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Signal Transduction Laboratory, Methodist Research Institute, Indianapolis, Indiana 46202 [J. C., F. L. L., B. K., M. T. R.], and Pharmacia Corporation, St. Louis, Missouri 63198 [O. C. T.]

2 To whom requests for reprints should be addressed, at Signal Transduction Laboratory, Methodist Research Institute, Clarian Health, 1701 North Senate Blvd., Indianapolis, IN 46202. Phone: (317) 962-6891; Fax: (317) 962-7549; E-mail: mrizzo{at}clarian.org

Angiogenesis plays a crucial role in tumor development and growth. The present investigation was undertaken to test the potential involvement of the cyclooxygenase-2 (COX-2) pathway in the regulation of angiogenesis and growth in pancreatic cancer. We compared the angiogenic characteristics of a COX-2-positive human pancreatic tumor cell line, BxPC-3, with those of a COX-2-negative pancreatic tumor cell line, AsPC-1. Cultured BxPC-3 cells promoted a marked increase of endothelial cell migration in comparison with migration that occurred in the absence of cancer cells. Furthermore, BxPC-3 cell culture supernatants induced endothelial cell capillary morphogenesis in vitro and neovascularization in vivo. In contrast, cultured AsPC-1 cells elicited a modest effect on endothelial cell migration and neovascularization in vivo. Pretreatment of BxPC-3 cells with the selective COX-2 inhibitor NS-398 (50 µM) dramatically decreased angiogenic responses of endothelial cells. NS-398 (25–100 µM) caused inhibition of BxPC-3 cell proliferation but had no effect on AsPC-1 cell growth. SC-560, a selective COX-1 inhibitor, had no effect on growth of either cell lines. These results suggest an involvement of COX-2 in the control of tumor-dependent angiogenesis and growth in certain pancreatic cancers and provide the rational for inhibition of the COX pathway as an effective therapeutic approach for pancreatic tumors.

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