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INHIBITION OF CYCLOOXYGENASE-2 SUPPRESSES ANGIOGENESIS AND THE GROWTH OF PROSTATE CANCER IN VIVO

Authors
Journal
The Journal of Urology
0022-5347
Publisher
Elsevier
Publication Date
Volume
164
Issue
3
Identifiers
DOI: 10.1016/s0022-5347(05)67321-1
Keywords
  • Cyclooxygenase-2
  • Prostate Cancer
  • Angiogenesis
  • Apoptosis
  • Ns398
Disciplines
  • Biology
  • Chemistry

Abstract

Purpose Cyclooxygenase (COX)-2, an inducible enzyme which catalyzes the formation of prostaglandins from arachidonic acid, is expressed in prostate cancer specimens and cell lines. To evaluate the in vivo efficacy of a COX-2 inhibitor in prostate cancer, NS398 was administered to mice inoculated with the PC-3 human prostate cancer cell line. Materials and Methods A total of 28 male nude mice were inoculated subcutaneously 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 weekly for 9 weeks. Tumors were measured at weekly intervals. After a 10-week experimental period, mice were euthanized and tumors were immuno- histochemically assayed for proliferation (PCNA), apoptosis (TUNEL) and microvessel density (MVD) (Factor-VIII-related antigen). Tumor VEGF content was assayed 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 mice was 285 mm. 2 as compared with 22 mm. 2 from treated mice (93% inhibition, p <0.001). Immunohistochemical analysis revealed that NS398 had no effect on proliferation (PCNA), but induced apoptosis (TUNEL) and decreased MVD (angiogenesis). VEGF expression was also significantly down regulated in the NS398-treated tumors. Conclusions These results demonstrate that a selective COX-2 inhibitor suppresses PC-3 cell tumor growth in vivo. Tumor growth suppression is achieved by a combination of direct induction of tumor cell apoptosis and down regulation of tumor VEGF with decreased angiogenesis

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