Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Methylnitronitrosoguanidine”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources
PubMed1976

Concentration-dependent mutation of diploid human lymphoblasts by methylnitronitrosoguanidine: the importance of phenotypic lag.

The mutation of diploid human lymphoblasts by methylnitronitrosoguanidine (MNNG) was measured over the range of 0--45 ng of MNNG/ml of of medium. We found a 12-day lag in the phenotypic expression of 6-thioguanine resistance; the occurrence of this lag was independent of MNNG concentration. We hypothesize that the unexpectedly long lag period reflects a requirement for the loss of previously existing molecules of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT) after mutation at the HGPRT locus.

Cell Survival↗
PubMed1980

Comparison of toxicity and mutagenicity of methylnitrosourea, methylnitronitrosoguanidine and ICR-191 among human lymphoblast lines.

The toxic and mutagenic effects of the alkylating agents methylnitrosourea (MNU) and methylnitronitrosoguanidine (MNNG) and of the frameshift mutagen, ICR-191 were compared among 3 human diploid lymphoblast lines, MIT-2, WI-L2 and GM 130. The MIT-2 and WI-L2 lines were both sensitive to the toxic and mutagenic effects of all 3 agents tested. The WI-L2 line was more sensitive to the toxic effects of MNU and MNNG than the MIT-2 line, while it was somewhat less sensitive to the mutagenic effects of these alkylating agents. The GM 130 line was strikingly resistant to both the toxic and mutagenic effects of the alkylating agents. The order of sensitivity to the toxic effect of ICR-191 was MIT-2 greater than WI-L2 greater than GM 130, while the order of sensitivity to the mutagenic effects of this frameshift mutagen was GM 130 greater than MIT-2 greater than WI-L2. These results point to the importance of accounting possible variations in mutability among individuals when extrapolating from any single mutagenicity assay for human risk assessment.

Aminacrine↗
PubMed2001

Effect of selenomethionine on N-methylnitronitrosoguanidine-induced colonic aberrant crypt foci in rats.

An association between low selenium intake and the incidence or prevalence of cancers is well known. Selenium in the form of selenomethionine supplemented in drinking water has been found to be highly effective in reducing tumour incidence and preneoplastic foci during the development of hepatocarcinogenesis in rats in our previous studies. Here, an attempt has been made to investigate whether the dose and form of selenium found to be effective during hepatocarcinogenesis is equally effective in N-methylnitronitrosoguanidine-induced colorectal carcinogenesis in terms of antioxidant defence enzyme systems, DNA chain breaks and incidences of aberrant crypt foci. Treatment with selenomethionine either on initiation or on selection/promotion, or during the entire experiment showed that selenomethionine was most effective in regulating the cellular antioxidant defence systems, DNA chain break control and reducing aberrant crypt foci in the colorectal tissues of rats. Our results also confirm that selenium is particularly effective in limiting the action of the carcinogen during the initiation phase of this colorectal carcinogenesis, just as we found with hepatocarcinogenesis in our previous studies.

Animals↗
PubMed1989

[Effect of methylnitronitrosoguanidine on DNA synthesis in animal cells: decrease in the rate of replication fork movement].

The effect of methylnitronitrosoguanidine (MNNG) on the rate of DNA replication fork (RF) progress has been studied by DNA fiber autoradiography in asynchronous Microtus agrestis and Chinese hamster cells. The rate of RF progress has been shown to be decreased by 14% and 36% at MNNG concentrations of 50 and 100 microM in M. agrestis cells; the rate of DNA synthesis being reduced by 50 and 75% respectively. In Chinese hamster cells the MNNG concentration of 5 microM does not affect the rate of RF and that of 10 microM decreases the latter by 11%, the respective fall in the synthesis of DNA rate being 13 and 57%. It has been concluded that the decreased RF rate contributes only partially to the overall DNA synthesis inhibition following the MNNG administration. Inhibition of DNA synthesis at the MNNG concentrations reducing the DNA synthesis by less then 40-50% is mainly caused by the inhibition of the initiation points and, possibly, by the stopping of operating RF. Further DNA synthesis inhibition (at the MNNG concentrations leading to DNA synthesis decrease exceeding 50%) is mostly due to the reduced RF progress rate.

Animals↗
PubMed1985

[The effect of methylnitronitrosoguanidine on DNA synthesis in human and animal cells. Inhibition of DNA synthesis in asynchronous and synchronous cultured cells].

Methylnitronitrosoguanidine (MNNG) is reported to inhibit DNA synthesis in intact human cells, in the cells from patients with ataxia telangiectasia (AT) or the cells from two rodent species. DNA synthesis in different cell lines exhibits varying sensitivity to MNNG inhibitory effect. 4-5-fold higher concentrations of MNNG are required for 50% inhibition of DNA synthesis in AT cells or in field vole cells as compared with the concentration required for human cells or Chinese hamster. The different compactness of two chromatin fractions might possibly result in lower sensitivity of DNA synthesis in heterochromatin to MNNG-induced inhibition as compared with the sensitivity of euchromatin. The genetic expression of AT defect on the cellular level is supposed to be connected with changes in supramolecular packaging of chromatin in interphase nuclei.

Animals↗
PubMedDate not supplied

Conversion of premalignant human cells to tumorigenic cells by methylmethane sulfonate and methylnitronitrosoguanidine.

Nine human tumor cell lines derived from both epithelial and mesenchymal tumors exhibited either an anchorage-independent growth non-tumorigenic phenotype or an anchorage-independent tumorigenic phenotype. Transformed epithelial cell lines with the non-tumorigenic phenotype could be converted to a progressively growing tumor phenotype following treatment with either methylmethane sulfonate (MMS) or N-methyl-N'-nitro-N-nitro-soguanidine (MNNG). In contrast, sarcoma derived cell lines with a non-tumorigenic phenotype could be converted to a progressively growing tumor phenotype only with MNNG. SV40 immortalized HET-1A non-tumorigenic phenotype cells could be converted to a progressively growing tumorigenic phenotype, infrequently, when treated with MNNG, but not MMS. Progressively growing tumors produced by either MMS or MNNG treated non-tumorigenic phenotypes exhibited metastatic potential in nude mice. Chemically treated HET-1A cells acquired the ability to produce tumor in mice but the tumor did not exhibit metastatic potential. In contrast, populations of tumorigenic cells were not rendered more biologically aggressive after treatment with either MMS or MNNG; i.e., the latency period for tumor development was not accelerated and the tumors did not exhibit metastatic potential. These results suggest that the biological effects of MMS and MNNG on non-tumorigenic, tumorigenic and immortalized cell lines are phenotype specific.

Animals↗
PubMed1984

Factors modifying 3-aminobenzamide cytotoxicity in normal and repair-deficient human fibroblasts.

3-Aminobenzamide (3-AB), an inhibitor of poly(ADP-ribosylation), is lethal to human fibroblasts with damaged DNA. Its cytotoxicity was determined relative to a number of factors including the types of lesions, the kinetics of repair, and the availability of alternative repair systems. A variety of alkylating agents, UV or gamma irradiation, or antimetabolites were used to create DNA lesions. 3-AB enhanced lethality with monofunctional alkylating agents only. Within this class of compounds, methylmethanesulfonate (MMS) treatments made cells more sensitive to 3-AB than did treatment with methylnitrosourea (MNU) or methylnitronitrosoguanidine (MNNG). 3-AB interfered with a dynamic repair process lasting several days, since human fibroblasts remained sensitive to 3-AB for 36-48 hours following MMS treatment. During this same interval, 3-AB caused these cells to arrest in G2 phase. Alkaline elution analysis also revealed that this slow repair was delayed further by 3-AB. Human mutant cells defective in DNA repair differed in their responses to 3-AB. Among mutants sensitive to monofunctional alkylating agents, ataxia telangiectasia cells were slightly more sensitive to 3-AB than control cells, while Huntington's disease cells had a near-normal response. Among UV-sensitive strains, xeroderma pigmentosum variant (XPV) cells were more sensitive to 3-AB after MMS than were XP complementation group A (A) cells, which responded normally. Greater lethality with 3-AB could be dependent on inability of the mutant cells to repair damage by other processes.

Benzamides↗
PubMed1989

In vitro developmental toxicity of five direct-acting alkylating agents in rodent embryos: structure-activity patterns.

Five direct-acting alkylating agents were examined qualitatively and quantitatively for their ability to produce developmental toxicity in rodent postimplantation embryos. These agents were structurally related and were capable of donating either a methyl (methylnitrosourea, MNU; methylnitronitrosoguanidine, MNNG; methyl methanesulfonate, MMS) or ethyl (ethylnitrosourea, ENU; ethyl methanesulfonate, EMS) group to nucleophiles. These agents' reactivities were known to differ. In day 10 rat embryos in vitro a single, 2-hour exposure was shown to be sufficient to elicit dose-dependent increases in embryo lethality and malformations. Qualitatively, the patterns of embryo malformations reported in treated embryos paralleled those observed in in vivo studies, especially in regard to adverse effects on central nervous system and craniofacial systems. Quantitatively, the order of potency of these agents in vitro was: MNNG greater than MNU greater than ENU greater than MMS greater than EMS. In vivo studies reported a different order of potency. In vitro, methylating agents were consistently more potent than ethylating agents. Other chemical properties such as nucleophilic reactivity or half-life under physiological conditions could not explain observed potency relationships. Future investigation of other chemical properties of these agents such as specific alkylation and carbamylation reactivities may expand these initial structure-activity observations.

Alkylating Agents↗
PubMed1995

A role for mismatch repair in production of chromosome aberrations by methylating agents in human cells.

We have shown previously that certain alkylation products, or alkylation derived lesions, which induce chromosome aberrations (abs) persist for at least two cell cycles in Chinese hamster ovary cells. The increase in abs in the second cycle after treatment contrasts with the classical observation of reduction in ab yield with successive mitoses following ionizing radiation. Here we present evidence that processing of lesions by mismatch repair is a mechanism for ab induction by methylating agents. Our previous studies implicated O6-methylguanine (O6MeG) as an important lesion in induction of abs, particularly in the second cell cycle after treatment. In the absence of repair of O6MeG by alkylguanine DNA alkyltransferase (AGT), new abs were induced in the second cycle after treatment with e.g. methylnitronitrosoguanidine (MNNG) and methylnitrosourea (MNU). Thus, we hypothesized that abs were produced not by O6MeG or its repair in the first S phase, but by subsequent processing of the lesions. We suggested that after replication proceeded past the O6MeG lesion in the first S phase, inserting an incorrect base on the newly synthesized strand, recognition and repair by mismatch repair in the second S phase led to a chromosome ab. Here we used MT1 cells, a human lymphoblastoid cell line that has a defect in strand-specific mismatch repair. MT1 cells are alkylation tolerant and have a mutator phenotype, compared with their parent line, TK6; both MT1 and TK6 cells lack AGT so do not remove the methyl group from O6MeG. While the initial levels of abs at the first metaphase were similar in MT1 and TK6 cells, ab levels in MT1 cells were greatly reduced in the second and third cell cycles following treatment with MNNG, dimethylnitrosamine and MNU, in contrast with the parent TK6 cells, which had more abs in the second cell cycle than in the first. This supports the hypothesis that repair of mismatched base pairs involving O6MeG is one mechanism for induction of chromosome abs. In contrast to the difference in response to methylating agents between TK6 cells and mismatch repair-deficient MT1 cells, the profile of ab induction by an ethylating agent, ethylnitronitrosourea, was similar in MT1 cells to those for TK6 cells and CHO cells.

Alkylating Agents↗
PubMed1987

Inhibition of bleomycin-induced DNA strand breaks in V 79 Chinese hamster cells by the antioxidant propylgallate.

Bleomycin induced DNA single-strand breaks in Chinese hamster V 79 cells which were detected by the alkaline filter elution assay. In the presence of propylgallate, an antioxidant, the amount of DNA single-strand breaks was significantly reduced. The production of DNA strand breaks by methylnitronitrosoguanidine used as a positive control was not influenced by propylgallate. It is suggested that propylgallate inhibits the generation of DNA single-strand breaks by trapping reactive oxygen species produced by the bleomycin-iron(II) complex.

Animals↗
PubMed1989

Characterization of variant and parental-cross-protective immunity to immunogenic variants of a murine fibrosarcoma using the local adoptive transfer assay.

The purpose of this study was to characterize the lymphocyte populations responsible for rejection of immunogenic (Imm+) tumor variants, and the cross-protective immunity engendered by Imm+ variants against the weakly immunogenic parental tumor. Immunogenic clones of the weakly immunogenic methylcholanthrene-induced fibrosarcoma MCA-F have been generated using 1-methyl-3-nitro-1-nitrosoguanidine, 5-aza-2'-deoxycytidine, or ultraviolet radiation (UV-B; 280-320 nm). These clones grow progressively in immunosuppressed adult-thymectomized irradiated mice, but are rejected by immunocompetent syngeneic hosts. The parental MCA-F tumor grows progressively in both groups. Mice that have rejected a challenge of 1 x 10(5) Imm+ cells show an anamnestic immune response against both the Imm+ clone and the parental MCA-F tumor. Using the local adoptive transfer assay and depletion of T-cell subsets with antibody plus complement, we show that immunity induced by the Imm+ variants against the parent MCA-F was mediated by the Thy1.2+, L3T4a+ population without an apparent contribution by Lyt2.1+ cells. Although antivariant immunity was also dependent upon Thy1.2+ cells, depletion of either the L3T4a+ or the Lyt2.1+ cells failed to abolish immunity against the variant. A role for Lyt2.1+ T lymphocytes in antivariant immunity, but not antiparent immunity, was supported by the results of cytotoxic T lymphocyte (CTL) assays. Following immunization with high numbers (1 x 10(5) to 5 x 10(5) of viable Imm+ cells, antivariant, but not antiparent CTL activity was detected in mixed lymphocyte tumor cell cultures. Immunization with lower numbers (3 x 10(4] of viable Imm+ or with high numbers of mitomycin-C-treated Imm+ engenders only antivariant immunity without parental cross-protection. Under these conditions lymphocytes mediating immunity against the variant in the local adoptive transfer assay were exclusively of the Thy1.2+, L3T4a+ phenotype, with no contribution from the Lyt2.1+ cells. Identical results were obtained for Imm+ clones of MCA-F induced by methylnitronitrosoguanidine, 5-azadeoxycytidine, and UV-B, suggesting that the nature of the antitumor immunity engendered by Imm+ is not significantly affected by the agent used. Furthermore, these results demonstrate that the cross-reactivity and cellular effectors of antitumor immunity in this system are influenced by the immunizing dose of Imm+ cells: the predominant effectors of both antivariant and parental-cross-reactive immunity were of the CD4+ T cell subclass, with a CD8+ cytotoxic population contributing to antivariant immunity only after high-dose immunization.

Animals↗
PubMed1987

Oxidative damage to DNA and replicative lifespan in cultured adrenocortical cells.

Oxidative damage to DNA in cultured bovine adrenocortical cells was investigated by exposing cells to a sublethal concentration (10 microM) of cumene hydroperoxide under conditions previously shown to be deficient in the biological antioxidants selenium and alpha-tocopherol (vitamin E). DNA prepared from cells incubated for 4 h with 10 microM cumene hydroperoxide had a greater fraction showing resistance to S1 nuclease after denaturation and reassociation to a log C0t of -3. Cross-linking by cumene hydroperoxide was abolished in cells that had been grown in the presence of 20 nM selenite or 1 microM alpha-tocopherol for 96 h prior to peroxide addition, whereas such cells remained susceptible to cross-linking by nitrogen mustard. Extensive strand breaks in DNA from peroxide-treated cells as assessed by alkaline sucrose gradient centrifugation were greatly reduced in cells grown in selenite or alpha-tocopherol. Despite the evidence of damage to DNA, cumene hydroperoxide was not detectably mutagenic, in contrast to 5 microM methylnitronitrosoguanidine (MNNG), when assessed as the incidence of resistance to 25 microM ouabain. We confirmed that cumene hydroperoxide at greater than 10 microM lowers cloning efficiency and that this is largely prevented by selenite or alpha-tocopherol. Additionally, selenite or alpha-tocopherol produced increased clonogenicity in cells not incubated with peroxide. To examine effects of the biological antioxidants on replicative lifespan, cells were grown continuously in fetal bovine serum (FBS), fibroblast growth factor (FGF), and selenite or alpha-tocopherol. Selenium increased replicative lifespan by 10-20% and alpha-tocopherol by 22-30%. Levels of DNA cross-links and strand breaks did not differ under any circumstances between early (second) passage and late (30th) passage cells. The experiments on replicative potential were all performed in the presence of FGF. When FGF was omitted from the culture medium, replicative lifespan was reduced by 85%. We conclude that types of damage to DNA resulting from peroxide exposure are not present in cells under standard culture conditions at early or late stages of the lifespan. Other work has noted a relationship between clonogenicity and replicative lifespan; thus, the increase in cloning efficiency seen with selenium and alpha-tocopherol may cause the observed slight increase in replicative lifespan. Oxidative damage does not appear to be a major determinant of cellular senescence in adrenocortical cells.

Adrenal Cortex↗
PubMed1977

Chemical mutation in human lymphoblasts.

We have developed a facile and reliable assay for mutation by chemicals and other mutagenic agents induced in the hgprt locus of diploid human lymphoblasts. We discuss here the detailed protocol and summarize the experiments, reported elsewhere, in which we tested the method for possible systemic bias. The concentration dependence of mutation for methylnitronitrosoguanidine, methylnitrosourea, ICR-191, and bromodeoxyuridine are also summarized to demonstrate the responsiveness of the new system to alkylating agents, an intercalating agent, and a base analog, respectively.

Alkylating Agents↗
PubMed1995

Cancer risk among workers in biomedical research.

OBJECTIVE: This epidemiologic study was undertaken after a cluster of five cases of rare forms of cancer (bone sarcoma, non-Hodgkin's lymphoma) had been observed among biomedical research workers at the Pasteur Institute in Paris to ascertain whether their disease was connected with exposure during this research. METHODS: A mortality study included 3765 people who worked at the Pasteur Institute between 1971 and 1986 and were followed until the end of 1987. Within this cohort a nested case-referent study included 23 cases of cancer [non-Hodgkin's lymphoma (6), multiple myeloma (1), leukemia (3), pancreatic cancer (7), bone cancer (3), brain tumor (3)], and four referents per case, matched for gender and year of birth. RESULTS: Total mortality from cancer was less than expected, the standardized mortality ratio (SMR) being 72 for the men and 82 for the women. Among the women the proportion of pancreatic cancer cases was larger than expected [SMR 490, 95% confidence interval (95% CI) 158-1144], as was the number of brain cancer cases (SMR 239, 95% CI 48-696). Among the men, mortality from bone cancer was greater than expected (SMR 553, 95% CI 62-2006). In the nested case-referent study, more cases than referents had worked in the areas of molecular biology [odds ratio (OR) 7.1, 95% CI 1.5-33] and microbial genetics (OR 6.7, 95% CI 1.3-35). These cases especially included non-Hodgkin's lymphoma and bone cancer. Associated with this finding was the fact that more cases had used certain chemicals, including ethidium bromide, acrylamide, methylnitronitrosoguanidine and ethylmethanesulfonate, and radioactive compounds (essentially 32phosphorus). CONCLUSIONS: As the products used are potent genotoxicants, the present findings suggest that work in biomedical research might well involve an increased risk of certain types of cancer; this conclusion should be balanced by the fact that two of the five index cases were included in the mortality study and four in the nested case-referent study.

Academies and Institutes↗
PubMed1982

Cancer induction after pyloroplasty in rats: treatment with N-methyl-N'-nitro-N-nitrosoguanidine.

Nineteen male Wistar rats received N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in drinking water (83 mg/L) to initiate glandular adenocarcinoma of the stomach; eight control rats received tap water. After 12 weeks a pyloroplasty was performed on nine rats receiving MNNG and three control rats. Ten MNNG-treated rats and five control rats had no operation. All were observed for 38 weeks before being killed. No difference in the incidence of antral adenocarcinomas was found between the MNNG-treated groups; however, those without operation showed in situ changes in the duodenum and those treated with pyloroplasty showed five invasive adenocarcinomas. In this model pyloroplasty alone did not increase the risk of gastric cancer but increased the risk of duodenal tumors. Pyloroplasty apparently accelerated the gastric evacuation rate, resulting in greater insult to the duodenal mucosa. Such a condition may require a higher proliferative rate in the duodenum and may increase subsequent formation of malignant tumors.

Adenocarcinoma↗
PubMed1999

trans-dominant mutations in the GPR1 gene cause high sensitivity to acetic acid and ethanol in the yeast Yarrowia lipolytica.

Acetate non-utilizing strains harbouring trans-dominant mutations in the GPR1 gene (GPR1(d)) of the dimorphic yeast Yarrowia lipolytica have been selected and characterized. These mutants are highly sensitive to low concentrations of acetic acid and ethanol, even in presence of glucose. The toxic effect of acetic acid is pH-dependent and has the strongest effect at low pH. In contrast, the action of ethanol is pH-independent. One GPR1(d) mutant has been detected that was highly sensitive to acetic acid but could still grow on ethanol, which indicates putative differences in the function of the GPR1 gene product in the sensitivity to acetic acid and ethanol. The GPR1(d) mutants exhibit a complex pleiotropic phenotype. The mutations cause changed colony morphology as well as dimorphism of cells, and induce early cell death during growth on glucose, even without the presence of dicarbon compounds. Composition of intracellular membranes, as well as morphology of vacuole and mitochondria, were strongly changed. Back-crosses with wild-type strains and analysis of recombinant strains have shown that the expression of the pleiotropic phenotype depends on the site of mutation in the GPR1 gene, as well as on the genetic background of the strain harbouring the responsive mutation. Our data suggest that Gpr1p is involved in a general response of cells to the toxic action of dicarbon compounds like acetic acid and ethanol.

Acetic Acid↗