considered a pivotal factor in the causation of SCC of the oesophagus. [3] The probable reason for the change was that agricultural production of maize was more profitable, and although sorghum can grow in harsh environments, the yields are lower. Of note, sorghum is the staple diet of Nigeria, where SCC of the oesophagus is infrequent. [4] SA, where maize is the staple diet, has a high incidence of SCC of the oeso phagus. [3] Background. Before the 1930s, squamous cell carcinoma (SCC) of the oesophagus was almost unknown among black South Africans. From the 1930s the annual frequency rose. A dietary cause was sought, the staple diet of black people having changed from sorghum to maize (corn), with traditional beer being brewed from maize. Carcinogenic N-nitrosamines in traditional beer were suggested as a cause of SCC of the oesophagus, with Fusarium moniliforme, a corn saprophyte, thought to play a role. Objectives. To confirm the presence of N-nitrosamines in traditional beer and demonstrate a mechanism for the oncogenesis of oesophageal carcinoma. Methods. Analysis by high-performance liquid chromatography was conducted for the identification of nitrosamines in traditional beer samples, and molecular docking studies were employed to predict the affinity between N-nitrosamines and the S100A2 protein. Results. Carcinogenic N-nitrosamines were identified in all six samples of traditional beer examined (N=18 analyses), and docking studies confirmed a high affinity of the nitrosamine N-nitrosopyrrolidone with the S100A2 protein. This may result in the altered expression of the S100A2 protein, leading to tumour progression and prognosis. Conclusion. It is suggested that carcinogenic N-nitrosamines in traditional beer are a major factor in the causation of SCC of the oesophagus in black South Africans. N-nitrosamines have been shown to produce cancer experimentally, but there has not been conclusive epidemiological evidence that N-nitrosamines are carcinogenic to humans. This study is the first to demonstrate the potential link between N-nitrosamines and a human tumour.
Metabolism of N-nitrosamines by cultured human and rat esophagus
Cancer research, 1982
The metabolism of several N-nitrosamines (N-nitrosodimethylamine, N-nitrosoethylmethylamine, N-nitrosodiethylamine, N-nitrosobenzylmethylamine, and N-nitrosopyrrolidine) in cultured human and rat esophagus has been investigated by measuring (a) CO2, (b) metabolites with an oxo group, and (c) metabolites bound to DNA. Both acyclic and cyclic N-nitrosamines were metabolized by rat esophagus. The highest level of metabolite binding was seen with N-nitrosobenzylmethylamine, an organotrophic carcinogen for the rat esophagus. The binding level was about 100-fold higher than in human esophagus. This compound methylated rat esophageal DNA at positions 7 and O6 of guanine. The level of benzylation in rat was one-tenth of the level of methylation. Formation of benzaldehyde exceeded that of formaldehyde plus CO2 by a factor of six, indicating that the methylene group was preferentially oxidized. N-Nitrosoethylmethylamine, another unsymmetrical N-nitrosamine, was preferentially oxidized by rat ...
Carcinogenesis, 1998
The ability of dietary isothiocyanates to inhibit the esophageal metabolism of NЈ-nitrosonornicotine (NNN) was examined in F344 rats. Following feeding of benzyl isothiocyanate (BITC), phenethyl isothiocyanate (PEITC), 3phenylpropyl isothiocyanate (PPITC), 4-phenylbutyl isothiocyanate (PBITC) or 6-phenylhexyl isothiocyanate for 2 weeks, rats were killed and the esophagi were incubated in vitro with [5-3 H]NNN. While dietary BITC, PEITC and PBITC all decreased NNN metabolism, dietary PPITC had the greatest effect, yielding inhibition ranging from 55 to 91% of the control production of various NNN metabolites. To determine the chemopreventive efficacy of PPITC on NNN-induced esophageal tumorigenesis, rats were fed AIN-76A diets containing 0, 1.0 or 2.5 µmol/g PPITC and were given untreated drinking water or drinking water containing 5 p.p.m. NNN. After 87 weeks, the experiment was terminated and the esophageal tumors were counted. Rats that were given untreated drinking water developed no tumors. Rats that were given 5 p.p.m. NNN and unadulterated AIN-76A diet had an esophageal tumor incidence of 71% and a multiplicity of 1.57 tumors/ animal. The two dietary concentrations of PPITC reduced the incidence and multiplicity of NNN-induced esophageal tumors by >95%. These results demonstrate the remarkable chemopreventive efficacy of PPITC in the NNN-induced esophageal tumor model.
Carcinogenesis, 1998
Esophageal cancer has been associated with tobacco smoking, and nitrosamines are possible causative agents for this cancer. The present study investigated the metabolism of the tobacco carcinogens NЈ-nitrosonornicotine (NNN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and N-nitrosodimethylamine (NDMA), as well as the presence of xenobiotic-metabolizing enzymes in human esophageal tissues from individuals in the United States and Huixian, Henan Province, China (a high-risk area for esophageal cancer). All esophageal microsomal samples activated NNN and the metabolic rate was 2-fold higher in the esophageal samples from China than the USA. All microsomal samples activated NDMA. However, most of the microsomal samples did not activate NNK. Troleandomycin (an inhibitor of cytochrome P450 3A) decreased the formation of NNNderived keto acid by 20-26% in the esophageal microsomes. The activities for NADPH: cytochrome c reductase, ethoxycoumarin O-deethylase, NAD(P)H: quinone oxidoreductase and glutathione S-transferase were present in the esophageal samples. Coumarin 7-hydroxylase (a representative activity for P450 2A6) activity was not detected in the esophageal microsomal samples. The activities for nitrosamine metabolism and xenobiotic-metabolizing enzymes were decreased (by 30-50%) in the squamous cell carcinomas compared with their corresponding non-cancerous mucosa. The presence of activation and detoxification enzymes in the esophagus may play an important role in determining the susceptibility of the esophagus to the carcinogenic effect of nitrosamines. Our results suggest that P450s 3A4 and 2E1 are involved in the activation of NNN and NDMA, respectively, in the human esophagus.
Dietary enhancement of nitrosamine carcinogenesis
Cancer research, 1974
Previous studies have shown that a diet high in fat and marginally deficient in lipotropes enhances aflatoxin B] hepatocarcinogenesis and depresses hepatic drug metabolism in rats. In this study we have compared induction of tumors by jV-nitrosodimethylamine, ./V-nitrosodiethylamine, or jV-nitrosodibutylamine in normal or marginally lipotrope-deficient rats fed a high-fat diet. The deficiency significantly enhanced hepatocarcinogenesis by both JV-nitrosodiethylamine and Nnitrosodibutylamine and may have enhanced esophageal carcinogenesis by ./V-nitrosodiethylamine. Induction of tumors by yV-nitrosodimethylamine and jV-nitrosodimethylamine metabolism in vitro in liver slices were not significantly affected by the diet. protein. Before the effects of individual diets were examined, studies were undertaken to compare the effect of the 2 diets on carcinogenesis by other compounds and in other organs in order to determine whether enhancement of carcinogenesis by the deficient diet was specific for AFB!. The 1st group of carcinogens studied was the nitrosamines, which comprise a large group of tumor-inducing compounds in many different organs of expermental animals. They are also found in human foods and are suspected to be a causative factor in human esophageal carcinoma (1, 3,6,8, 10, 24). The carcinogenic effect of the simplest compound, DMN, is susceptible to dietary alteration. Protein deficiency increases the number of renal tumors induced, while depressing induction of hepatic tumors, and decreases the ability of the liver to metabolize DMN (7, 13, 27).