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Departments of ¹ Surgery, ² Radiation Oncology, and ³ Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA

Requests for Reprints: Susan Lanza-Jacoby, Department of Surgery, Jefferson Medical College, Thomas Jefferson University, 1025 Walnut Street, Philadelphia, PA 19107. Phone: (215) 955-7903; Fax: (215) 923-1420. E-mail: Susan.Lanza-Jacoby{at}jefferson.edu

Cyclooxygenase (COX)-2-derived prostaglandins (PGs) are thought to contribute to tumor growth and resistance to radiation therapy. COX-2 protein expression is increased in many tumors including those of the breast. COX-2-derived PGs have been shown to protect cells from radiation damage. This study evaluated the role of COX-2-derived PG in radiation treatment by using the NMF11.2 mammary tumor cell line originally obtained from HER-2/neu mice that overexpress HER-2/neu. We determined whether the effects of the COX-2 inhibitor SC236 on cell growth, radiation-induced PGE₂ production and COX expression, cell cycle redistribution, and vascular endothelial growth factor (VEGF) were acting through COX-2-dependent mechanisms. The NMF11.2 cells expressed both COX-1 and COX-2 protein and mRNA. The radiation treatment alone led to a dose-dependent increase in the levels of COX-2 mRNA and COX-2 protein, which was associated with an increase in the production of PGE₂ and prostacyclin (PGI₂). Treating NMF11.2 cells with high concentrations (20 µM) of SC236 for 48 h reduced the radiation-induced increase in COX-2 activity and also decreased cell growth. SC236 (20 µM) increased the accumulation of the cells in the radiosensitive G₂-M phase of the cell cycle. However, a low concentration (5 µM) of SC236 was adequate to reduce COX-2 activity. The lower concentration of SC236 (5 µM) also decreased cell growth after a longer incubation period (96 h) and, in combination with a 2 or 5 Gy dose, led to an accumulation of cells in G₂-M phase. Restoring PG to control values in cells treated with 5 µM SC236 prevented the growth inhibition and G₂-M cell cycle arrest. Radiation treatment of NMF11.2 cells also increased VEGF protein expression and VEGF secretion in a dose-dependent manner, which was blocked in those cells pretreated with 20 µM SC236 but not in those pretreated with 5 µM SC236. These findings indicate that the COX-2 inhibitor SC236 reduced cell growth and arrested cells in the G₂-M phase of the cell cycle by mechanisms that are both dependent and independent of PG production while its effects on VEGF appear to be independent of COX-2.

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Received 8/22/03; revised 12/30/03; accepted 1/26/04.

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