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CHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Inhibition of Cyclooxygenase-2 by Celecoxib Reverses Tumor-Induced Wasting

Oncology, PTC Therapeutics, South Plainfield, New Jersey (T.W.D.); and Oncology Discovery Research, Pfizer Corporation, St. Louis, Missouri (B.S.Z., J.M.O., D.M.H., A.L.A., T.O.H.)

There have been a number of reports suggesting inhibition of prostaglandin production may impact tumor-mediated wasting and levels of associated humoral factors such as hypercalcemia. These reductions were achieved using traditional nonsteroidal anti-inflammatory drugs (NSAIDs), which are often contraindicated in cancer patients. This is especially true during chemotherapeutic regimens due to concerns of bleeding from gastrointestinal and hematopoietic toxicities associated with inhibition of the housekeeping cyclooxygenase enzyme COX-1. Here, we report that celecoxib, one of the new class of selective COX-2 inhibitors, has the potential to reverse tumor-mediated wasting and associated humoral factors such as interleukin (IL)-6 and hypercalcemia in preclinical models of cachexia. Tumor bearing mice in late stage cachexia regained weight within days of the start of celecoxib treatment. Two models were tested. The first was the Colon 26 (Col26) syngeneic murine model that induces high levels of circulating IL-6 and hypercalcemia. The second was the human head and neck 1483 HNSCC xenograft model, which is less inflammatory and produces less prostaglandin than Col26. Despite the observation that no significant impact on tumor growth was observed between vehicle and celecoxib-treated animals over the course of the studies, celecoxib rapidly reversed weight loss in both cachectic models. With the added safety of celecoxib over traditional NSAIDs, these results suggest a possible therapeutic use for celecoxib for treating tumor-mediated wasting.

Address correspondence to: Dr. Thomas W. Davis, PTC Therapeutics, 100 Corporate Ct., South Plainfield, NJ 07080. E-mail: tdavis{at}ptcbio.com

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