title: Antitumor and anti-metastatic effects of cyclooxygenase-2 inhibition             by celecoxib on human colorectal carcinoma xenografts in nude mouse rectum.
abstract: We examined the effects of the preferential cyclooxygenase-2 (COX-2) inhibitor             celecoxib on tumorigenesis, angiogenesis, apoptosis, vascular endothelial growth             factor (VEGF) protein expression and metastasis in HT-29 human colorectal carcinoma             cell xenografts in nude mouse rectum. COX-2 mRNA expression was examined in the             xenograft and metastatic sites. The antitumor effect of celecoxib in the xenografts             was evaluated by measuring the weight of the peri-ano-rectal tumor. The anti-metastatic             effect of celecoxib was assessed by quantification of lymph node and lung metastases             by amplification of a cancer-related human DNA by TaqMan PCR. The effects of celecoxib             on angiogenesis, apoptosis, prostaglandin E2 (PGE2) production and VEGF protein             expression in the xenografts were evaluated by means of microvessel density (MVD)             counting, terminal deoxynucleotidyl transferase-mediated nick end labeling assay,             quantitative enzyme-linked immunosorbent assay and western blotting, respectively.             The rectal xenograft model showed lymph node and lung metastases with enhanced             expression of COX-2 mRNA in each organ. Celecoxib inhibited rectal xenograft growth             in a dose-dependent manner as follows: 150 ppm, 33.0% (p=0.000220); 750 ppm, 46.4%             (p=0.0000292); 1500 ppm, 63.4% (p=0.0000109). Celecoxib inhibited lymph node metastasis             in a dose-dependent manner as follows: 150 ppm, 86.7% (p=0.0263); 750 ppm, 90.3%             (p=0.00638); 1500 ppm, 96.0% (p=0.000894). Celecoxib also inhibited lung metastasis             as follows: 750 ppm, 53.3% (p=0.0107); 1500 ppm, 78.3% (p=0.00022). Celecoxib             (1500 ppm) significantly inhibited PGE2 production by 68.4% (p=0.000157) and MVD             counting by 48.2% (p=1.3x10-12) and induced apoptosis 2.5-fold (p=3.0x10-14) in             the rectal xenograft. Celecoxib suppressed VEGF protein expression in the rectal             xenograft. These studies demonstrate that celecoxib reduces the growth and metastatic             potential of colorectal carcinoma in mice through COX-2 inhibition, anti-angiogenesis             and apoptosis induction. The studies using HT-29 human colorectal carcinoma cell             xenografts in nude mouse rectum also provide important information that supports             that the COX-2 inhibitor celecoxib has a high potential for use as a clinical             agent for inhibition of hematological and lymphatic metastases of colorectal cancer.
authors: Gastroenterologic Surgery, Department of Oncology, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Ishikawa 920-8641, Japan. nino@staff.kanazawa-u.ac.jp
authors: Itasu
authors: I
authors: Ninomiya
authors: Noboru
authors: N
authors: Nagai
authors: Katsunobu
authors: K
authors: Oyama
authors: Hironori
authors: H
authors: Hayashi
authors: Hidehiro
authors: H
authors: Tajima
authors: Hirohisa
authors: H
authors: Kitagawa
authors: Sachio
authors: S
authors: Fushida
authors: Takashi
authors: T
authors: Fujimura
authors: Tetsuo
authors: T
authors: Ohta
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D000068579:Celecoxib; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015232:Dinoprostone / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D019073:HT29 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000517:prevention & control* / Q000556:secondary; D008207:Lymphatic Metastasis; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D047368:Tumor Burden / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D042461:Vascular Endothelial Growth Factor A; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D000068579:Celecoxib; D015232:Dinoprostone