Source:http://linkedlifedata.com/resource/pubmed/id/12907609
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rdf:type | |
lifeskim:mentions |
umls-concept:C0022660,
umls-concept:C0024121,
umls-concept:C0026809,
umls-concept:C0054201,
umls-concept:C0079419,
umls-concept:C0442805,
umls-concept:C0443199,
umls-concept:C0449258,
umls-concept:C0449822,
umls-concept:C0525037,
umls-concept:C0596988,
umls-concept:C0870432,
umls-concept:C1280500,
umls-concept:C1510707,
umls-concept:C1515926,
umls-concept:C1516463,
umls-concept:C1555465,
umls-concept:C1705280,
umls-concept:C1705417
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pubmed:issue |
15
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pubmed:dateCreated |
2003-8-8
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pubmed:abstractText |
p53 transgenic mice carrying a dominant negative mutation were crossed with Ink4A/Arf heterozygous-deficient mice to investigate whether there is a synergy between these two germ-line mutations in promoting carcinogen-induced lung tumor progression in mice. Mice with a p53 dominant negative mutation and Ink4A/Arf heterozygous deficiency exhibited >20-fold increase in tumor volume compared with approximately 4-fold increase in Ink4A/Arf heterozygous-deficient mice and a 9-fold increase in mice with only the p53 dominant negative mutation. The effect of Ink4A/Arf heterozygous deficiency on lung tumor progression occurred late in the carcinogenesis process (>30 weeks after carcinogen treatment). In addition, most of the lung tumors (approximately 80%) from mice with a p53 mutation and deletion of Ink4A/Arf were lung adenocarcinomas. In contrast, lung adenocarcinomas were seen in <10% of the lung tumors from the wild-type mice and approximately 50% of the lung tumors from Ink4a/Arf heterozygous-deficient or p53 mutant mice. These results indicate a significant synergistic interaction between the presence of a mutant p53 transgene and the Ink4A/Arf deletion during lung tumor progression (P < 0.01). The usefulness of this new mouse model in lung cancer chemoprevention was examined. The chemopreventive efficacy of budesonide was examined in wild-type mice, mice with Ink4A/Arf heterozygous deficiency, mice with a mutation in the p53 gene, or mice with both a mutation in the p53 gene and deletion in the Ink4A/Arf locus. Mice treated with budesonide displayed an average of 90% inhibition of lung tumor progression in a standard 18-week chemoprevention assay, regardless of p53 and/or Ink4A/Arf status. However, the efficacy of budesonide against lung tumor progression decreased from 94 to 77% (P = 0.07) in mice with alterations in both p53 and Ink4A/Arf in a 40-week chemoprevention assay. Similarly, when mice bearing established lung adenomas were treated with budesonide, genotype-dependent differential effects of budesonide in wild-type and mutant mice were clearly revealed with a 82, 64, 45, and 33% decrease in tumor volume in wild-type mice, p53(+/+)Ink4a/Arf(+/-) mice, p53(+/-)Ink4a/Arf(+/+) mice, and p53(+/-)Ink4a/Arf(+/-), respectively. Thus, mutant mice with alterations in p53 and/or Ink4A/Arf exhibited a significant resistance to chemoprevention by budesonide. Because p53 and Ink4a/Arf mutations are the most prevalent mutations in human lung cancers, the effectiveness of chemopreventive agents on the mutant A/J mice containing alterations with p53 and Ink4a/Arf is the best preclinical estimate of their efficacy in humans. Thus, the mutant A/J mouse model should prove useful for chemoprevention studies.
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pubmed:grant | |
pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Anticarcinogenic Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Benzo(a)pyrene,
http://linkedlifedata.com/resource/pubmed/chemical/Budesonide,
http://linkedlifedata.com/resource/pubmed/chemical/Carcinogens,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclin-Dependent Kinase Inhibitor...
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pubmed:status |
MEDLINE
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pubmed:month |
Aug
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pubmed:issn |
0008-5472
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:day |
1
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pubmed:volume |
63
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
4389-95
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pubmed:dateRevised |
2007-11-14
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pubmed:meshHeading |
pubmed-meshheading:12907609-Adenocarcinoma,
pubmed-meshheading:12907609-Animals,
pubmed-meshheading:12907609-Anticarcinogenic Agents,
pubmed-meshheading:12907609-Benzo(a)pyrene,
pubmed-meshheading:12907609-Budesonide,
pubmed-meshheading:12907609-Carcinogens,
pubmed-meshheading:12907609-Cyclin-Dependent Kinase Inhibitor p16,
pubmed-meshheading:12907609-Disease Progression,
pubmed-meshheading:12907609-Female,
pubmed-meshheading:12907609-Genes, p53,
pubmed-meshheading:12907609-Genetic Predisposition to Disease,
pubmed-meshheading:12907609-Germ-Line Mutation,
pubmed-meshheading:12907609-Inbreeding,
pubmed-meshheading:12907609-Lung Neoplasms,
pubmed-meshheading:12907609-Male,
pubmed-meshheading:12907609-Mice,
pubmed-meshheading:12907609-Mice, Inbred A,
pubmed-meshheading:12907609-Mice, Transgenic
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pubmed:year |
2003
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pubmed:articleTitle |
Mice with alterations in both p53 and Ink4a/Arf display a striking increase in lung tumor multiplicity and progression: differential chemopreventive effect of budesonide in wild-type and mutant A/J mice.
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pubmed:affiliation |
Department of Surgery, The Alvin J. Siteman Cancer Center, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.
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