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dc.contributor.authorYan, Min
dc.contributor.authorMyung, Seung-Jae
dc.contributor.authorFink, Stephen P
dc.contributor.authorLawrence, Earl
dc.contributor.authorLutterbaugh, James
dc.contributor.authorYang, Peiying
dc.contributor.authorZhou, Xiaohua
dc.contributor.authorLiu, Danielle
dc.contributor.authorRerko, Ronald M
dc.contributor.authorWillis, Joseph
dc.contributor.authorDawson, Dawn
dc.contributor.authorTai, Hsin-Hsiung
dc.contributor.authorBarnholtz-Sloan, Jill S
dc.contributor.authorNewman, Robert A
dc.contributor.authorBertagnolli, Monica M
dc.contributor.authorMarkowitz, Sanford D
dc.date.accessioned2010-03-18T11:16:46Z
dc.date.available2010-03-18T11:16:46Z
dc.date.issued2009-06-09
dc.identifier.citation15-Hydroxyprostaglandin dehydrogenase inactivation as a mechanism of resistance to celecoxib chemoprevention of colon tumors. 2009, 106 (23):9409-13 Proc. Natl. Acad. Sci. U.S.A.en
dc.identifier.issn1091-6490
dc.identifier.pmid19470469
dc.identifier.doi10.1073/pnas.0902367106
dc.identifier.urihttp://hdl.handle.net/10147/94497
dc.description.abstractPharmacologic inhibitors of the prostaglandin-synthesizing COX-2 oncogene prevent the development of premalignant human colon adenomas. However, resistance to treatment is common. In this study, we show that the adenoma prevention activity of the COX-2 inhibitor celecoxib requires the concomitant presence of the 15-hydroxyprostaglandin dehydrogenase (15-PGDH) tumor suppressor gene, and that loss of 15-PGDH expression imparts resistance to celecoxib's anti-tumor effects. We first demonstrate that the adenoma-preventive activity of celecoxib is abrogated in mice genetically lacking 15-PGDH. In FVB mice, celecoxib prevents 85% of azoxymethane-induced tumors >1 mm in size, but is essentially inactive in preventing tumor induction in 15-PGDH-null animals. Indeed, celecoxib treated 15-PGDH null animals develop more tumors than do celecoxib naive WT mice. In parallel with the loss of tumor prevention activity, celecoxib-mediated suppression of colonic PGE(2) levels is also markedly attenuated in 15-PGDH-null versus WT mice. Finally, as predicted by the murine models, humans with low colonic 15-PGDH levels also exhibit celecoxib resistance. Specifically, in a colon adenoma prevention trial, in all cases tested, individuals who developed new adenomas while receiving celecoxib treatment were also found as having low colonic 15-PGDH levels.
dc.language.isoenen
dc.subject.meshAdenoma
dc.subject.meshAnimals
dc.subject.meshColon
dc.subject.meshColonic Neoplasms
dc.subject.meshColonoscopy
dc.subject.meshDrug and Narcotic Control
dc.subject.meshHumans
dc.subject.meshHydroxyprostaglandin Dehydrogenases
dc.subject.meshIntestinal Mucosa
dc.subject.meshMice
dc.subject.meshMice, Knockout
dc.subject.meshPyrazoles
dc.subject.meshSulfonamides
dc.subject.otherCOLORECTAL CANCERen
dc.title15-Hydroxyprostaglandin dehydrogenase inactivation as a mechanism of resistance to celecoxib chemoprevention of colon tumors.en
dc.contributor.departmentDepartment of Medicine and Pathology, Ireland Cancer Center, Case Western Reserve University and Case Medical Center, Cleveland, OH 44106, USA.en
dc.identifier.journalProceedings of the National Academy of Sciences of the United States of Americaen
refterms.dateFOA2018-08-31T05:02:29Z
html.description.abstractPharmacologic inhibitors of the prostaglandin-synthesizing COX-2 oncogene prevent the development of premalignant human colon adenomas. However, resistance to treatment is common. In this study, we show that the adenoma prevention activity of the COX-2 inhibitor celecoxib requires the concomitant presence of the 15-hydroxyprostaglandin dehydrogenase (15-PGDH) tumor suppressor gene, and that loss of 15-PGDH expression imparts resistance to celecoxib's anti-tumor effects. We first demonstrate that the adenoma-preventive activity of celecoxib is abrogated in mice genetically lacking 15-PGDH. In FVB mice, celecoxib prevents 85% of azoxymethane-induced tumors >1 mm in size, but is essentially inactive in preventing tumor induction in 15-PGDH-null animals. Indeed, celecoxib treated 15-PGDH null animals develop more tumors than do celecoxib naive WT mice. In parallel with the loss of tumor prevention activity, celecoxib-mediated suppression of colonic PGE(2) levels is also markedly attenuated in 15-PGDH-null versus WT mice. Finally, as predicted by the murine models, humans with low colonic 15-PGDH levels also exhibit celecoxib resistance. Specifically, in a colon adenoma prevention trial, in all cases tested, individuals who developed new adenomas while receiving celecoxib treatment were also found as having low colonic 15-PGDH levels.


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