Clastogenic effects of methylnitrosourea and ethylnitrosourea on chromosomes from human fibroblasts cell lines

Sanger, Warren G.; Eisen, James D.

doi:10.1016/0027-5107(76)90219-0

Cited by 14 publications

(4 citation statements)

References 26 publications

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“…In contrast, the values for MN-RET frequency appeared to fall within the background frequency range for the vehicle control at lower doses, i.e., 0.3 mg/kg/day or below. These results suggest that chromosomal clastogenicity is a more sensitive indicator of MNU genotoxicity in the low-dose region than mutagenicity, consistent with the known mechanism of action of this alkylating agent; MNU was described as a ''super clastogen'' by Sanger et al (1976). Interestingly, emerging data in the low-dose region for MNU in the comet assay appears to indicate similar levels of assay sensitivity when compared to the MN data (data not shown).…”

Section: Discussionsupporting

confidence: 79%

International Pig‐a gene mutation assay trial (Stage III): Results with N‐methyl‐N‐nitrosourea

Lynch

Giddings

Custer

et al. 2011

Environ and Mol Mutagen

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N-methyl-N-nitrosourea (MNU) was evaluated in the in vivo Pig-a mutation assay as part of an International Collaborative Trial to investigate laboratory reproducibility, 28-day study integration, and comparative analysis with micronucleus (MN), comet, and clinical pathology endpoints. Male Sprague Dawley rats were treated for 28 days with doses of 0, 2.5, 5, and 10 mg MNU/kg/day in two independent laboratories, GlaxoSmithKline (GSK) and Bristol Myers Squibb (BMS). Additional studies investigated the low-dose region (<2.5 mg/kg/day). Reticulocytes were evaluated for Pig-a phenotypic mutation, CD59-negative reticulocytes/erythrocytes (RETs(CD592-)/ RBCs(CD592-)) on Days 1, 4, 15, 29, 43, and 57, and for micronucleated reticulocytes (MN-RETs) on Days 4 and 29. Comet analysis was conducted for liver and whole blood, and hematology and clinical chemistry was investigated. Dose-dependent increases in the frequency of RETs(CD592-) and RBCs(CD592-) were observed by Day 15 or 29, respectively. Dose-dependent increases were observed in %MN-RET on Days 4 and 29, and in mean %tail intensity in liver and in blood. Hematology/clinical chemistry data demonstrated bone marrow toxicity. Data comparison between GSK and BMS indicated a high degree of concordance with the Pig-a mutation assay results, consistent with previous observations with MNU and N-ethyl-N-nitrosourea. These data confirm that complementary genotoxicity endpoints can be effectively incorporated into routine toxicology studies, a strategy that can provide information on gene mutation, chromosome damage, and DNA strand breaks in a single repeat dose rodent study. Collectively, this would reduce animal usage while providing valuable genetic toxicity information within the context of other toxicological endpoints.

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Section: Discussionsupporting

confidence: 79%

International Pig‐a gene mutation assay trial (Stage III): Results with N‐methyl‐N‐nitrosourea

Lynch

Giddings

Custer

et al. 2011

Environ and Mol Mutagen

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“…For random mutagenesis and clone tracing, Pfeiffer cells were mutagenized with N-ethyl-N-nitrosourea (ENU), which induces point mutations and chromosome aberrations (Sanger and Eisen, 1976; Shibuya and Morimoto, 1993). One million mutagenized clones were barcoded using a lentiviral DNA barcode library (ClonTracer; Bhang et al, 2015).…”

Section: Resultsmentioning

confidence: 99%

A curative combination cancer therapy achieves high fractional cell killing through low cross-resistance and drug additivity

Palmer

Chidley

Sorger

2019

eLife

106

101

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Curative cancer therapies are uncommon and nearly always involve multi-drug combinations developed by experimentation in humans; unfortunately, the mechanistic basis for the success of such combinations has rarely been investigated in detail, obscuring lessons learned. Here, we use isobologram analysis to score pharmacological interaction, and clone tracing and CRISPR screening to measure cross-resistance among the five drugs comprising R-CHOP, a combination therapy that frequently cures Diffuse Large B-Cell Lymphomas. We find that drugs in R-CHOP exhibit very low cross-resistance but not synergistic interaction: together they achieve a greater fractional kill according to the null hypothesis for both the Loewe dose-additivity model and the Bliss effect-independence model. These data provide direct evidence for the 50 year old hypothesis that a curative cancer therapy can be constructed on the basis of independently effective drugs having non-overlapping mechanisms of resistance, without synergistic interaction, which has immediate significance for the design of new drug combinations.

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“…ENU is also mutagenic at the chromosomal level. ENU treatment of human diploid cell lines in vitro induced both chromatid and chromosome aberrations (Sanger and Eisen, 1976). ENU also induced DNA strand breaks in mouse lymphoma cells at concentrations of Ͼ5 mM (Garberg et al, 1988) and increased the frequency of micronuclei in mice (Suzuki et al, 1997).…”

Section: Introductionmentioning

confidence: 94%

Mutant frequencies and loss of heterozygosity induced by N-ethyl-N-nitrosourea in the thymidine kinase gene of L5178Y/TK+/--3.7.2C mouse lymphoma cells

Chen

Harrington‐Brock²,

Moore³

2002

Mutagenesis

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N-ethyl-N-nitrosourea (ENU) is a potent monofunctional ethylating agent that has been found to be mutagenic in a wide variety of organisms from viruses to mammalian germ cells. To elucidate the mutagenicity of ENU at the Tk(+/-) locus of mouse lymphoma cells and to confirm the ability of the mouse lymphoma assay (MLA) to detect both point mutations and large DNA alterations, Tk(+/-) L5178Y cells were exposed to different doses of ENU. Treatment of the cells with ENU resulted in a linear dose response with mutant frequencies of up to 16-fold over control. Evaluation of mutant clone size showed that 36% of the 100 microg/ml ENU-induced clones (66% in control) were small colony mutants and 64% (34% in control) were large colony mutants. DNA isolated from mutants in the control culture and the 100 microg/ml ENU treatment group was analyzed for loss of heterozygosity (LOH) using allele-specific PCR. The majority of the small colony mutants, both ENU-treated (97%) and spontaneous (91%), lost the Tk1b allele. The percentage of allele loss in ENU-induced large colony mutants was distinctly different from that of the control. Twenty-three percent of ENU-induced large colony mutants lost their Tk1b alleles, whereas 73% of the large colony mutants from the control culture lost the allele (P < 0.001). Overall, 50% of the Tk mutants from the 100 microg/ml ENU-treated cultures (86% in control) showed LOH. Our data indicate that ENU is a potent mutagen in mouse lymphoma cells and that 100 microg/ml ENU induces equal numbers of point mutations and chromosomal mutations. This study serves to verify that the MLA detects both point mutations and chromosomal mutations.

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Clastogenic effects of methylnitrosourea and ethylnitrosourea on chromosomes from human fibroblasts cell lines

Cited by 14 publications

References 26 publications

International Pig‐a gene mutation assay trial (Stage III): Results with N‐methyl‐N‐nitrosourea

International Pig‐a gene mutation assay trial (Stage III): Results with N‐methyl‐N‐nitrosourea

A curative combination cancer therapy achieves high fractional cell killing through low cross-resistance and drug additivity

Mutant frequencies and loss of heterozygosity induced by N-ethyl-N-nitrosourea in the thymidine kinase gene of L5178Y/TK+/--3.7.2C mouse lymphoma cells

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