Gut-Restricted Selective Cyclooxygenase-2 (COX-2) Inhibitors for Chemoprevention of Colorectal Cancer
| Autor: | Shannon Dallas, Thomas Wilde, Avijit Ghosh, Jianyao Wang, Yawei Dong, Gaochao Tian, Daohong Liao, Xueliang Li, Lawrence Szewczuk, Peter King, David C. Evans, Yifan Shi, Kurtis E. Bachman, Javier Suarez, Beth Pietrak, James P. Edwards, Carlo Sensenhauser, Hao Chen, Vineet Pande, Peter J. Connolly, Karen DiLoreto, William G Bonnette, Shefali Patel, Zhuming Zhang |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Adenoma Cell Survival Colorectal cancer Antineoplastic Agents Disease Etoricoxib Mice Structure-Activity Relationship In vivo Drug Discovery medicine Animals Humans Cell Proliferation Cyclooxygenase 2 Inhibitors Dose-Response Relationship Drug Molecular Structure biology Chemistry medicine.disease Mice Inbred C57BL Celecoxib Cyclooxygenase 2 biology.protein Cancer research Chemoprotective Molecular Medicine Cyclooxygenase Drug Screening Assays Antitumor Colorectal Neoplasms Ex vivo medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 64:11570-11596 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Selective cyclooxygenase (COX)-2 inhibitors have been extensively studied for colorectal cancer (CRC) chemoprevention. Celecoxib has been reported to reduce the incidence of colorectal adenomas and CRC but is also associated with an increased risk of cardiovascular events. Here, we report a series of gut-restricted, selective COX-2 inhibitors characterized by high colonic exposure and minimized systemic exposure. By establishing acute ex vivo 18F-FDG uptake attenuation as an efficacy proxy, we identified a subset of analogues that demonstrated statistically significant in vivo dose-dependent inhibition of adenoma progression and survival extension in an APCmin/+ mouse model. However, in vitro-in vivo correlation analysis showed their chemoprotective effects were driven by residual systemic COX-2 inhibition, rationalizing their less than expected efficacies and highlighting the challenges associated with COX-2-mediated CRC disease chemoprevention. |
| Databáze: | OpenAIRE |
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