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Molecular Carcinogenesis Jun 2000Nullizygous p53 knockout (p53(-/-)) mice are highly susceptible to spontaneous tumorigenesis, in particular malignant lymphomas at an early age. Heterozygous p53...
Nullizygous p53 knockout (p53(-/-)) mice are highly susceptible to spontaneous tumorigenesis, in particular malignant lymphomas at an early age. Heterozygous p53 knockout (p53(+/-)) mice develop spontaneous tumors less frequently but may show increased susceptibility to chemical carcinogens. In this study, p53(-/-), p53(+/-), and p53 wild-type (p53(+/+)) mice were treated with N-methylnitrosourea (MNU) by gastric intubation (5 microg/g body weight) three times per week for 5 wk, starting at 5-6 wk of age. The surviving mice were killed when they were 56-57 wk old. All eight p53(-/-) mice treated with MNU developed malignant lymphomas with a shorter latent period (mean age = 16.4+/-0.5 wk) than their spontaneous tumors (61%, at age 23.3+/-1.4 wk). In p53(+/-) mice treated with MNU, malignant lymphomas developed at a higher frequency (eight of 27, 30%) than did spontaneous lymphomas (5%). Development of sarcomas in p53(-/-) and p53(+/-) mice was also significantly enhanced by treatment with MNU. All eight thymic lymphomas and three sarcomas in the p53(+/-) mice showed a loss of the remaining wild-type p53 allele. These results indicate that intragastric MNU treatment significantly enhanced spontaneous development of malignant lymphomas and sarcomas in both p53(-/-) and p53(+/-) mice. In the stomachs of 12 p53(+/-) mice, that were killed at the end of the experiment, two adenomas, one carcinoma in situ, and four adenocarcinomas were observed. In the stomachs of 31 p53(+/+) mice, eight adenomas and one carcinoma in situ were detected. The overall incidence of tumorous changes in the stomachs of p53(+/-) (seven of 12, 58%) and p53(+/+) (nine of 31, 29%) mice were not significantly different (P = 0.090). However, adenocarcinomas invading the submucosa were observed in p53(+/-) mice (four of 12, 33%) but not in p53(+/+) mice (zero of 31; P = 0. 004), suggesting a slightly higher susceptibility to gastric carcinogenesis induced by MNU in p53(+/-) mice. Mol. Carcinog. 28:97-101, 2000.
Topics: Adenocarcinoma; Alleles; Animals; Carcinogens; Female; Genes, p53; Lymphoma; Male; Methylnitrosourea; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutation; Sarcoma, Experimental; Stomach; Stomach Neoplasms
PubMed: 10900466
DOI: 10.1002/1098-2744(200006)28:2<97::aid-mc5>3.0.co;2-o -
STAR Protocols Dec 2021N-Methyl-N-nitrosourea, an N-nitroso compound converted from dietary nitrite by , causes somatic mutations in epithelial cells and induces gastric premalignancy. Here,...
N-Methyl-N-nitrosourea, an N-nitroso compound converted from dietary nitrite by , causes somatic mutations in epithelial cells and induces gastric premalignancy. Here, we describe a detailed protocol for induction of gastric tumor and analysis of tumor phenotypes in mice. This model can be widely used for studying the initiation and growth of gastric cancer. For complete details on the use and execution of this protocol, please refer to Li et al. (2021).
Topics: Animals; Male; Methylnitrosourea; Mice; Mice, Inbred C57BL; Neoplasms, Experimental; Stomach; Stomach Neoplasms
PubMed: 34585155
DOI: 10.1016/j.xpro.2021.100814 -
Carcinogenesis Jul 1989Clones (13 and B) of O6-methylguanine-DNA-methyl-transferase-proficient (MT+) CHO cells showing different levels of resistance to N-methyl-N'-nitro-N-nitrosoguanidine...
Clones (13 and B) of O6-methylguanine-DNA-methyl-transferase-proficient (MT+) CHO cells showing different levels of resistance to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) but similar MT activity, were found to be sensitive to methyl methanesulphonate and resistant to N-methyl-N-nitrosourea (MNU). A 2.8-fold increase in resistance to MNU-induced cytotoxicity was observed in clone 13 and a 16-fold increase in clone B. A slight increase in survival (1.5-fold) after N-ethyl-N-nitrosourea treatment was observed in clone B. These data indicate that the resistant phenotype is specific for agents that preferentially methylate O atoms in DNA. The survival of MNNG- and MNU-resistant clones as well as of the parental CHO cell line was analysed after exposure to purine analogues substituted in different positions, 8-azaguanine (8-AG), 8-azaadenine (8-AA) and 6-thioguanine (6-TG). A 6-fold increase in resistance to 6-TG was found in clone B, although the hypoxanthine guanine phosphoribosyltransferase gene is functional in these cells. The same cytotoxicity was found in all the lines after treatment with 8-AG and 8-AA. These data are in agreement with the previous observation that clone 13 and clone B belong to two different classes of resistance, clone 13 resistance being explained by MT levels. The finding that clone B is cross-resistant to 6-TG is discussed in the light of a mechanism of tolerance to modifications at specific positions of guanine.
Topics: Animals; Cell Line; Cell Survival; Clone Cells; Cricetinae; Cricetulus; DNA Damage; Drug Resistance; Female; Methyl Methanesulfonate; Methylnitrosourea; Methyltransferases; O(6)-Methylguanine-DNA Methyltransferase; Ovary; Thioguanine
PubMed: 2736715
DOI: 10.1093/carcin/10.7.1219 -
Carcinogenesis 1982To study the relationship between epidermal DNA synthesis and carcinogenesis, groups of hairless mice were given a single skin application of 2 mg N-methyl-N-nitrosourea...
To study the relationship between epidermal DNA synthesis and carcinogenesis, groups of hairless mice were given a single skin application of 2 mg N-methyl-N-nitrosourea (MNU) in acetone. One group received no pretreatment, another group was injected i.p. with 5 mg hydroxyurea (HU) 30 min before MNU, and a further group with 0.5 mg Colcemid 3 h before MNU. Other groups were injected i.p. 14 and 4 h before MNU with either saline, 5 mg crude aqueous skin extract, 2 mg dialysed skin extracts of two types, or 2 mg dialysed extracts of liver or heart muscle, respectively. All substances were dissolved in 0.5 ml distilled water. Cell kinetic studies showed that the three skin extracts inhibited epidermal DNA synthesis and mitosis. HU inhibited DNA synthesis and increased the mitotic rate. The other pretreatments had no effect on epidermal DNA synthesis. There was a significant enhancement of the production of skin tumors in the groups pretreated with epidermal extracts or HU. MNU is a short-acting carcinogen with a half-life in the cell of 30 min. Hence, the results show that when DNA synthesis is inhibited at the time of MNU application, more tumors are produced in the skin. A possible explanation of the enhancement is that a compensatory wave of proliferation a short time after carcinogen binding may fix a DNA injury before repair can take place.
Topics: Animals; Cell Division; DNA; Female; Hydroxyurea; Male; Methylnitrosourea; Mice; Mice, Inbred Strains; Neoplasms, Experimental; Nitrosourea Compounds; Skin; Skin Neoplasms; Tissue Extracts; Tritium
PubMed: 7127669
DOI: 10.1093/carcin/3.8.881 -
Chemical Research in Toxicology Apr 2014For DNA-reactive chemicals, a low dose linear assessment of cancer risk is the science policy default. In the present study, we quantitated the endogenous and exogenous...
For DNA-reactive chemicals, a low dose linear assessment of cancer risk is the science policy default. In the present study, we quantitated the endogenous and exogenous N7-methyl-G and O(6)-methyl-dG adducts in human lymphoblastoid cells exposed to low dose [D3]-methylnitrosourea. Endogenous amounts of both adducts remained nearly constant, while the exogenous adducts showed linear dose-responses. The data show that O(6)-methyl-dG adducts ≥1.8/10(8) dG correlated with published studies that demonstrated significant increases of mutations under these conditions. The combined results do not support linear extrapolations to zero when data are available for science-based regulations.
Topics: Cells, Cultured; Deoxyguanosine; Dose-Response Relationship, Drug; Guanine; Humans; Methylnitrosourea
PubMed: 24628573
DOI: 10.1021/tx5000602 -
IARC Monographs on the Evaluation of... May 1978
Review
Topics: Animals; Carcinogens; Chemical Phenomena; Chemistry; Female; Humans; Methylnitrosourea; Mutagens; Nitrosourea Compounds; Pregnancy; Teratogens
PubMed: 355099
DOI: No ID Found -
Bollettino Della Societa Italiana Di... Sep 1985
Topics: Animals; Cattle; Guanosine; Hydrogen-Ion Concentration; Liver; Methylation; Methylnitrosourea; RNA, Transfer; Time Factors
PubMed: 4074537
DOI: No ID Found -
Carcinogenesis Apr 1989Relatively simple and rapid analytical procedures involving two sequential HPLC separations were developed for the isolation of methylated purines in the urine of rats...
Relatively simple and rapid analytical procedures involving two sequential HPLC separations were developed for the isolation of methylated purines in the urine of rats administered radiolabeled methylating carcinogens. Following a dose of [3H]N-methyl-N-nitrosourea (MNU), 7-methyl-adenine (m7Gua) was detected by chromatography as a urinary methylpurine in addition to the expected 7-methylguanine (m7Gua) and 3-methyladenine (m3Ade). When methyl-labeled methionine was given to rats concurrently with MNU, urinary m7Gua was labeled, but no radioactivity was recovered in either of the two methyladenine fractions. The profile of urinary methylated purines following a dose of dimethyl sulfate to the rat was similar. Small amounts of 1-methyladenine (m1Ade) and 3-methylguanine (m3Gua) were also detected in the urine. The excretion of m7Ade derived from the methyl group of the carcinogen rather than from the normal precursor for methylation, implies that this adduct, like m3Ade, may serve as an indicator in urine for exposure to methylating carcinogens.
Topics: Adenine; Chromatography, High Pressure Liquid; Methionine; Methylnitrosourea; Sulfuric Acid Esters
PubMed: 2702723
DOI: 10.1093/carcin/10.4.757 -
PloS One 2023Carcinogenicity tests predict the tumorigenic potential of various substances in the human body by studying tumor induction in experimental animals. There is a need for...
Carcinogenicity tests predict the tumorigenic potential of various substances in the human body by studying tumor induction in experimental animals. There is a need for studies that explore the use of FVB/N-Trp53em2Hwl/Korl (FVB-Trp53+/-) mice, created by TALEN-mediated gene targeting in Korea, in carcinogenicity tests. This study was performed to determine whether FVB-Trp53+/- mice are a suitable model for short-term carcinogenicity studies. To compare the carcinogenicity at different concentrations, 25, 50, and 75 mg/kg of N-methyl-N-nitrosourea (MNU), a known carcinogen, were administered intraperitoneally to FVB-Trp53+/- and wild-type male mice. After 26 weeks, the survival rate was significantly reduced in FVB-Trp53+/- mice compared to the wild-type mice in the 50 and 75 mg/kg groups. The incidence of thymic malignant lymphoma (TML) in the 50 and 75 mg/kg groups was 54.2 and 59.1% in FVB-Trp53+/- male mice, respectively. TML metastasized to the lungs, spleen, lymph nodes, liver, kidney, and heart in FVB-Trp53+/- male mice. Furthermore, the incidence of primary lung tumors, such as adenomas and adenocarcinomas, was 65.4, 62.5, and 45.4% in the FVB-Trp53+/- mice of the 25, 50, and 75 mg/kg groups, respectively. The main tumor types in FVB-Trp53+/- mice were TML and primary lung tumors, regardless of the dose of MNU administered. These results suggest that systemic tumors may result from malfunctions in the p53 gene and pathway, which is an important factor in the pathogenesis of human cancers. Therefore, FVB-Trp53 heterozygous mice are suitable for short-term carcinogenicity tests using positive carcinogens, and that the best result using MNU, a positive carcinogen, might have a single dose of 50 mg/kg.
Topics: Humans; Mice; Male; Animals; Methylnitrosourea; Carcinogens; Mice, Inbred Strains; Thymus Neoplasms; Lung Neoplasms; Carcinogenicity Tests
PubMed: 36608059
DOI: 10.1371/journal.pone.0280214 -
Mutation Research May 1980The toxic and mutagenic effects of the alkylating agents methylnitrosourea (MNU) and methylnitronitrosoguanidine (MNNG) and of the frameshift mutagen, ICR-191 were...
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.
Topics: Aminacrine; Aminoacridines; Cell Line; Dose-Response Relationship, Drug; Humans; Lymphocytes; Methylnitronitrosoguanidine; Methylnitrosourea; Mutagens; Nitrogen Mustard Compounds; Nitrosourea Compounds
PubMed: 7383041
DOI: 10.1016/0027-5107(80)90026-3