Celecoxib Prevents Tumor Growth in Vivo without Toxicity to Normal Gut: Lack of Correlation between in Vitro and in Vivo Models

Experimental Therapeutics

Celecoxib Prevents Tumor Growth in Vivo without Toxicity to Normal Gut: Lack of Correlation between in Vitro and in Vivo Models¹

Christopher S. Williams, Alastair J. M. Watson, Hongmiao Sheng, Rania Helou, Jinyi Shao and Raymond N. DuBois²

Departments of Medicine [C. S. W., H. S., R. H., J. S., R. N. D.], and Cell Biology, [C. S. W., R. N. D.], The Vanderbilt Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee 37232-2279; Veterans Administration Medical Center [R. N. D.], Nashville, Tennessee 37232-2279; and Department of Medicine, University of Liverpool, Liverpool, United Kingdom [A. J. M. W.]

Nonsteroidal anti-inflammatory drugs have potential for usein the prevention and/or treatment of colorectal cancer. Wehave studied the cytotoxic effect of a specific COX-2 inhibitor,celecoxib, against LLC, HCA-7, and HCT-15 cells grown in cellculture and have compared these results with its effect on HCA-7cells grown as xenografts in nude mice. "High-dose" celecoxib(>20 µM) reduced the viability of all three cell linesin vitro as measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromideassay. Flow cytometric analysis demonstrated that this lossof viability was attributable to the induction of apoptosis. Significantly,concentrations of the drug <10 µM had no effect oncell viability in vitro. The cytotoxic effects of high-dosecelecoxib were independent of COX-2 inhibition because similareffects were observed in cox-2 (+/+), cox-2 (+/-) and cox-2(-/-) fibroblasts. A plasma concentration of 2.3 ± 0.7 µMwas achieved when celecoxib (1250 mg/kg of chow) was fed toanimals ad libitum. Despite a lack of toxicity at 2–3µM celecoxib in vitro, there was attenuation of HCA-7xenograft growth in vivo. Celecoxib had no effect on apoptosis,cell division, or the epithelial architecture of the normalgut in treated mice. These results support the need for additionalclinical evaluation of celecoxib for treatment and/or preventionof colorectal cancer in humans.

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