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  • Online Resource  (8)
  • SAGE Publications  (8)
  • Devereux, Theodora R.  (8)
  • 1
    Online Resource
    Online Resource
    Predominant p53 G→A Transition Mutation and Enhanced Cell Proliferation in Uterine Sarcomas of CBA Mice Treated with 1,2-Dimethylhydrazine
    SAGE Publications ; 1998
    In:  Toxicologic Pathology Vol. 26, No. 3 ( 1998-05), p. 367-374
    Details
    In: Toxicologic Pathology, SAGE Publications, Vol. 26, No. 3 ( 1998-05), p. 367-374
    Abstract: Mouse uterine tumors were examined for genetic alterations in the ras proto-oncogene and p 53 tumor suppressor gene arid for other biologically relevant immunohistochemical markers that may increase our understanding of the events that occur in uterine cancer. Fourteen dimethylhydrazine (DMH)-induced uterine sarcomas, including 3 primary malignant fibrous histiocytomas (MFH), 7 transplanted MFH, 3 stromal sarcomas, and 1 undifferentiated sarcoma, were first screened by immunohistochemistry for p53 missense mutations, followed by single strand conformation polymorphism analysis and DNA sequencing for the identification of point mutations. There was 100% correlation between p 53 protein immunopositivity and subsequent detection ofp53 mutations in DMH-induced malignant fibrous histiocytomas. All MFH had a characteristic p 53 G:C→A:T transition mutation, consistent with O 6 -methylguanine mispairing with thymine, the most common DNA lesion caused by alkylating agents. DMH-induced uterine MFH with p 53 mutations also had a higher proliferative rate (qualitatively evaluated by immunohistochemical detection of proliferating cell nuclear antigen) when compared with other DMH-induced sarcomas. Uterine sarcomas were further evaluated for biological end points, such as estrogen receptor and desmin. Neoplastic cells from stromal sarcomas (SS), undifferentiated sarcomas (US), and MFH did not stain for desmin. The estrogen receptor was detected in normal uteri and a small portion of MFH, SS, and US. Our data suggest that DMH-induced uterine sarcomas are not consistent with smooth muscle cell origin and that a subset of these tumors, specifically DMH-induced malignant fibrous histiocytomas, have unique p 53 G:C→A:T transitions and a high proliferative rate.
    Type of Medium: Online Resource
    ISSN: 0192-6233 , 1533-1601
    URL: Article
    DOI: 10.1177/019262339802600310
    Language: English
    Publisher: SAGE Publications
    Publication Date: 1998
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  • 2
    Online Resource
    Online Resource
    Frequency of ras Mutations in Liver Neoplasms from B6C3F 1 Mice Exposed to Tetrafluoroethylene for Two Years
    SAGE Publications ; 1998
    In:  Toxicologic Pathology Vol. 26, No. 5 ( 1998-09), p. 646-650
    Details
    In: Toxicologic Pathology, SAGE Publications, Vol. 26, No. 5 ( 1998-09), p. 646-650
    Abstract: Tetrafluoroethylene (TFE) was evaluated for carcinogenicity in inhalation studies because of its high use in the production of Teflon. There was clear evidence of hepatocarcinogenic activity in B6C3F 1 mice after 2 yr of TFE exposure. The present study was designed to characterize the mutation profiles of H- and K- ras oncogenes in liver neoplasms in mice after exposure to 0, 312, 625, or 1,250 ppm TFE. ras mutations were identified by restriction fragment length polymorphism, single-stranded conformation polymorphism analysis, and direct sequencing of polymerase chain reaction amplified-DNA isolated from frozen or paraffin-embedded liver neoplasms. A low frequency (15%, 9/59) of H- ras codon 61 mutations was detected in hepatocellular neoplasms when compared with the higher frequency (59% of this study and 56% of historical data) in spontaneously occurring liver neoplasms. There was no difference in the mutation frequency or spectrum among exposure groups or between benign and malignant hepatocellular neoplasms. K- ras mutations at codons 12, 13, and 61 and H- ras mutations at codon 117 were not detected in hepatocellular neoplasms. These data suggest that TFE-induced hepatocellular neoplasms are developed by pathways that are mostly independent of ras mutations. The ras mutation frequency and spectrum were similar to those of the structurally related chemical tetrachloroethylene.
    Type of Medium: Online Resource
    ISSN: 0192-6233 , 1533-1601
    URL: Article
    DOI: 10.1177/019262339802600508
    Language: English
    Publisher: SAGE Publications
    Publication Date: 1998
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  • 3
    Online Resource
    Online Resource
    Gene Expression Studies Demonstrate that the K- ras /Erk MAP Kinase Signal Transduction Pathway and Other Novel Pathways Contribute to the Pathogenesis of Cumene-induced Lung Tumors
    SAGE Publications ; 2008
    In:  Toxicologic Pathology Vol. 36, No. 5 ( 2008-07), p. 743-752
    Details
    In: Toxicologic Pathology, SAGE Publications, Vol. 36, No. 5 ( 2008-07), p. 743-752
    Abstract: National Toxicology Program (NTP) inhalation studies demonstrated that cumene significantly increased the incidence of alveolar/bronchiolar adenomas and carcinomas in B6C3F1 mice. Cumene or isopropylbenzene is a component of crude oil used primarily in the production of phenol and acetone. The authors performed global gene expression analysis to distinguish patterns of gene regulation between cumene-induced tumors and normal lung tissue and to look for patterns based on the presence or absence of K- ras and p53 mutations in the tumors. Principal component analysis segregated the carcinomas into groups with and without K- ras mutations, but failed to separate the tumors based on p53 mutation status. Expression of genes associated with the Erk MAP kinase signaling pathway was significantly altered in carcinomas with K- ras mutations compared to tumors without K- ras mutations or normal lung. Gene expression analysis also suggested that cumene-induced carcinomas with K- ras mutations have greater malignant potential than those without mutations. In addition, significance analysis of function and expression (SAFE) demonstrated expression changes of genes regulated by histone modification in carcinomas with K- ras mutations. The gene expression analysis suggested the formation of alveolar/bronchiolar carcinomas in cumene-exposed mice typically involves mutation of K- ras, which results in increased Erk MAP kinase signaling and modification of histones.
    Type of Medium: Online Resource
    ISSN: 0192-6233 , 1533-1601
    URL: Article
    DOI: 10.1177/0192623308320801
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2008
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  • 4
    Online Resource
    Online Resource
    Predominant K-ras Codon 12 G → A Transition in Chemically Induced Lung Neoplasms in B6C3F1 Mice
    SAGE Publications ; 2004
    In:  Toxicologic Pathology Vol. 32, No. 1 ( 2004-01), p. 16-21
    Details
    In: Toxicologic Pathology, SAGE Publications, Vol. 32, No. 1 ( 2004-01), p. 16-21
    Abstract: Based on long-term toxicity and carcinogencity studies in B6C3F1 mice conducted by the National Toxicology Program, 2,2-Bis(bromomethyl)-1,3-propanediol (BMP) and tetranitromethane (TNM) have been identified as carcinogens. Following 2 yr of exposure to 312, 625, or 1,250 ppm BMP in feed, or exposure to 0.5 or 2 ppm TNM by inhalation, increased incidences of lung neoplasms were observed in B6C3F1 mice at all exposure concentrations compared to unexposed mice. The present study characterizes genetic alterations in the K- ras protooncogene in BMP- and TNM-induced lung neoplasms, respectively, and compares the findings to spontaneous lung neoplasms from corresponding control mice. The frequencies of the K- ras mutations were 57% (29/51) in BMP-induced lung neoplasms compared to 15% (3/20) in lung neoplasms from dosed feed control mice, and 54% (14/26) in TNM-induced lung neoplasms compared to 60% (3/5) in lung neoplasms from inhalation control mice. G → A transitions at the second base of the K- ras codon 12 (GGT → GAT) were the most frequent pattern of K- ras mutations identified in BMP-induced (20/29) and TNM-induced lung neoplasms (13/14), which differed from the mutational patterns identified in the lung neoplasms from unexposed control mice. These results indicate that mutations in the K- ras gene are involved in B6C3F1 lung carcinogenesis following BMP- and TNM-exposure, and the high frequency and specificity of the ras mutation profile in lung neoplasms (G → A transition) may be due to in vivo genotoxicity by the parent compounds or their metabolites.
    Type of Medium: Online Resource
    ISSN: 0192-6233 , 1533-1601
    URL: Article
    DOI: 10.1080/01926230490260682
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2004
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  • 5
    Online Resource
    Online Resource
    Genetic Alterations in Brain Tumors Following 1,3-Butadiene Exposure in B6C3F1 Mice
    SAGE Publications ; 2005
    In:  Toxicologic Pathology Vol. 33, No. 3 ( 2005-04), p. 307-312
    Details
    In: Toxicologic Pathology, SAGE Publications, Vol. 33, No. 3 ( 2005-04), p. 307-312
    Abstract: The nervous system of the B6C3F1 mouse has rarely been a target for chemical carcinogenesis in the National Toxicology Program (NTP) bioassays. However, 6 malignant gliomas and 2 neuroblastomas were observed in B6C3F1 mice exposed to 625 ppm 1,3-butadiene (NTP technical reports 288 and 434). These mouse brain tumors were evaluated with regard to the profile of genetic alterations that are observed in human brain tumors. Alterations in the p53 tumor suppressor gene were common. Missense mutations were observed in 3/6 malignant gliomas and 2/2 neuroblastomas and were associated with loss of heterozygosity. Most of the mutations occurred in exons 5–8 of the p53 gene and were G → A transitions, and did not involve CpG sites. Loss of heterozygosity at the Ink4a/Arf gene locus was observed in 5/5 malignant gliomas and 1/1 neuroblastoma, while the PTEN (phosphatase and tensin homologue) gene locus was unaffected by deletions. One of 2 neuroblastomas had a mutation in codon 61 of H-ras, while H-ras mutations were not observed in the malignant gliomas examined. Only 1 brain tumor has been reported from control mice of over 500 NTP studies. This malignant glioma showed no evidence of alterations in the p53 gene or K - and H-ras mutations. It is likely that the specific genetic alterations observed were induced or selected for by 1,3-butadiene treatment that contributed to the development of mouse brain tumors. The observed findings are similar in part to the genetic alterations reported in human brain tumors.
    Type of Medium: Online Resource
    ISSN: 0192-6233 , 1533-1601
    URL: Article
    DOI: 10.1080/01926230590922848
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2005
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  • 6
    Online Resource
    Online Resource
    Mutations of ras Protooncogenes and p53 Tumor Suppressor Gene in Cardiac Hemangiosarcomas from B6C3F1 Mice Exposed to 1,3-Butadiene for 2 Years
    SAGE Publications ; 2000
    In:  Toxicologic Pathology Vol. 28, No. 4 ( 2000-07), p. 529-534
    Details
    In: Toxicologic Pathology, SAGE Publications, Vol. 28, No. 4 ( 2000-07), p. 529-534
    Abstract: 1,3-Butadiene is a multisite carcinogen in rodents. Incidences of cardiac hemangiosarcomas were significantly increased in male and female B6C3F1 mice that inhaled 1,3-butadiene (BD) for 2 years. Eleven BD-induced cardiac hemangiosarcomas were examined for genetic alterations in ras protooncogenes and in the p53 tumor suppressor gene. Nine of 11 (82%) BD-induced hemangiosarcomas had K- ras mutations and 5 of 11 (46%) had H-ras mutations. All of the K- ras mutations were G→C transversions (GGC→CGC) at codon 13; this pattern is consistent with reported results in BD-induced lung neoplasms and lymphomas. Both K- ras codon 13 CGC mutations and H- ras codon 61 CGA mutations were detected in 5 of 9 (56%) hemangiosarcomas. The 11 hemangiosarcomas stained positive for p53 protein by immunohistochemistry and were analyzed for p53 mutations using cycle sequencing of polymerase chain reaction (PCR) amplified DNA isolated from paraffin-embedded sections. Mutations in exons 5 to 8 of the p53 gene were identified in 5 of 11 (46%) hemangiosarcomas, and all of these were from the 200- or 625-ppm exposure groups that also had K-ras codon 13 CGC mutations. Our data indicate that K- ras, H- ras, and p53 mutations in these hemangiosarcomas most likely occurred as a result of the genotoxic effects of BD and that these mutations may play a role in the pathogenesis of BD-induced cardiac hemangiosarcomas in the B6C3F1 mouse.
    Type of Medium: Online Resource
    ISSN: 0192-6233 , 1533-1601
    URL: Article
    DOI: 10.1177/019262330002800404
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2000
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  • 7
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    Online Resource
    Analysis of p53 Tumor Suppressor Gene, H-ras Protooncogene and Proliferating Cell Nuclear Antigen (PCNA) in Squamous Cell Carcinomas of HRA/Skh Mice Following Exposure to 8-Methoxypsoralen (8-MOP) and UVA Radiation (PUVA Therapy)
    SAGE Publications ; 2005
    In:  Toxicologic Pathology Vol. 33, No. 2 ( 2005-02), p. 292-299
    Details
    In: Toxicologic Pathology, SAGE Publications, Vol. 33, No. 2 ( 2005-02), p. 292-299
    Abstract: Treatment with 8-methoxypsoralen (8-MOP) and ultraviolet radiation (primarily UVA), called PUVA therapy, has been used to treat different chronic skin diseases but led to a significant increased risk for skin cancer. The National Toxicology Program (NTP) performed a study in mice treated with PUVA that showed a significant increase in squamous cell carcinomas of the skin. In the present study, we evaluated the protein expression of p53 and PCNA and DNA mutations of p53 and H-ras genes in both hyperplastic and neoplastic squamous cell lesions from the NTP study. By immunohistochemical staining, protein expression of both p53 and PCNA was detected in 3/16 (19%) of hyperplastic lesions and 14/17 (82%) of SCCs in groups treated with both 8-MOP and UVA. The mutation frequency of p53 in SCCs from mice administered 8-MOP plus UVA was 15/17 (88%) with a predominant distribution of mutations in exon 6 (14/15 – 93%). No H-ras mutations were detected in the hyperplastic lesions/tumors. The mutagenic effect of PUVA on the p53 tumor suppressor gene may lead to a conformational modification and inactivation of the p53 protein, which are considered critical steps in PUVA-induced skin carcinogenesis. The p53 mutational frequency and patterns from our study were different from those reported in human PUVA-type tumors.
    Type of Medium: Online Resource
    ISSN: 0192-6233 , 1533-1601
    URL: Article
    DOI: 10.1080/019262390908380
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2005
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  • 8
    Online Resource
    Online Resource
    High Frequency of Ras Mutations in Forestomach and Lung Tumors of B6C3F1 Mice Exposed to 1-Amino-2,4-dibromoanthraquinone for 2 Years
    SAGE Publications ; 2001
    In:  Toxicologic Pathology Vol. 29, No. 4 ( 2001-06), p. 422-429
    Details
    In: Toxicologic Pathology, SAGE Publications, Vol. 29, No. 4 ( 2001-06), p. 422-429
    Abstract: 1-Amino-2,4-dibromoanthraquinone (ADBAQ) is an anthraquinone-derived vat dye, and a potent carcinogen in laboratory animals. In a 2-year study with dietary exposure to 10,000 or 20,000 ppm ADBAQ, increased incidence of forestomach and lung tumors were observed in B6C3F 1 mice. The present study indentified genetic alterations in H- ras and K- ras proto-oncogenes in ADBAQ-induced tumors. Point mutations in ras proto-oncogenes were identified by restriction fragment length polymorphism, single-stranded conformational polymorphis m analysis and cycle sequencing of polymerase chain reaction-amplified DNA isolated from paraffin-embedded squamous cell papillomas and carcinomas in the forestomach, and alveolar/bronchiolar adenomas and carcinomas in the lung. A higher frequency of ras mutations was identified in ADBAQ-induced forestomach (23/32, 72%) and lung tumors (16/23, 70%) than in spontaneous forestomach (4/11, 36%) and lung tumors (26/86, 30%). H- ras codon 61 CTA mutations were detected in (4/8, 50%) ADBAQ-induced forestomach squamous cell papillomas and (10/24, 42%) squamous cell carcinomas, but not in the spontaneous forestomach tumors examined. H- ras codon 61 CGA mutation (6/24, 25%) was also detected in ADBAQ-induced forestomach squamous cell carcinomas. K- ras codon 61 A to T transversions and A to G transitions were prominent in ADBAQ-induced lung alveolar/bronchiolar adenomas and alveolar/bronchiolar carcinomas. The major finding of A to T transversions or A to G transitions in forestomach and lung tumors suggests that ADBAQ or its metabolites target adenine bases in the ras proto-oncogene s and that these mutations play a dominant role in multi-organ carcinogenesi s in the B6C3F 1 mouse.
    Type of Medium: Online Resource
    ISSN: 0192-6233 , 1533-1601
    URL: Article
    DOI: 10.1080/01926230152499908
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2001
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