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


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
Liu
X H
XH
Departments of Urology and Medicine, Divisions of Endocrinology and Neoplastic Diseases, Mount Sinai School of Medicine, New York, NY 10029, USA.
Kirschenbaum
A
A
Yao
S
S
Lee
R
R
Holland
J F
JF
Levine
A C
AC
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D004195:Disease Models, Animal; D016228:Endothelial Growth Factors / Q000032:analysis; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020287:In Situ Nick-End Labeling; D007274:Injections, Intraperitoneal; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D008222:Lymphokines / Q000032:analysis; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008819:Mice, Nude; D008833:Microcirculation / Q000187:drug effects; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D009578:Nitrobenzenes / Q000008:administration & dosage / Q000627:therapeutic use*; D010544:Peroxidases / Q000037:antagonists & inhibitors*; D014677:Pharmaceutical Vehicles; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D011451:Prostaglandin-Endoperoxide Synthases / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D020033:Protein Isoforms / Q000032:analysis; D011897:Random Allocation; D013449:Sulfonamides / Q000008:administration & dosage / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014841:von Willebrand Factor / Q000032:analysis
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D016228:Endothelial Growth Factors; D007527:Isoenzymes; D008222:Lymphokines; D008565:Membrane Proteins; D009578:Nitrobenzenes; D014677:Pharmaceutical Vehicles; D018809:Proliferating Cell Nuclear Antigen; D020033:Protein Isoforms; D013449:Sulfonamides; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014841:von Willebrand Factor; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D010544:Peroxidases; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases