SEARCH · PubMed Health
Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
N-nitroso-N-methylurea (a total dosage--6 mg per animal), administered by a catheter in the urinary bladder cavity in female rats, following 9--56 weeks induced in 16 of 23 rats tumors of the vesical mucous membrane (mostly transitional cell papillomas).
beta-Mercaptoethylamine (MEA) decreased the accumulation of enzymatic single- and double-strand breaks in DNA of thermophilic bacteria exposed to gamma- and UV-radiation and treated with N-nitroso-N-methylurea. The protective effect of MEA, as registered according to accumulation of single-strand and double-strand breaks in DNA of Bac. stearothermophilus immediately after irradiation and after 30 min postirradiation incubation, was similar.
1. The effect of urea on the lactate-dehydrogenase activities of human-heart and -liver tissue extracts and on crystalline ox-heart and rabbit-muscle enzyme have been determined. Similar studies on electrophoretically separated isoenzyme fractions have shown an inverse relationship between sensitivity to urea inhibition and electrophoretic mobility. 2. With pyruvate as substrate a sharp change in the nature of the inhibition of tissue lactate dehydrogenase with increasing concentrations of urea occurs at 1 m or 4 m with the electrophoretically slow and fast isoenzymes respectively. 3. At concentrations of urea less than 1 m, inhibition of the purified enzymes is competitive with respect to pyruvate and 2-oxobutyrate. 4. Similar studies have been carried out with methylurea and hydantoic acid, both of which are more potent inhibitors than urea.
Inhibitory effects of eugenol, a compound present in many spices such as cloves, cardamom etc. and the extracts of Anacyclus pyrethrum and Spilanthes calva which are traditionally used in India during the preparation of chewable tobacco, on tobacco-induced mutagenesis were evaluated using Ames Salmonella/microsome assay. Eugenol significantly inhibited (P < 0.001) tobacco-induced mutagenicity at concentrations of 0.5 and 1 mg/plate. Anacyclus pyrethrum extract (1 mg/plate) produced 74.33% inhibition while the extract of Spilanthes calva at 2 mg/plate inhibited tobacco-induced mutagenesis by 86.4%. Eugenol and the plant extracts also inhibited the nitrosation of methylurea in a dose-dependent manner.
Strain XVII mice with Graffi virus induced leukemia of various hematological types showed a pronounced thrombocytopenia which was severe in erythroblastic leukemia and weaker in lymphatic ones. The thrombocytic reactions shortly following Friend and Rauscher virus applications and occurred 3 weeks after birth in AKR mice are not found in Graffi virus system. A significant preleukemic thrombocytopenia did appear only 8 weeks after Graffi virus infection. The origin of both the preleukemic and the secondary thrombocytic reactions are discussed. (XVII X AKR) F1 hybrids, neonatally treated with N-nitroso-N-methylurea (NMU), resulted also in a decline in the number of thrombocytes after manifestation of leukemia. In contrast to the expection following NMU treatment a preleukemic thrombocytopenia appeared as in viral leukemogenesis too. The possibility of a co-operation of oncogenic viruses in chemical carcinogenesis is considered.
A diet high in fat and iron is known as a risk factor in cancer epidemiology. However, the details of the molecular mechanism remains to be elucidated. We examined the possible implication of lipid peroxyl radicals generated from fatty acids and heme-iron in DNA damage, and hence in the possibility of colon cancer. F344 female rats were given N-nitroso-N-methylurea six times during a 2-week period and then fed diets containing different amounts of safflower oil and hemoglobin (rich in iron) for 36 weeks; the occurrence of colon cancer was determined by H&E staining. In this animal model, simultaneous feeding of a fat diet and heme-iron produced a significant increase (P < 0.05) in the incidence of colon cancer compared with a diet without hemoglobin. Electron paramagnetic resonance and chemiluminescence studies revealed that oxidized refined vegetable oils, particularly safflower oil, readily generated lipid peroxyl radicals in the presence of various heme compounds, and the peroxyl radicals did effectively cleave DNA. Unpurified native vegetable oils contain a high amount of peroxyl radical scavengers, whereas conventional refining processes seem to reduce the levels of many valuable anti-peroxyl radical compounds abundant in plant seeds. In conclusion, lipid peroxides and heme components generate peroxyl radical species that exert DNA-cleaving activity. A plausible explanation is that lipid peroxyl radicals thus generated, which originated from routine dietary components such as fat and red meat, may contribute, at least in part, to the high incidence of colon cancer.
The effect of the ureic herbicide Linuron [3-(3,4-dichlorophenyl)-1-methoxy-1-methylurea] on the levels of some hepatic xenobiotic metabolizing enzymes was studied in rats. The cytochrome P450-dependent monooxigenase activities of aryl hydrocarbon hydroxylase (AHH) and of aminopyrine N-demethylase (APD) were measured in rat livers after a 14-d treatment by gavage with Linuron. AHH was employed as a marker of the catalytic activity of P450IA1 and APD as a marker of the catalytic activity of P450IIB1/2. Furthermore, the enzymatic activities of the cytosolic via glutathione detoxifying enzymes glutathione peroxidase and glutathione S-transferase were assessed. Three doses of Linuron (both as pure compound and as commercial preparation) were tested. The doses tested were 150, 300, and 450 mg/kg body weight for the pure compound and 315.8, 631.6, and 947.4 mg/kg for the commercial preparation. Differences were found in the relative liver weight only in rats treated with the commercial formulation. The aryl hydrocarbon hydroxylase activity was increased with all the tested doses of pure and commercial Linuron. A reduction in the aminopyrine N-demethylase activity was noted for the highest dose of pure Linuron, whereas an increment in this activity was observed for all the doses of the commercial preparation tested. The activity of glutathione peroxidase was not affected by treatment with the pure product; however, an increment in activity was observed at all the tested doses of the commercial preparation. The glutathione S-transferase activity was reduced in both cases.
Metallothioneins (MTs) are low molecular weight proteins, mainly implicated in metal ion detoxification. Increase in MT contents is considered to be a specific biomarker of metal exposure. Recently it has been demonstrated that MTs participate in several cellular functions such as regulation of growth, and antioxidative defenses. Therefore, the induction of MTs as biomarkers of exposure to the pesticide isoproturon has been investigated in the aquatic worms Tubifex tubifex. MT levels in exposed worms increased significantly (p < 0.05) after 2, 4, and 7 days of exposure to different concentrations of isoproturon (maximum increase compared to unexposed controls: +148.56% for 10 mg l(-1) after 4 days of exposure). In response to isoproturon, the activity of glutathione-S-transferase (max. +52%), glutathione-reductase (max. +100%), and catalase (max. +117%) increased, demonstrating the occurrence of an oxidative stress response to the herbicide. Thus, the increase in MT contents caused by isoproturon was interpreted as a defense response towards increased oxidative stress generated by the herbicide. Residues of isoproturon and its metabolites, 1-(4-isopropylphenyl)-3-methylurea, 1-(4-isopropylphenyl) urea, and 4-isopropylanilin were detected in the worm growth medium. Half-life of the herbicide was shorter at a low (0.1 mg l(-1)) initial concentration. The herbicide accumulated in T. tubifex but no metabolite could be detected.
Antimutagenic, anticlastogenic, and bioprotective effect of polysaccharide glucomannan (GM) isolated from Candida utilis was evaluated in four model test systems. The antimutagenic effect of GM against 9-aminoacridine (9-AA)- and sodium azide (NaN3)-induced mutagenicity was revealed in the Salmonella typhimurium strains TA97 and TA100, respectively. GM showed anticlastogenic effect against N-nitroso-N'-methylurea (NMU) induced chromosome aberrations in the Vicia sativa assay. The bioprotective effect of GM co-treated with methyl-methane-sulphonate (MMS) was also established in Chlamydomonas reinhardtii repair deficient strains uvs10 and uvs14. The statistically significant antimutagenic potential of GM was not proved against 4-nitro-quinoline-1-oxide (4-NQO)-induced mutagenicity in Saccharomyces cerevisiae D7 assay. It may be due to bioprotectivity of alpha-mannan and beta-glucan, which are integral part of S. cerevisiae cell walls. Due to the good water solubility, low molecular weight (30 kDa), antimutagenic/anticlastogenic, and bioprotective activity against chemical compounds differing in mode of action, GM appears to be a promising natural protective (antimutagenic) agent.
The conventional treatment of uterine leiomyomas, or fibroids, with gonadotropin-releasing hormone (GnRH) agonists is often associated with serious side effects, necessitating short-term, palliative use of this therapy. Therefore, we examined a retinoid X receptor (RXR)-selective ligand, LGD1069, as a possible treatment for leiomyoma. LGD1069 has demonstrated efficacy as a chemopreventive agent in the N-nitroso-N-methylurea (NMU)-induced rat mammary carcinoma model and is a therapeutic agent in several epithelial tumor models. Previous studies have shown that it has both antitumor effects and antiestrogenic activity in the rat uterus, suggesting the potential utility of this agent for treatment of hormonally dependent uterine fibroids. The expression of retinoid receptors in tumors and cell lines derived from leiomyomas arising in the Eker rat was confirmed by Northern analysis. After treatment for 4 months with LGD1069, the number of grossly observable tumors was substantially reduced although the total incidence of tumors, including microscopic lesions, remained unaffected, suggesting an effect of the compound on tumor growth kinetics rather than on tumor initiation. Analysis of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining and determination of 5-bromo-2-deoxyuridine (BrdU) incorporation indicated that the reduction in grossly observable tumors that occurred in treated animals was mediated by a significant increase in the level of apoptosis rather than a decrease in cell proliferation. These results suggest that LGD1069 may be an effective therapeutic agent for uterine leiomyoma that may inhibit tumor growth and, consequently, alleviate the symptoms associated with this disease.
A series of iron(III) complexes of the tetradentate ligand BPMEN (N,N'-dimethyl-N,N'-bis(2-pyridylmethyl)ethane-1,2-diamine) were prepared and structurally characterized. Complex [Fe(2)(mu-O)(mu-OH)(BPMEN)(2)](ClO(4))(3) (1) contains a (mu-oxo)(mu-hydroxo)diiron(III) diamond core. Complex [Fe(BPMEN)(urea)(OEt)](ClO(4))(2) (2) is a rare example of a mononuclear non-heme iron(III) alkoxide complex. Complexes [Fe(2)(mu-O)(mu-OC(NH(2))NH)(BPMEN)(2)](ClO(4))(3) (3) and [Fe(2)(mu-O)(mu-OC(NHMe)NH)(BPMEN)(2)](ClO(4))(3) (4) feature N,O-bridging deprotonated urea ligands. The kinetics and equilibrium of the reactions of 1 with ligands L (L = water, urea, 1-methylurea, 1,1-dimethylurea, 1,3-dimethylurea, 1,1,3,3-tetramethylurea, and acetamide) in acetonitrile solutions were studied by stopped-flow UV-vis spectrophotometry, NMR, and mass spectrometry. All these ligands react with 1 in a rapid equilibrium, opening the four-membered Fe(III)(mu-O)(mu-OH)Fe(III) core and forming intermediates with a (HO)Fe(III)(mu-O)Fe(III)(L) core. The entropy and enthalpy for urea binding through oxygen are DeltaH degrees = -25 kJ mol(-1) and DeltaS degrees = -53.4 J mol(-1) K(-1) with an equilibrium constant of K(1) = 37 L mol(-1) at 25 degrees C. Addition of methyl groups on one of the urea nitrogen did not affect this reaction, but the addition of methyl groups on both nitrogens considerably decreased the value of K(1). An opening of the hydroxo bridge in the diamond core complex [Fe(2)(mu-O)(mu-OH)(BPMEN)(2)] is a rapid associative process, with activation enthalpy of about 60 kJ mol(-1) and activation entropies ranging from -25 to -43 J mol(-1) K(-1). For the incoming ligands with the -CONH(2) functionality (urea, 1-methylurea, 1,1-dimethylurea, and acetamide), a second, slow step occurs, leading to the formation of stable N,O-coordinated amidate diiron(III) species such as 3 and 4. The rate of this ring-closure reaction is controlled by the steric bulk of the incoming ligand and by the acidity of the amide group.
The value of alpha,beta-unsaturated ketones as key intermediates for the combinatorial assembly of four different templates on the solid phase, namely pyrimidines, dihydropyrimidinones, pyridines, and pyrazoles, was explored with individual syntheses of variably substituted model compounds. Starting from aldehydes grafted on polystyrene support, the Wittig and the Claisen-Schmidt reaction conditions were adapted to efficiently prepare alpha,beta-unsaturated ketones on the solid phase. Further derivatization of the alpha,beta-unsaturated ketones to form pyrimidines succeeded with a number of amidines. In a feasibility study, the potential to obtain, in a modular fashion, other small heterocycles from the same intermediates was assessed. In this solid-phase approach alpha,beta-unsaturated carbonyl intermediates can act as a three-carbon component and a primary enamine is utilized to complement the system for pyridine ring formation. Instead, with N-methylurea a dihydropyrimidinone is obtained. As an alternative, substituted hydrazines are incorporated in one orientation, providing pyrazoles with defined regioisomerism. The study indicates that alpha,beta-unsaturated ketones grafted on the solid phase can take a pivotal role as branching points in a number of synthetic diversity schemes and, therefore, represent versatile intermediates for the efficient preparation of combinatorial small molecule libraries.
The cycle of Chlorella cells development is shortened under the action of NMU. The effect of stimulation is dependent on the cell developmental stage at the time of treatment with the mutagen. This effect is absent in cells being at the first and final stages of the development. The maximum stimulation is observed after treatment of the 14 hours old culture (the mutagen concentration being 35.10(-7) M) and proceeds during several generations.
The interactions between N-methylurea, N,N'-dimethylurea, N,N-dimethylurea, tetramethylurea, and thiourea and the hydroxide-bridged dinickel complex [Ni(2)(mu-OH)(mu-H2O)(bdptz)(H2O2](OTs)(3) were investigated. Structural characterization of [Ni(2)(mu-OH)(mu-H2O)(bdptz)(Me-urea)(CH3CN)](ClO4)(3) (1) and [Ni(2)(mu-OH)(mu-H2O)(bdptz)(thiourea)(CH3CN)](ClO4)(3) (2) provided insight into the interactions of the substrates with the dinickel center. In 1, the methylurea molecule coordinates to the dinickel complex through its carbonyl oxygen atom. Complex 2 has a similar geometry, with the thiourea molecule bound to a nickel ion through its sulfur atom. When the urea substrates are heated in the presence of the hydroxide-bridged dinickel complex, N-methylurea and N,N-dimethylurea react to form methylammonium cyanate and dimethylammonium cyanate, respectively. After long reaction times, thiourea reacts similarly, producing ammonium thiocyanate. The other substrates are unreactive. These results indicate that the dinickel complex promotes the elimination of alkylamines from urea substrates to form cyanate but cannot effect the direct hydrolysis of such substrates.
Three varieties of kola nut, Cola acuminata, C. nitida and Garcinia cola, of Nigerian origin, were analysed for their content of primary and secondary amines, and assessed for their relative methylating potential due to nitrosamide formation. Primary and secondary amines were determined as benzene sulfonamides by gas chromatography/thermal energy analysis (GC/TEA). Dimethylamine, methylamine, ethylamine and isopentylamine were detected in all kola nut varieties, while pyrrolidine, piperidine and isobutylamine were detected in one or more varieties. Estimated average total daily intake of aliphatic amines by a typical kola nut chewer varied from 260 to 1040 micrograms/day for secondary amines and from 2430 to 9710 micrograms/day for primary amines. Methylating activity of the nitrosated kola nuts, expressed as N-nitroso-N-methylurea equivalents, was also determined by GC/TEA. Methylating activity was significantly higher in kola nuts (170-490 micrograms/kg) than has ever been reported for a fresh plant product. These data suggest that the possible role of kola nut chewing in human cancer aetiology should be explored in countries where kola nuts are widely consumed as stimulants.
The function of: (see article), fits the tumors weight growth for all studied generations in both control and treated animals. Morphological studies show the transplantable tumors in A mice to lose their similarity to a spontaneous tumor--low differentiated adenocarcinoma. Meanwhile, the tumors in C3H mice have a high differentiation level which is typical for the original tumor. 1-nitroso-1-methylurea is very effective against the first generation of tumors in both strains of mice. The tumors response to the drug becomes weaker with further passages. 1-nitroso-1-methyl urea is superior to other nitrous derivatives when used in such tumor models as breast adenocarcinoma in C3H mice.
Tumors in the soft tissues of the oral cavity of rats developed at predetermined sites as a result of a combination of an intraperitoneal injection of a direct-acting carcinogen. N-nitro-N-methylurea, and a continuous irritation of the buccal mucosa by a stainless steel wire. The incidence of histologically malignant tumors was significantly higher in the irritated area than in any other area of the body. These results constitute evidence for a carcinogenic mechanism whereby the cells that develop into tumors may require the promotional effect of a nonspecific, nonmutagenic stimulus.
The carcinogenic effect of several dose levels and regimens of an aqueous solution of N-methyl-N-nitrosourea (MNU) administered intrarectally to mice and rats is reported. In Ha/ICR Swiss mice, a single dose of 1.8 mg MNU induces mainly lymphomas and pulmonary tumors in less than 20 weeks. Repeated doses of 1.5 mg MNU induces lymphomas, pulmonary tumors, and also large bowel tumors in less than 20 weeks. Doses of 0.3 mg decreased the yield of lymphomas and increased large bowel neoplasms over a period of 40 to 60 weeks. Repeated doses of 0.06 mg also gave a low yield of lymphomas and large bowel tumors over a 60-week period. Thus, a maximal yield of lymphomas is seen with a brief regimen of high doses, whereas large bowel tumors occur with a more frequent lower dose rate. Male Fischer strain rats given 1.0 or 2.5 mg MNU 3 times a week for 10 weeks had a multiplicity of large bowel tumors, proportional to dose, in 25 to 30 weeks. In fact, the high dose level led to a 100% yield in less than 20 weeks. Lymphomas were seen only at the higher dose when the animals were were young, at the beginning of the test. In mice and rats the carcinomas were polypoid or plaque shaped and were well differentiated with extensive invasion but no metastases. The adenomas were pedunculated or sessile. Intrarectal administration of a mixture of methylurea and nitrite for 20 weeks and further observation of the rats for an additional 35 weeks yielded no colon tumors. Thus, there is indirect evidence of a lack of the in situ formation of carcinogenic MNU in the large bowel under physiological conditions.