Details

Autor(en) / Beteiligte

• Yan, Min
• Myung, Seung-Jae
• Fink, Stephen P
• Lawrence, Earl
• Lutterbaugh, James
• Yang, Peiying
• Zhou, Xiaohua
• Liu, Danielle
• Rerko, Ronald M
• Willis, Joseph
• Dawson, Dawn
• Tai, Hsin-Hsiung
• Barnholtz-Sloan, Jill S
• Newman, Robert A
• Bertagnolli, Monica M
• Markowitz, Sanford D

Titel

15-Hydroxyprostaglandin dehydrogenase inactivation as a mechanism of resistance to celecoxib chemoprevention of colon tumors

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2009-06, Vol.106 (23), p.9409-9413

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2009

Link zum Volltext

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• Pharmacologic 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 PGE₂ 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.