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PubMed2001

A technetium-99m-labelled cyclam acid porphyrin (CAP) for tumour imaging.

A new water-soluble cyclam acid porphyrin (CAP), 5,10,15,20-tetrakis [4-[4',8',11'-tris(carboxymethyl)-1'-(1',4',8',11'-tetraazacyclotetradecane)amidomethyleneoxy]phenyl] porphyrin has been synthesised, characterised and labelled with 99mTc. In vivo distribution studies were performed in C6-gliomas and N-nitroso-N-methylurea (NMU) induced mammary tumour bearing rats and scintiimages were obtained at 5 h post-administration of the labelled ligand using gamma camera computer system. Tumour to muscle (T/M) ratios were determined and compared with currently available tumour seeking radiopharmaceuticals such as 99mTc(V)-DMSA, 99mTc-Citrate and 201TlCl. In the case of NMU induced mammary tumour rats the ratios were 6.93, 1.97, 5.30 and 3.29; while in the case of C6-gliomas the ratios were 5.58, 2.18, 3.96 and 3.02 for 99mTc-CAP, 99mTc(V)-DMSA, 99mTc-Citrate and 203TlCl, respectively.

Animals↗

PubMed1982

[Microbial side chain splitting of phenylurea and carbonic acid anilides].

A Gram- negative rod-shaped bacterium 28/1 isolated by enrichment cultures is able to hydrolyze the amide bond of some phenylurea herbicides and acid anilide herbicides by an inducible amidase. 7.5% of 0.3 mumol.ml-1 linuron (3-(3,4-dichlorophenyl)-1-methoxy-1-methylurea) are hydrolyzed after 16 hours. 1,1-Dimethylphenylureas are not degraded. Acid anilides are hydrolyzed at a higher rate, 80% of 0.5 mumol.ml-1 N-(4-chlorophenyl)-propionamide and N-(4-nitrophenyl)-propionamide are transformed after 6 hours. The 1-methoxy-1-methyl phenylureas are effective inducers. Linuron-induced cells have a specific activity of 3-4 nmol per mg dry weight per min on the substrate N-(3,4-dichlorophenyl)-propionamide (Propanil). The rate of hydrolysis is influenced by substituents of the aniline ring and by the structure of the side chain of the acid anilides.

Amidohydrolases↗

PubMed1981

N-Nitroso-N-methylurea elicits mammary cancer in resistant and sensitive rat strains.

A single intravenous (i.v.) injection of the water-soluble mammary carcinogen N-nitroso-N-methylurea (NMU; 35 mg/kg of body weight) elicited cancer of the breast in young female rats of two strains in the following incidence: Long-Evans strain, 4%; Sprague-Dawley strain, 70%. In sisters of these rats, a set of 5 i.v. injections of NMU (35 mg/kg at biweekly intervals) evoked mammary carcinoma as follows: Long-Evans strain, 76%; Sprague-Dawley strain, 100%. In its effectiveness in evoking mammary cancer in Sprague-Dawley rats, the lipid-soluble mammary carcinogen 7,8,12-trimethylbenz[a]anthracene exceeded NMU in rapidity of development of cancer and in tumor yield.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1980

[Mammary gland tumor induction in rats by N-nitroso-N-methylurea and N-methyl-N1-nitro-N-nitrosoguanidine].

Cancer of the mammary gland was induced in female non-inbred rats under the local effect of N-nitroso-N-methylurea (NMU) and N-methyl-N-nitro-N-nitrosoguanidine (MNNG). During 10 weeks 2.5 mg of the substance in 0.2 ml of saline was injected in the region of the third mammary gland once a week. Under NMU exposure a primary tumor arose 3 months following the initiation of the experiment, the average latent period being 5.8 months, the incidence rate--76.7%. All tumors of this series were adenocarcinomas, in 5 cases there were noted sites of fibroadenomatosis with malignification along the tumor node margins. MNNG produced a primary tumor at the 7th month of the experiment, an average latent period--8.3 months, the incidence rate--56.7%. Tumors were mostly adenocarcinomas.

Animals↗

PubMed1977

[Effect of N-nitroso-N'-methylurea on the cellular kinetics in tumors].

Single intrafemoral injection of NMU in the dosage of 80 mg/Kh in mice with ascites leucemia L1210 induced considerable disorders in the tumor cell cycle. The passage of phase S by cells was markedly retarded during the period from 1 hour to 6 days, while after injection of the substance under study a maximum duration of phase G2 increased from 4 to 12 hours. Inhibition of phase S onset was provisional, and already 6 hours following NMU injection all cells entered phase S. In mice mammary tumors the label index fell markedly (by 90%) during the period from 6 hours to 8 days after NMU injection. The intensity of 3H-thymidine incorporation during the whole period of observation was approximately twice reduced.

Animals↗

PubMed1999

Mutagenesis induced by oral carcinogens in lacZ mouse (MutaMouse) tongue and other oral tissues.

Animal models for carcinogenesis of the oral cavity are limited, although this disease is often fatal or disfiguring and its incidence in the USA is approximately 30 000 cases/year. Short-term whole-animal models for this disease should prove valuable in the investigation of factors affecting oral carcinogenesis. In this study we observed that a group of oral carcinogens are clearly mutagenic in the lacZ transgenic mouse oral cavity. The carcinogens 4-nitroquinoline-N-oxide (4-NQO), benzo[a]pyrene (B[a]P), N-nitroso-N-methylurea (NMU), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), nitrosonornicotine (NNN) and 7,12-dimethylbenzanthracene (DMBA) were all mutagenic in a mixture of pooled oral tissues (gingival, buccal, pharyngeal and sublingual) and in the tongue. All agents except DMBA (which was swabbed in the oral cavity) and B[a]P (by gavage) were given in drinking water for 2-4 weeks followed by a 2 week expression period before killing. With one exception, groups of 4-5 female mice were treated. The doses and mutant fractions (MF) in DNA isolated from pooled oral tissues (in mutants/10(5) p.f.u. +/- SD) were: 4-NQO (20-80 microg/ml, over 4 weeks) 78 +/- 16; B[a]P (five doses of 125 mg/ml) 33.2 +/- 10.9; NMU (20-80 microg/ml over 4 weeks) 7.8 +/- 2.6; NNK (0.1 mg/ml, weeks 1-2, 0.2 mg/ml, weeks 3-4) 9.1 +/- 3.0; NNN (same dose as NNK) 9.2 +/- 1.6 and DMBA (0.5 mg/ml in corn oil, 3 weeks) 7.1 +/- 2.7. The corresponding value for untreated controls was 3.2 +/- 1.8. Values for induced mutagenesis in tongue from the same animals were similar except for 4-NQO which was about twice as potent in tongue. Mutagenesis by several compounds was compared in other organs. B[a]P was assayed in lung and kidney and was about twice as mutagenic in oral tissues as in lung, but several times less mutagenic in kidney. Lung, but not kidney is a target organ for B[a]P-induced carcinogenesis in the mouse. NNK was somewhat more mutagenic in lung (MF of 15.0 +/- 5.5) than in oral tissues, corresponding with previous reports on carcinogenesis by NNK. Mutagenesis induced by NNN was also assayed in esophagus, a target organ in rodents, and was similar to that in oral tissue. In all cases the MF in untreated control group was about 3-4. These results suggest that: (i) the oral cavity has a significant capacity for metabolic activation of carcinogens; (ii) DNA damage in the oral cavity can be converted to mutations; and (iii) there is significant target organ specificity. The results also tend to support the concept that the anatomical components of the upper aerodigestive tract, in general, behave similarly with respect to genotoxicity. As carcinogenesis is believed to involve mutagenesis, this study demonstrates the utility of the lacZ mouse for investigations involving initiation of carcinogenesis of the oral cavity.

Animals↗

PubMed1978

Primary culture of rat mammary epithelial cells. II. Cytotoxic effect and metabolism of 7,12-dimethylbenz[a]anthracene and N-nitroso-N-methylurea.

To determine the cytotoxicity of 7,12-dimethylbenz[a]anthracene (DMBA) and N-nitroso-N-methylurea (NMU) on primary cultures of rat mammary cells, cultures were exposed to various concentrations of these carcinogens. Cytotoxicity was evident after exposure for 24 hours to as little as 0.1 microgram DMBA/ml. Cytotoxicity was evident after exposure for 2 hours with NMU at concentrations between 80 and 160 microgram/ml. Primary cultures of rat mammary cells were also examined for their ability to metabolize [3H]DMBA into water-soluble products. During a 48-hour period, mammary cells could convert 2.2% [3H]DMBA to water-soluble metabolites. The cells retained (for at least 4 days) small quantities of [3H]DMBA that were insoluble in organic solvents.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1976

[Effect of N-nitroso-N-methylurea on DNA and RNA synthesis in cells of liver and spleen tumors in leucosis L-1210].

During the development of leucosis a progressively retarded incorporation of 2-C14-thymidine and C14-uridine into DNA and RNA of a separate tumor cell and an active incorporation of 2-C14-thymidine into DNA of hepatic and splenic cells were observed. Repeated injections of NMU (20 mg/Kg X 5) in tumor-bearing animals result in a twice increase of life terms in mice and suppression of total tumor cells growth. The observed therapeutic effect is related with deep inhibition of DNA and RNA synthesis in leucosis L-1210 cells, while DNA synthesis in hepatic and splenic cells is only insignificantly suppressed (compared with the normal level typical for intact animals), but RNA synthesis in these organs is actually not involved.

Animals↗

PubMed1984

[Effect of nitrosourea in small doses on the frequency of mutation in Salmonella typhimurium].

The effect of N-nitroso-N-methylurea (NMU), N-nitroso-N,N'-dimethylurea (NDMU) and N-nitroso-N-ethylurea (NEU) at doses less than 100 mkg/ml on mutability of Salmonella typhimurium strains of Ames' system (G-46, TA-1950, TA-1535, TA-100, TA-1538) has been studied. NMU and NEU at doses of 5-10 mkg/ml have been found to increase the survival and decrease the number of reversions from auxotrophity in histidine to prototrophity. The effect of given doses of NMU and NEU on bacteria repair activity has been shown. The role of pk M101 plasmide in this process is being discussed. NDMU in contrast to NMU and NEU induces read frome shift mutations and exhibits high mutagenous activity at all doses examined.

Dose-Response Relationship, Drug↗

PubMed1982

[Determination of target cells in the by N-nitroso-N-methylurea induced leukemogenesis in the mouse].

Using the model of chemically induced leukemogenesis of mice by N-nitroso-N-methyl urea (NMU) studies were done to find out the primary point of attack of the chosen carcinogen on cellular level. After application of 14C-NMU (XVII X AKR) F1 hybrid mice were killed at different times, and the 14C activity was determined in various organs by scintillation counting and autoradiography. Contrary to expectations, the bone marrow showed a significantly higher activity than the thymus, which is supposed to be the target organ for lymphatic leukemogenesis. The specificity of the enrichment of 14C activity in bone marrow could be assured by comparative proliferation studies. The autoradiographic results favor the lymphatic cells of bone marrow as target for NMU. The target cell problem is discussed in respect to thymectomy and recent results on nude mice. With high probability the thymus is not essential for lymphatic leukemogenesis and, consequently, is not the target organ.

Animals↗

PubMed2001

Occurrence of antifouling biocides in the Spanish Mediterranean marine environment.

A compilation of the results of a monitoring program of the recently used antifouling pesticides diuron (3-(3,4-dichlorophenyl)-1,1-dimethylurea), Irgarol 1051 (2-methylthio-4-tertiary-butylamino-6-cyclopropylamino-s-teiazine), seanine 211 (4,5-dichloro-2-n-octyl-4-isothazolin-3-one), chlorothalonil (2,4,5,6-tetrachloro-isophthalonitrile), dichlofluanid (N'-dimethyl-N-phenylsulphanamide), TCMTB ((2-thiocyanomethylthio) benzothiazole), and three degradation products demethyldiuron (3-(3,4-dichlorophenyl)-1-methylurea),3,4-dichlorophenylurea and 2-methylthio-4-tert-butylamino-s-triazine (Irgarol degradation product) that was carried out between April 1996 and February 2000 in enclosed seawaters from Catalonia and Almería (Spanish Mediterranean coast) is reported. Nine points were sampled along the Catalan coast: Barcelona Olympic port, Masnou, Blanes, Sant Carles de la Ràpita, Tarragona, Cambrils and Salou marinas as well as the Cambrils and Tarragona fishing harbors and in marinas and ports from Almeria: Aguadulce port, Almería port, Almerimar fishing harbour and Almerimar marina. The analytical methodologies were based on Solid Phase Extraction followed by liquid chromatography (LC) or gas chromatography (GC) coupled to a mass spectrometry (MS) or -Diode Array Detector. The main pollutants found in the sampled points were diuron and Irgarol 1051 that were detected at concentrations up to 2.19 micrograms l-1 and 0.33 microgram l-1, respectively. On the other hand, seanine 211 was found at the highest concentration (up to 3.7 micrograms l-1) during the summer of 1999. Low concentrations of dichlofluanid and the above mentioned degradation products were detected for the first time in the Spanish coasts. Chlorothalonil, TCMTB were not found at concentrations higher than 1 and 20 ng l-1 respectively which were the limit of determination (LOD) of the method for these compounds. In general the contamination at the different marinas is higher at the end of spring and in summer where the boating activity is also higher. This paper shows for the first time that the contamination by the new antifouling pesticides in Spanish coastline, basically marinas and fishing harbours, is permanent along the whole calendar year. So, preventive actions by the harbour authorities will be needed in the near future in order to monitor and control the levels and effects of the new antifouling biocides in the marine environment.

Chromatography, High Pressure Liquid↗

PubMed1983

Adenocarcinomas of the prostate induced by N-nitroso-N-methylurea in rats pretreated with cyproterone acetate and testosterone.

Prostatic adenocarcinomas were induced in 5 out of 20 Wistar rats upon a single administration of 50 mg/kg N-nitroso-N-methylurea (NMU). The rats were pretreated with a daily dose of 50 mg/kg cyproterone acetate for 3 weeks followed by 3 daily injections of 100 mg/kg testosterone. All tumours developed in the dorsolateral prostate and were invasively growing. In 2 cases distant metastases were found. Three proliferative lesions classified as carcinomas in situ were also found in the dorsolateral prostate. A total of 7/20 animals (35%) carried an adenocarcinoma and/or a carcinoma in situ. In addition, 6 epithelial hyperplasias were observed in the dorsolateral and 1 in the ventral prostate of non-tumour-bearing rats. The method described may provide a good animal model for cancer of the prostate and lead to a better understanding of prostatic carcinogenesis.

Adenocarcinoma↗

PubMed1980

[Comparative effectiveness of using different tests to determine the mutagenicity of certain factors in mammals. I. Frequency of dominant lethal mutations and chromosome aberrations in mouse bone marrow cells induced by N-nitrosomorpholine, N-nitroso-N-methylurea and cyclophosphamide].

Two tests (the frequency of dominant lethal mutations at different stages of spermatogenesis and the yield of chromosome aberrations in bone marrow cells) were used to investigate mutagenisity of N-nitrosomorpholine (NM), N-nitroso-N-methylurea (NMU) and cyclophosphamide (CTX). The drugs were injected once intraperitoneally to male mice (F1 of CBA X C57BL) at doses of NM--50 mg/kg; NMU--50 mg/kg; CTX--50, 100, 200 and 300 mg/kg. It was established that NM was not mutagenic in the mouse as measured by these two tests. NMU was a weak mutagen at the stated exposure, since there was only slight increase in the frequency of dominant lethal mutations in late spermatids and spermatogonia, and also a low yield of chromosome aberrations in bone marrow cells was induced. CTX had a strong mutagenic effect on postmeiotic stages of spermatogenesis and in bone marrow cells.

Animals↗

PubMed1982

Resistance of Salmonella typhimurium TA 1535 to O6-guanine methylation and mutagenesis induced by low doses of N-methyl-N'-nitro-N-nitrosoguanidine: an apparent constitutive repair activity.

Salmonella tester strains which are reverted by base-pair substitution mutagens are relatively insensitive to the mutagenic effects of N-methyl-N-nitroso compounds. One reason for this insensitivity is the ability of these strains to withstand low doses of these compounds before they become sensitive to their mutagenic effects. In this report it is shown that mutagenesis induced by treatment of Salmonella typhimurium TA 1535 with N-methyl-N'-nitro-N-nitroso-guanidine (MNNG) in buffer is biphasic with a low sensitivity range at low doses where little mutagenesis occurs, followed by a high sensitivity range whose onset begins after an apparent threshold dose has been exceeded. levels of O6-methylguanine (O6-MeG) in the DNA extracted from the bacteria follow a similar dose-response curve suggesting a dependency of mutagenesis on O6-MeG. In contrast, levels of 7-methylguanine (7-MeG) in the DNA increase linearly with dose. O6-MeG was undetectable at the lowest dose of MNNG whereas 7-MeG was readily detectable. Although such resistance to O6-alkylation has been demonstrated in MNNG- pretreated (adapted) E. coli, it has not been reported in unpretreated cells. Then isolated DNA was treated with MNNG a linear dose-response in the generation of O6-MeG was observed. The lack of O6-MeG in DNA isolated from MNNG treated cells after low doses is attributed to a saturable, constitutive repair activity in the bacteria. An attempt to observe the removal of O6-MeG from the bacteria after exposure to a short challenge dose of N-nitroso-N-methylurea (NMU) followed by a subsequent incubation in buffer was unsuccessful, probably because all the repair occurred within the time necessary to treat and lyse the cells.

Chromatography, High Pressure Liquid↗

PubMed1978

Effects of carcinogen dose on the characteristics of the tracheal tumor response induced by N-nitroso-N-methylurea in hamsters.

Tracheal tumors were induced by repeated intratracheal exposures to the carcinogen N-nitroso-N-methylurea (NMU), using a catheter system previously described. Carcinogen concentrations of 0.25, 0.50 and 1.0% were employed in 20 or 30 twice-weekly exposures. Most of the tumors developed in the mid-portion of the tracheas. Virtually all tumors developed after the end of the 10- to 15-week exposure period. Tumor incidence ranged from 20-94% with mean tumor induction times of 13-46 weeks, depending on NMU concentration and frequency of exposure (i.e., dose). At lower doses, mostly non-invasive tumors were induced; at higher doses, mostly invasive carcinomas of various histological types (epidermoid, adeno-, epidermoid-adeno, and anaplastic large- and small-cell carcinomas) were induced. Adenocarcinomas were most frequent at low NMU concentrations. The possible mechanisms of the carcinogen dose effects are discussed.

Adenocarcinoma↗

PubMed1981

Carcinogenesis and aging. I. Modifying effects of aging on N-methyl-N-nitrosourea-induced carcinogenesis in female rats.

3- or 14-month-old female rats were intravenously injected N-nitroso-N-methylurea (MNU), 50 mg/kg body weight, 2 or 4 times weekly. There was a direct correlation between the incidence of mammary carcinomas and MNU doses. Kidney tumors occurred inversely proportional to the dose of the carcinogen. Mammary adenocarcinomas were only observed in young MNU-treated rats. Cervicovaginal malignant tumors were only observed in old MNU-treated rats. The incidence of hematopoietic system tumors was the same in animals of both age groups. Rats treated with MNU showed acceleration of benign spontaneous tumor development. The effect of aging on the initial stage of MNU-induced carcinogenesis is believed to be determined by age-associated changes in the proliferative activity of target tissues. The effect of aging on the further development of carcinogenesis may be caused by age-associated hormonal, metabolic, and immunological shifts.

Aging↗

PubMed2000

Effects of in utero exposure to linuron on androgen-dependent reproductive development in the male Crl:CD(SD)BR rat.

Linuron (3-(3,4-dichlorophenyl)-1-methoxy-1-methylurea) is a herbicide that blocks androgen action in the male rat. Studies were undertaken to characterize the ability of linuron to activate transcription through the human androgen receptor (AR) in vitro and to determine whether in utero linuron exposure induces dose-responsive alterations in androgen-dependent reproductive development in the male rat. In vitro, linuron competitively antagonized transcriptional activity of the AR induced by dihydrotestosterone (DHT) in a dose-responsive manner with an equilibrium dissociation constant (K(B)) of 75.8 x 10(-8) M. Pregnant rats were administered linuron by gavage at 0, 12.5, 25, or 50 mg/kg/day (n = 11/group) from gestation day 12 to 21. Anogenital distance of resulting offspring was unaffected, whereas male areola/nipple retention was increased in a dose-responsive manner. Hypoplastic testes in adult offspring were seen in 2/56 rats (2/10 litters), 8/69 rats (4/11 litters), and 5/44 rats (3/8 litters), while hypoplastic epididymides occurred in 1/56 rats (1/10 litters), 8/69 rats (4/11 litters), and 2/44 rats (1/8 litters) in the 12.5, 25, and 50 mg/kg/day dose groups, respectively. Partial agenesis of the epididymides was observed in 3/44 rats (2/8 litters) only in the 50 mg/kg/day group. These data indicate that in utero exposure to linuron preferentially impairs testosterone-mediated, rather than DHT-mediated, reproductive development. This effect is distinctly different from the effects induced by flutamide, an AR antagonist that shares structural similarities with linuron. Furthermore, these data suggest that dose-response studies utilizing late gestational exposure to endocrine-active compounds may be more robust than the traditional or EPA-modified multigeneration protocols in identifying adverse effects.

Androgens↗

PubMed1974

The effect of N-nitroso-N-methylurea and N-dimethylnitrosamine on cell mediated and humoral immune responses in rats and mice.

N-Nitroso-N-methylurea (NMU) induced a marked dose dependent leucopoenia which was associated with an increased survival of skin allografts in adult rats and in 2 strains of mice. The humoral immune response to NMU as assessed by haemolytic plaque formation and haemagglutination was also much reduced. Dimethylnitrosamine (DMN) which, like NMU is a powerful carcinogen and an alkylating agent, showed no immunosuppressive activity after a single dose in rats on either a normal diet or fed a protein-free diet which enhances kidney tumourigenesis. In mice DMN at a near LD(50) dose (14 mg/kg) had no effect on skin graft survival but did reduce the humoral response. At half this dose level, however, no immunosuppressive effect was seen. The results support the conclusion that the immunosuppressive activity of a chemical carcinogen is not necessarily associated with the expression of its carcinogenicity.

Animals↗