Inhibition of cyclooxygenase-2 suppresses angiogenesis and the growth of prostate cancer in vivo

Purpose: Cyclooxygenase (COX)-2, an inducible enzyme which catalyzes the fo rmation of prostaglandins from arachidonic acid, is expressed in prostate c ancer specimens and cell lines. To evaluate the in vivo efficacy of a COX-2 inhibitor in prostate cancer, NS398 was administered to mice inoculated wi th the PC-3 human prostate cancer cell line. Materials and Methods: A total of 28 male nude mice were inoculated subcuta neously with 1 million PC-3 cells. Tumors were palpable in all 28 animals 1 week after inoculation and mice were randomized to receive either vehicle (control) or NS398, 3 mg./kg. body weight, intraperitoneally three times we ekly for 9 weeks. Tumors were measured at weekly intervals. After a 10-week experimental period, mice were euthanized and tumors were immuno- histoche mically assayed for proliferation (PCNA), apoptosis (TUNEL) and microvessel density (MVD) (Factor-VIII-related antigen). Tumor VEGF content was assaye d by Western blotting. Results: NS398 induced a sustained inhibition of PC-3 tumor cell growth and a regression of existing tumors. Average tumor surface area from control m ice was 285 mm.(2) as compared with 22 mm.(2) from treated mice (93% inhibi tion, p <0.001). Immunohistochemical analysis revealed that NS398 had no ef fect on proliferation (PCNA), but induced apoptosis (TUNEL) and decreased M VD (angiogenesis). VEGF expression was also significantly down regulated in the NS398-treated tumors. Conclusions: These results demonstrate that a selective COX-2 inhibitor sup presses PC-3 cell tumor growth in vivo. Tumor growth suppression is achieve d by a combination of direct induction of tumor cell apoptosis and down reg ulation of tumor VEGF with decreased angiogenesis.