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Direct Evidence for a Role of Cyclooxygenase 2-derived Prostaglandin E₂ in Human Head and Neck Xenograft Tumors

Pharmacology/Oncology, Pharmacia Corporation, St. Louis, Missouri 63198

Both nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase (COX) 2-selective inhibitors such as celecoxib are being reported as having potent anticancer activity in laboratory models. Several reports have suggested that the mechanism of action of these agents in reducing tumor volume/burden is unrelated to their inhibition of prostaglandin synthesis. Many in vitro reports use supraphysiological concentrations of these drugs to demonstrate COX-independent activities on apoptosis or proliferation. In vivo, most murine tumor models express COX-2 only in the vasculature and stroma, unlike human tumors that also express COX-2 in the tumor cells. In general, these models have the limitation of having no measurable, COX-2-derived, prostaglandins, the inhibition of which correlates with antitumor efficacy. We report here that 1483 human head and neck xenograft tumors express COX-2 similar to the pattern observed in human solid tumors and that COX-2 activity produces high levels of prostaglandin E₂ (PGE₂). Inhibition of COX-2 by celecoxib resulted in loss of intratumor PGE₂ levels and reduced tumor growth in a dose-dependent manner. In contrast, a selective COX-1 inhibitor, SC-560, did not measurably reduce tumor prostaglandin levels or tumor growth despite the presence of COX-1 in the host and tumor cells. Celecoxib-treated tumors showed reduced proliferation and increased apoptosis of both tumor and stromal cells compared with vehicle controls. Specific inhibition of PGE₂ activity by a neutralizing antibody mimicked the reduced tumor growth observed after celecoxib treatment, suggesting growth is PGE₂ mediated. These data indicate that a major antitumor mechanism of action of celecoxib is inhibition of COX-2-derived prostaglandins, particularly PGE₂, and suggest celecoxib as a novel therapeutic agent for human head and neck cancer.

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