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PubMed1989

Immunoanalytical detection of O4-ethylthymine in liver DNA of individuals with or without malignant tumors.

The detection and quantitation of carcinogen-DNA adducts in human cells are the key parameters in the molecular dosimetry of human exposure to environmental carcinogens. For investigating the possible relevance of alkylating N-nitroso compounds as causative agents in human carcinogenesis, we have quantitated O4-ethyl-2'-deoxythymidine (O4-EtdThd) in human liver DNA obtained from 33 autopsy specimens, i.e., 13 cases with primary liver cancer (LC), 8 with cancers other than liver cancer (OC), and 12 with noncancerous diseases (NC). None of the cases analyzed had a history of known occupational exposure to ethylating agents. The detection limit for O4-EtdThd was 3 X 10(-8) as a O4-EtdThd/dThd molar ratio in DNA, which was attained by the combination of prefractionation of DNA hydrolysates (= 20 mg of DNA/sample) by high performance liquid chromatography and competitive radioimmunoassay using anti-(O4-EtdThd) monoclonal antibody ER-01. Except for one case in each group, O4-EtdThd [or, alternatively, (an) unidentified structural modification(s) of DNA recognized by monoclonal antibody ER-01] was detected at mean (+/- SD) O4-EtdThd/dThd molar ratios of 39.9 +/- 40.2 x 10(-8), 53.5 +/- 74.0 X 10(-8), and 11.7 +/- 6.5 X 10(-8), respectively, in LC, OC, and NC. The difference of the O4-EtdThd content in DNA between LC and NC, or between LC + OC and NC, was statistically significant at P less than 0.05. These results suggest that humans are exposed to ethylating agents in vivo and that a premutagenic DNA lesion (O4-EtdThd) eventually accumulates in DNA, possibly to a biologically significant extent.

Adolescent↗
PubMed1985

[Forestomach carcinoma and hepatoma induced in mice and rats by N-3-methylbutyl-N-1-methylacetonylnitrosamine (MAMBNA)].

MAMBNA is a new N-nitroso compound isolated from Fusarium moniliforme-inoculated corn meal. In the present studies the carcinogenicity of MAMBNA is shown by the induction of forestomach carcinomas and liver tumors in mice and rats following the gastric intubation of this compound. Among 42 mice of Kunming (KM) stock treated with MAMBNA (10-20 mg/week), 22 showed epithelial hyperplasia of the esophagus, 29 papillomas and 4 squamous carcinomas in the forestomach, and there were 6 liver adenomas and 3 hepatomas. One mouse had forestomach carcinoma and carcinoma in the liver. Most tumors developed in mice receiving the treatment for 136-317 days, with a total dose of 210-670 mg (Table 1). No tumor was found in 12 controls observed for 239-357 days. In the experiment with 29 Wistar strain rats, administration of MAMBNA (20-120 mg/week) resulted in 11 epithelial hyperplasias in the lower esophagus, 14 atypical hyperplasias and papillomas, and 11 squamous carcinomas in the forestomach. The earliest forestomach carcinoma appeared in a rat treated for 454 days, receiving 4480 mg of MAMBNA, and the other 10 carcinomas occurred in animals treated for 518-640 days. Hyperplasia of liver cells was noted in 4 rats and liver adenoma in 7 and hepatocellular carcinoma in 8. Most hepatomas developed in rats treated for 480-640 days, and 5 rats had both forestomach carcinoma and hepatoma (Table 2). In 11 untreated rats observed for 411-644 days only one forestomach papilloma was noted.

Adenoma↗
PubMed1985

Diet and nutrition as risk factors for cancer.

Involvement of diet and nutrition as risk factors for human cancers has been established by two general types of evidence. Epidemiological studies in human populations have identified associations between patterns of incidence for various forms of cancer and diet composition or food consumption patterns. Such associations are particularly evident in studies on migrant populations and in patterns of geographic localization of specific forms of cancer. Reduction in gastric cancer (and increase in colon cancer) incidence has been observed in immigrants from Japan to the U.S. via Hawaii with concurrent change in dietary habits. High fat consumption has been linked to increased incidence of breast and colon cancer, and evidence is accumulating that suggests increased intake of dietary fiber (or some specific component of it) may be associated with diminished risk of colorectal cancer. Laboratory studies have demonstrated the existence of dietary constituents that might impact cancer risk in people consuming them. Substances in this class fall into two general categories: genotoxic carcinogens/mutagens; and protective factors which inhibit experimentally-induced chemical carcinogenesis in animals. Numerous naturally-occurring carcinogens/mutagens have been identified. Examples include aflatoxins, cycasin, and bracken fern carcinogen(s), among others. Genotoxic substances associated with the use of intentional food additives are the N-nitroso compounds formed as nitrosation products from nitrite. Potential carcinogenic risk from food constituents also comes from mutagens found in foods as natural components, or formed in the course of cooking.(ABSTRACT TRUNCATED AT 250 WORDS)

Carcinogens↗
PubMedDate not supplied

Metabolism of N-nitrosodimethylamine and N-nitrosomethylbenzylamine in domestic fowls: DNA alkylation and potential target sites for carcinogenicity.

The metabolism and reaction with DNA of N-nitrosodimethylamine (NDMA) and N-nitrosomethylbenzylamine (NMBzA) were investigated in chickens. These nitrosamines have been identified in a typical diet consumed in northern Chinese provinces with a high incidence of oesophageal cancer in both, humans and domestic fowls. Following i.m. or oral administration of the 14C-methyl labeled nitroso compounds (16.5 mumol/kg) less than 10% of the total radioactivity was exhaled as 14CO2 within 24 hr. DNA alkylation in chicken tissues was generally low, with highest values in liver (approximately 30 mumol N7-methylguanine/mol guanine) and kidney. In the gastrointestinal tract, concentrations of methylpurines were close to the limit of detection. After oral administration of NMBzA the reaction with DNA was more extensive, in particular in the diverticulum (crop), where N7-methylguanine and 0(6)-methylguanine amounted to 32 and 3.5 mumol/mol guanine, respectively. These values are more than 10-fold lower than those produced by a similar dose in rats, i.e. a species in which NMBzA induces a high incidence of oesophageal carcinomas. The low capacity of the chicken mucosa to bioactivate NDMA and NMBzA argues against these nitrosamines as agents responsible for oesophageal cancer in high risk areas.

Alkylation↗
PubMed1987

An exploratory case-control study of brain tumors in adults.

An exploratory study of brain tumors in adults was carried out using 215 cases diagnosed in Southern Ontario between 1979 and 1982, with an individually matched, hospital control series. Significantly elevated risks were observed for reported use of spring water, drinking of wine, and consumption of pickled fish, together with a significant protective effect for the regular consumption of any of several types of fruit. While these factors are consistent with a role for N-nitroso compounds in the etiology of these tumors, for several other factors related to this hypothesis, no association was observed. Occupation in the rubber industry was associated with a significant relative risk of 9.0, though no other occupational associations were seen. Two previously unreported associations were with smoking nonfilter cigarettes with a significant trend and with the use of hair dyes or sprays. The data do not support an association between physical head trauma requiring medical attention and risk of brain tumors and indicate that exposure to ionizing radiation and vinyl chloride monomer does not contribute any appreciable fraction of attributable risk in the population studied. The findings warrant further detailed investigation in future epidemiologic studies.

Adult↗
PubMed1987

[Dynamics of endogenous bacterial nitrite formation in the stomach. 2. Follow-up observations with standardized secretion from the porcine stomach].

The bacterial nitrite synthesis in gastric juice from porcine stomach mucin and the decrease of nitrite after adding acid, which has often been described in literature-results of an examination with a standardizable biomodel. A decrease of nitrite concentration was only seen after adding a small volume acid of high concentration. Simulating the acid secretion by a large volume of low concentrated acid mixed with pepsin-solution (artificial gastric secrete, DAB 8) a considerable increase of nitrite concentration can be observed. An explanation can be the structure of stomach mucous gel can be solubilized in water and thus the ions are liberized inside of the stomach mucin. In the discussion of the endogenous synthesis of cancerogenic N-Nitroso-compounds it must be considered if this phenomena also can be observed in human secretes.

Animals↗
PubMed1987

[Dynamics of endogenous bacterial nitrite formation in the stomach. 3. Dependence of nitrate and nitrite concentration on secretion volume].

The nitrate and nitrite concentration of 96 fasting gastric juice samples of young healthy volunteers were analysed. Two different methods have been used to take the gastric juice: 54 secrete samples were taken directly from the stomach, 42 secrete samples were taken after instillation of 500 ml sterile nitrite and nitrate free NaCl solution ("gastric-washing"). It could be shown that the expected high dilution of nitrite and nitrate concentration after gastric washing does not occur. A possible explanation might be that the solubilisation we could formerly observe in a biological pattern leads to a release of ions. This fact is very important for the question of endogen synthesis of cancerogenic N-nitroso compounds, because high nitrite and nitrate concentrations are subjects of interests as precursors of these compounds.

Bacteria↗
PubMed1987

[Dynamics of endogenous bacterial nitrite formation in the stomach. 4. Localization and reciprocal action of nitrate and nitrite in the healthy human stomach].

The nitrate and nitrite concentrations of 42 fasting gastric juice samples of young healthy human volunteers were analysed. It could be shown by separate determination of the concentration in the real secrete and the mucous gel that the amount of nitrate in the gel is about ten times higher than in the real secrete. The former conception, after which nitrate only gets by swallowed saliva into the stomach, has to be completed. It is obvious that the mucigenous glands of the stomach, like the saliva glands, are also able of nitrate enrichment and secretion. These results are very important for the evaluation of nitrate as a precursor of cancerogenic N-nitroso compounds.

Bacteria↗
PubMed1979

Gastric cancer in Colombia. IV. Nitrite and other ions in gastric contents of residents from a high-risk region.

Samples of gastric contents from 2 groups of patients from a region of high risk for gastric cancer were analyzed for pH, nitrite, nitrate, thiocyanate, and chloride. In each group, the patients could be divided into 2 subgroups: those with a gastric pH of less than 5 and those with a gastric pH of greater than 5. Above pH 5, nitrite was correlated with nitrate. The pH greater than 5 subgroups had significantly higher (P less than 0.01) nitrite content (20- to 100-fold). Some high- and low-nitrite samples were also analyzed for macro and trace metal ions, but differences were not significant. This is the first report in which patients with diagnosed gastric pathology related to a precancerous state were shown to have high levels of a putative carcinogen precursor. The results were compatible with our original hypothesis of intragastric nitrite formation by bacterial reduction of nitrate and concomitant synthesis of carcinogenic N-nitroso compounds.

Aged↗
PubMed1977

[Induction of tumours by different endogenously formed N-nitroso-ureas in the hooded rat (author's transl)].

By means of application of methyl-, ethyl-, n-propyl-, iso-propyl- and n-butylurea together with sodium nitrite the formation of corresponding carcinogenic N-nitroso compounds is demonstrated. The transplacental action of endogenously formed ethylnitrosourea led to a characteristic spectrum of tumours in the offspring comprising mainly neurogenic neoplasms of the brain and Nn. trigemini. The tumour incidence is especially high after application of precursors (ethylurea and nitrite) with the food. In postnatal experiments with methylurea and nitrite, there were induced mostly neurogenic tumours and reticulum cell sarcomas of the paracoecal region. A similar spectrum of tumours was found after postnatal application of iso-propylurea and nitrite by gastric tube. After a single dose of iso-propylurea and nitrite at day 21 of pregnancy there seems to be a slight carcinogenic effect in a small group of animals. The application of n-propylurea and n-butylurea, resp., together with nitrite led mainly to reticulum cell sarcomas of the paracoecal region after formation of corresponding alkylnitrosoureas. The spectrum of tumours is compared with that after the action of complete carcinogen and with the results obtained by other authors.

Animals↗
PubMed1987

O-Alkyl deoxythymidines are recognized by DNA polymerase I as deoxythymidine or deoxycytidine.

The O2- and O4-methyldeoxythymidine triphosphates (O-alkyl dTTP) can be used to substitute for dTTP in Escherichia coli DNA polymerase I (Pol I)-catalysed synthesis of poly[deoxyadenosine-deoxythymidine] (dA-dT). When incorporated into the polynucleotide, no detectable perturbation of structure occurred with even 20% O-methyldeoxythymidine in place of dT. However, on replication of such polymers with Pol I, significant amounts of deoxyguanosine triphosphate (dGTP) were incorporated, as well as high levels of deoxyadenosine triphosphate (dATP), indicating tautomer-like behaviour. Higher homologues, such as O4-ethyl (e4) dTTP or O4-isopropyl (ip4) dTTP, could also replace dTTP, but with lower efficiency. Nevertheless, their presence, like O4-methyl (m4) dT substitutions, caused transitions as well as inhibiting enzyme digestion with a variety of 3' nucleases, particularly to the 3'----5' exonuclease activity (proofreading) of polymerases. Further proof of mutagenicity comes from site-directed experiments placing m4dT or e4dT in place of dT at position 587 in am3 of phi X174, in which all revertants sequenced had A----G transitions. This implies that, since m4dT and e4dT are poorly repaired in eukaryotes, it is likely that they will remain in the DNA and lead to effects on enzyme activity, as well as mutations which contribute to the carcinogenicity of N-nitroso compounds.

Alkylation↗
PubMed1988

[Effects of nitrate and ascorbic acid on carcinogenesis in the operated rat stomach].

In the last few years, a great deal of attention has been paid to the hypothetical relationship between high nitrate intake, N-nitroso-compounds and gastric cancer. This long term study deals with the effect of nitrate and ascorbic acid contained in drinking water on the development of cancer in operated stomachs of rats without additional application of a carcinogen (tumor model). A total of 147 F1-Hybrids of WELS/Fohm X BD IX--rats were subjected to stomach operation (Gastroenterostomia antecolica anterior, truncular vagotomy and pyloroplasty). Carcinomas in stomach occurred within 33 weeks (post operationem). The surgical procedures altered the gastric flora, resulting in an increase and predominance of nitrate-reducing bacteria. The maximal tumor rate (10 of 13 rats) occurred in rats with gastroenterostomy and additional nitrate exposition. It may be possible, the nitrate is a precursor of gastric carcinogenesis. But we could not give any significant evidence of this fact. The addition of ascorbic acid to the drinking water lead to a suppression of the development of tumors. Our experience with the tumor model "operated stomach" underline the multifactorial genesis of stomach cancer in rats.

Animals↗
PubMed1987

Enhancement of N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide-induced carcinogenesis by urinary tract infection in rats.

Epidemiological studies suggest that urinary tract infection is an important risk factor in the development of bladder cancer. Chronic urinary tract infection in rats is associated with urothelial hyperplasia and papillomatosis. In the Sprague-Dawley strain, exposure to the 5-nitrofuran, N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT), is associated in particular with the development of renal pelvic tumors. The present study was designed to evaluate whether chronic urinary tract infection could enhance tumor development in FANFT-induced urinary tract carcinogenesis. One hundred forty-four female Sprague-Dawley rats were divided into the following groups. Group 1 received 0.2% FANFT in the diet for 7 wk followed by control diet. Group 2 received 0.2% FANFT in the diet for 7 wk followed by control diet. One wk after completion of FANFT administration, the suspension of 0.5 ml of Escherichia coli (06K13H1) was injected into the bladder through the urethra. Group 3 received 0.2% FANFT in the diet for 7 wk followed by control diet. One wk after completion of FANFT administration, a suspension of heat-killed E. coli (06K13H1) was injected into the bladder through the urethra. Group 4 received a suspension of 0.5 ml of E. coli (06K13H1) through the urethra and received control diet throughout the experiment. Group 5 was fed control diet only. The experiment continued for 104 wk. A significantly higher number of urinary tract tumors, particularly of the renal pelvis, was recorded in Group 2 compared to Groups 1, 3, 4, and 5. The majority of the rats in Groups 2 and 4 had morphological signs of urinary tract infections, particularly pyelitis and/or pyelonephritis. Thus, a single injection of E. coli (06K13H1) into the bladder results in an enhancement of FANFT-induced urinary tract carcinogenesis in the Sprague-Dawley rat, especially for renal pelvic tumors. The formation of dimethylnitrosamine or other nitroso compounds from nitrates in the urine or increased cell proliferation due to chronic inflammation or both may be important pathogenetic factors in the tumor development.

Animals↗
PubMed1986

Carcinogenicity of nitrosoureas in humans.

Literature on secondary tumours developing after cancer chemotherapy with nitrosoureas is reviewed. Many case studies show that combination treatments including BCNU and CCNU give rise predominantly to acute leukaemia within an average latent period of about 40 months. However, because other, potentially carcinogenic alkylating agents may be administered during treatment, no direct causal association with nitrosoureas can be made on the basis of these studies. A large case-control study by Boice et al. (1983), however, provides strong evidence of a causal relationship between the induction of acute nonlymphocytic leukaemia (ANLL) and treatment with methyl-CCNU. Among 2067 patients treated with methyl-CCNU and 5-fluorouracil as adjuvant chemotherapy after surgery for gastrointestinal cancers, nine cases of ANLL were observed, whereas 0.71 were expected; the relative risk was 15.9. The results are discussed and are interpreted as providing evidence for the carcinogenicity of methyl-CCNU to humans. They are therefore consistent with other epidemiological data on the carcinogenicity of N-nitroso compounds to man.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1987

Pulmonary metabolism of mutagens and its relationship with lung cancer and smoking habits.

The S-12 fractions of lung peripheral parenchyma obtained from 80 male individuals, aged 17-71 years, were assayed as blind samples for the ability either to convert promutagens into bacterial mutagens or to decrease the potency of direct-acting mutagens in the Ames reversion test. In this system, lung preparations were completely ineffective in activating an N-nitroso compound (i.e., N-nitrosomorpholine) and polycyclic aromatic hydrocarbons [i.e., 3-methylcholanthrene and benzo(a)pyrene] or their metabolites [i.e., 3-hydroxy-benzo(a)pyrene and benzo(a)pyrene-trans-7,8-diol]. They yielded a borderline and sporadic activation of a cigarette smoke condensate, and a weak but frequent activation of an aromatic amine (i.e., 2-aminofluorene), of a heterocyclic amine (i.e., 2-amino-3,4-dimethylimidazo[4,5-f] and of a diamide (i.e., cyclophosphamide). The pulmonary metabolism was more oriented in the sense of detoxification, as shown by the consistent decrease of potency of direct-acting mutagens, including a metal (i.e., sodium dichromate), an acridine and nitrogen mustard derivative (i.e., 2-methoxy-6-chloro-9-[3-(2-chloromethyl)aminopropylamino]acridine or ICR 191), an epoxide (i.e., epichlorohydrin) and an N-oxide (i.e., 4-nitroquinoline-N-oxide). As assessed by means of a numerical score quantifying the variation of mutagenicity, a marked interindividual variability (up to 20-fold) was detected in the ability of lung specimens to affect the mutagenicity of test compounds. Such variability was not significantly related to the protein concentration of S-12 fractions, nor to the age of the patients under scrutiny, who during hospitalization were on normal institutional diets and did not receive any special drug treatment. The only significant difference between 20 noncancer and 60 lung cancer patients, irrespective of the histological type, was a decreased activation of cyclophosphamide in the latter group. Probably due to the high prevalence of smokers among lung cancer patients, a significantly decreased activation of cyclophosphamide was also observed in the group of smokers. Smoking habits were associated with a stimulation of detoxifying mechanisms which, in agreement with the results of a previous study with human alveolar macrophages (F. L. Petrilli et al., J. Clin. Invest., 77:1917-1924, 1986), was significant in the case of sodium dichromate. Such effect was further enhanced by considering only individuals smoking during the last 24 h before collecting lung specimens, and under these conditions it became significant also for ICR 191.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1979

Formation of methylnitrosocyanamide from methylguanidine and sodium nitrite in simulated gastric juice and in stomachs of rats: quantitative estimation by a mutagenicity assay.

The formation of methylnitrosocyanamide (MNC), a carcionogenic N-nitroso compound, from methylguanidine (MG) and NaNO2 in simulated gastric juice (SGJ) and in the stomachs of rats was quantitatively investigated. With a reverse mutation assay in which a tester strain of Salmonella typhimurium was used, MNC formation was shown to increase linearly for about 40--60 minutes after the incubation of MG with NaNO2 in SGJ. However, it decreased rapidly thereafter. The initial rate of MNC formation was directly proportional to the initial molar ratio of MG to NaNO2, but the yields of MNC depended only on the amount of MG added and were fairly constant (0.3--0.5% of the initial MG). MNC did not form at a pH above 2.5 or in the presence of 2% casein in SGJ at pH 1.2. It decomposed rapidly in SGJ at pH 1.2 with a half-life of approximately 2 minutes, whereas it was stable in phosphate buffer at pH 7.0. Following concurrent administration of MG and NaNO2 via stomach tube, MNC formation was detected in the pylorus-ligated stomachs of rats preconditioned with a casein-free dextrin diet but not in those of rats preconditioned with a casein-containing or synthetic diet. The yields of MNC observed 40--60 minutes after administration of reactants ranged from 0.02 to 0.05% of the initial MG. The possible environment significance of MNC formation in vivo was considered.

Animals↗
PubMed1987

Marked synergism of dimethylnitrosamine carcinogenesis in rats exposed to cadmium.

The combined carcinogenic effect of cadmium and dimethylnitrosamine (DMN) was examined in male Wistar rats, to test whether the previously observed synergism in mutagenicity between cadmium and 2 N-nitroso compounds would be paralleled by a synergism in carcinogenicity. In experiment 1, 50 five-month old rats received 18 mg DMN/kg i.p. followed by cadmium i.m. in two injections totaling either 1.5 or 3.0 mg Cd2+/kg. In experiment 2, 30 weanling rats received five i.m. doses totaling 6 mg Cd2+/kg followed by 18 mg DMN/kg. After 52 weeks, the incidence of renal tubular neoplasms was significantly increased above additivity in both experiments (P = 0.0005 to 0.017). Experiment 1 also showed a synergistic increase in the incidence of neoplastic (P = 0.024) and preneoplastic (P less than 0.01) microscopic liver lesions, of tumors of organs other than liver and kidney (P less than 0.01), of malignant versus benign tumors (P = 0.038), and of multiple versus single tumors (P = 0.0019). In experiment 2, the incidence of DMN-induced hepatocellular adenomas was significantly lower than additivity, suggesting an antagonistic, protective effect of cadmium pretreatment. The overall incidence of tumors of any type was 17.5 versus 67.7% in control (one agent or none) versus test animals. Malignant tumors included carcinomas, sarcomas, and lymphomas, involving nine different sites. Cadmium appears to enhance the initiation of carcinogenesis induced by DMN. Both cadmium and nitrosamines are known environmental contaminants present in air, food, water supplies, and tobacco smoke.

Animals↗
PubMed1987

Magnetic semipermeable aqueous polyethyleneimine microcapsules for monitoring N-nitrosating species in the gastrointestinal tract.

Magnetic polyethyleneimine (PEI) microcapsules have been developed for trapping electrophilic intermediates in the gastrointestinal (GI) tract. The N-nitrosation of these microcapsules at acid pH was found to be linearly dependent on nitrite concentration, without a pH maximum and with efficient conversion to N-nitrosated products which were detected by a total N-nitroso assay procedure. The limit of detection is in the range 1-10 nmol N-nitroso compound, depending on microcapsule preparation conditions. Nuclear magnetic resonance (NMR) indicates that such N-nitrosation is favoured by incomplete protonation of the polyamine. Microcapsules administered orally to rats were recovered magnetically from faeces and showed extensive N-nitrosation when nitrite was administered in the drinking-water.

Digestive System↗