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PubMed2004

Extending the working range of immunoanalysis by exploitation of two monoclonal antibodies.

A newly established rat monoclonal antibody (mAb) for isoproturon, namely, IOC 10G7, is described. This mAb shows a standard curve for isoproturon in phosphate-buffered saline with a test midpoint of 5.5 +/- 1.8 microg/L (n = 15). In combination with the formerly developed mAb IOC 7E1, IOC 10G7 can be exploited to extend the working range for the analysis of isoproturon. Both antibodies were formatted into a competitive enzyme-linked immunosorbent assay (ELISA), using the same enzyme-tracer. MAb IOC 7E1 and mAb IOC 10G7 have different affinities for the target compound, but the signal-response curves of the single antibodies overlap. Cross-reactivity (CR) patterns of both antibodies are comparable, showing the highest CR for the metabolite 1-(4-isopropylphenyl)-3-methylurea (IOC 10G7, 9%; IOC 7E1, 19%). The system described here includes the combined, but individual, usage of both assays on one microtiter plate, as well as the strategy for mixing the two antibodies for the utilization in one assay. When standards are performed in Milli-Q water, the working range for isoproturon with the individual ELISAs using mAb IOC 7E1 is from 0.01 to 1 microg/L (test midpoint = 0.11 +/- 0.03 microg/L; n = 17) and with IOC 10G7, it is 1-100 microg/L (test midpoint = 10.3 +/- 1.6 microg/L; n = 32). The working range with mixed antibodies is usually on the order of 0.03-30 microg/L (test midpoint = 0.5 +/- 0.2 microg/L; n = 17). These strategies (mAbs individually and mixed) cover a range of 4 and 3 orders of magnitude, respectively. As a demonstration, water samples of different origins and an extract of mixed sediment were analyzed. The advantages of these strategies are discussed.

Animals↗
PubMed1993

Use of fluorescently tagged DNA and an automated DNA sequencer for the comparison of the sequence selectivity of SN1 and SN2 alkylating agents.

This paper describes the application of the novel nonradioactive technique for studying the sequence selectivity of selected alkylating agents. N-Nitroso-N-methylurea (MNU) and N-methyl-N'-nitro-nitrosoguanidine (MNNG) were chosen from the SN1 group of alkylating agents. Dimethyl sulphate (DMS) was used to represent alkylation profile produced by the SN2 compounds. Results of SN1 compounds indicated that in a run (G)3 the latter two Gs are more susceptible to alkylation than the most 5' G. Moreover, in a GG sequence the 3' G seems to be more alkylated. This effect is more evident when the GG site was preceded by a 5' pyrimidine. These findings suggest that a regio-selective mechanism, rather than the formation of diazonium ions, accounts for DNA alkylation by SN1 compounds. On the other hand, DMS showed preferential alkylation of the 5' end in a (G)3 run. However, at GG sequences no clear preferred site of alkylation could be distinguished. Lack of specificity of SN2 compound would seem to suggest that other factors as well as the primary DNA structure may play a role in determining the extent of alkylation at a certain site.

Alkylating Agents↗
PubMed1984

On-line combination of high-performance liquid chromatography and total N-nitroso determination apparatus for the determination of N-nitrosamides and other N-nitroso compounds, and some recent data on the levels of N-nitrosoproline in foods and beverages.

A simple high-performance liquid chromatographic chemiluminescence detection method has been developed for the quantitative determination of N-nitrosamides and is based on post-column denitrosation of the compounds with hydrogen bromide-acetic acid or hydrogen iodide-acetic acid, followed by detection of the liberated NO by a chemiluminescence detector (TEATM). The method was used for the simultaneous analysis of DiazaldR, N-nitroso-N-methylurea, N-methyl-N'-nitro-N-nitrosoguandine and streptozotocin standards, and for N-methyl-N-nitrosourea extracted from model-system reaction mixtures and spiked, cured meats. The minimum detection limit of N-methyl-N-nitrosourea was about 0.5 ng. The method for the determination of N-nitrosarcosine and N-nitrosoproline in foods and beverages has been improved by replacing diazomethane with a mixture of BF3-methanol as the esterifying reagent and by simplifying the clean-up technique for purifying the prepared methyl esters. The average levels of N-nitrosoproline detected in 11 malts, 37 beers, 11 samples of fried bacon and 18 cured-meat products were found to be 24.1 micrograms/kg (5-113), 1.7 micrograms/kg (undetectable-6.0), 19.0 micrograms/kg (0.9-67.5), and 3.2 micrograms/kg (undetectable-21.6), respectively.

Amino Acids↗
PubMed1980

Synthesis and biological activities of chloroethylurea, methylurea, and nitrosourea analogues of N-deacetylmethylthiocolchicine.

A series of urea and nitrosourea analogues of N-deacetylmethylthiocolchicine (1) has been synthesized, and their antineoplastic and antiviral activities were evaluated. The objective for combination of two active moieties, such as thiocolchicine and nitrosourea, into one molecule was the generation of compounds with potential improved biological and pharmacological properties. The ED50 for 2, 3, 4, and 5 was 1.6, 1.2, 3.3, and 1.8 X 10(-8) M for L1210 cells and 3.0, 2.7, 2.9, and 2.6 X 10(-8) M for S-180 cells, respectively. The synthesis and cytotoxic and antiviral properties of these compounds are discussed.

Animals↗
PubMed1990

Genotoxic potency of monofunctional alkylating agents in E. coli: comparison with carcinogenic potency in rodents.

A quantitative correlation between carcinogenicity and genotoxicity was investigated by a comparison between the carcinogenic potency in rodents and the mutagenic (M), recombinogenic (R) and SOS-inducing (I) potencies in a bacterial test (E. coli multitest) for 9 monofunctional alkylating agents: N-nitroso-N-methylurethane, N-nitroso-N-ethylurea, epichlorohydrin, N-nitroso-N-methylurea, N-nitroso-N-methyl-N'-nitroguanidine, methyl methanesulfonate, diethylsulfate, dimethylsulfate, ethyl methanesulfonate. A significant positive correlation between the carcinogenic potency and the product of the mutagenic and recombinogenic potencies was found for all tested compounds. Thus, the E. coli multitest may be used as a simple test to search for correlations between carcinogenicity and genotoxicity of DNA-damaging agents.

Alkylating Agents↗
PubMed1987

Dose-response curves for liver DNA fragmentation induced in rats by sixteen N-nitroso compounds as measured by viscometric and alkaline elution analyses.

A new viscometric technique, capable of detecting DNA strand breaks and alkali-labile sites by monitoring time-dependent changes of DNA-reduced viscosity, has been used to analyze dose-response curves for the induction of DNA damage in liver of rats treated with single p.o. doses of sixteen N-nitroso compounds. Statistically significant changes of DNA viscometric parameters, which are considered indicative of DNA fragmentation, were produced by N-nitrosodimethylamine (0.022 mg/kg), N-nitrosomethylethylamine (0.025 mg/kg), N-nitrosodiethylamine (0.067 mg/kg), N-nitrosodiethanolamine (1.03 mg/kg), N-nitrosodi-n-propylamine (0.31 mg/kg), N-nitrosodi-n-butylamine (0.083 mg/kg), N-nitroso-N-methylurea (0.56 mg/kg), N-nitroso-N-ethylurea (0.37 mg/kg), N-nitroso-N-butylurea (0.16 mg/kg), streptozotocin (20 mg/kg), N-nitrosomorpholine (0.4 mg/kg), N-nitrosopiperidine (2.22 mg/kg), N-nitrosopyrrolidine (5.0 mg/kg), 1-nitroso-2-imidazolidinone (0.31 mg/kg), and N-methyl-N'-nitro-N-nitrosoguanidine (5.57 mg/kg). The contemporary measurement of liver DNA fragmentation by the alkaline elution technique revealed that in our experimental conditions higher doses are needed to produce a statistically significant increase of DNA elution rate. This suggests that the viscometric method is capable of detecting smaller levels of N-nitroso compound-induced DNA fragmentation, but it does not exclude that the sensitivity of alkaline elution can be improved by appropriate modifications of the experimental procedure. With both techniques DNA damage was undetectable in liver of rats treated with 540 mg/kg of the non-hepatocarcinogen N-nitrosodiphenylamine. With the exception of N-nitrosodiethanolamine, that exhibited a plateau effect, all the other N-nitroso compounds examined displayed a linear dose-response curve over the entire wide range of doses tested. Consequently, a nonlinearity of the relationship between dose and tumor response cannot be attributed to a nonlinearity of the pharmacokinetic processes involved in the formation of DNA damage.

Animals↗
PubMed1988

Regeneration of O6-alkylguanine-DNA alkyltransferase in human lymphocytes after nitrosourea exposure.

Mitogen-stimulated human lymphocytes have an increased capacity to repair many forms of DNA damage caused by UV, ionizing radiation, and chemical carcinogens. Human lymphocytes rely on a particular DNA repair protein, O6-alkylguanine-DNA alkyltransferase (alkyltransferase) to repair efficiently O6-alkylguanine, an important mutagenic adduct formed by nitrosoureas and other N-nitroso compounds. The alkyltransferase is a "suicide" protein which becomes inactivated during the repair process. Thus, basal activity and the ability to synthesize new protein activity are important compounds of O6-alkylguanine repair. We compared basal and regenerated alkyltransferase activity in resting and mitogen-stimulated human lymphocytes. During stimulation with L-phytohemagglutinin, alkyltransferase activity increased by a mean of 70% over resting cells. Following exposure to N-nitroso-N-methylurea (MNU), alkyltransferase activity was consumed in a dose-dependent manner in both resting and L-phytohemagglutinin-stimulated cells by the repair of MNU-induced O6-methylguanine-DNA adducts. Recovery of alkyltransferase activity began within 1 day of MNU exposure in the L-phytohemagglutinin-stimulated lymphocytes but did not occur in resting cells. Enzyme induction was not observed. When the alkyltransferase was only partially inactivated by low dose MNU, resting lymphocytes still failed to recover alkyltransferase activity. The rate of recovery of alkyltransferase activity in proliferating cells was dependent on the basal level of activity, which varied about 3-fold among donors. These data indicate that mitogen-stimulated lymphocytes develop an increased capacity to repair nitrosourea-induced DNA damage and are able to regenerate activity following nitrosourea exposure. In contrast, resting lymphocytes do not rapidly synthesize new alkyltransferase molecules after nitrosourea exposure and appear susceptible to DNA damage caused by persistent O6-alkylguanine adducts. Thus, both basal alkyltransferase activity and the proliferative state of normal lymphocytes influence the response to nitrosourea exposure.

Cycloheximide↗
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↗