Gut-Restricted Selective Cyclooxygenase‑2 (COX-2) Inhibitors for Chemoprevention of Colorectal Cancer

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.