Published in Cancer Detection and Prevention 2000; 24(Supplement 1).

Evidence for potential chemopreventive and chemotherapeutic utility of the cyclooxygenase-2 specific inhibitor, celecoxib, in epithelial cancers

AT Koki PhD 1, K Seibert PhD 1, KM Leahy MS 1, BS Zweifel MS 1, RJ Moore MS 1, D Heuvelman MS 1, BM Woerner MS 1, AJ Dannenberg MD 2, RL Ornberg PhD 1, JL Masferrer PhD 1

1 Pharmacia Corporation, St Louis, MO, 2 Strang Cancer Prevention Center, New York Presbytarian Hospital, New York, NY,

AIMS: Cyclooxygenase-2 (COX-2) is overexpressed in many human epithelial tumors, including colon, breast, prostate, head and neck, esophageal, skin, pancreatic, cervical, endometrial, ovarian, and lung. In these human cancers, COX-2 immunoreactivity is detected in the neoplastic cells per se, and in the vasculature adjacent to and within tumorous nests. This distribution implies COX-2 derived prostaglandins may contribute directly to the maintenance and growth of tumors cells, and contribute to the induction of new blood vessels. METHODS: The COX-2 specific inhibitor, celecoxib, was evaluated as a monotherapy and in combination with cyclophosphamide or 5-Fluorouracil for anti-cancer activity in relevant models of lung and human colon cancer. RESULTS: In C57/B6 mice bearing Lewis lung carcinoma, celecoxib inhibited tumor growth in a dose dependent fashion with maximum inhibition of 86% in tumor volume. Addition of cyclophosphamide to celecoxib resulted in near complete (97%) inhibition of tumor growth. Furthermore, a reduction of number and size of lung metastases was observed in celecoxib treated mice. Similar to the Lewis lung model, celecoxib dose-dependently suppressed human colon tumors (HT-29) implanted into nude mice; an effect that was augmented by 5-Fluorouracil (5-FU = 61%, Cel =68%, 5-FU + Cel = 83% inhibition). Mechanistically, celecoxib demonstrated potent antiangiogenic activity. In a rat model of angiogenesis, corneal blood vessel formation was dose-dependently suppressed by celecoxib, but not by a selective COX-1 inhibitor. CONCLUSIONS: The ability of celecoxib to inhibit tumor growth, suppress metastasis, and block neoangiogenesis, suggests a novel application of this anti-inflammatory drug in the prevention and treatment of human cancer.

KEY WORDS: anti-angiogenic.

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Paper presented at the International Symposium on Impact of Biotechnology on Cancer Diagnostic & Prognostic Indicators; Geneva, Switzerland; October 28 - 31, 2000; in the section on satellite symposium.