Selective inhibition of cyclooxygenase-2 suppresses metastatic disease without affecting primary tumor growth in a murine model of Ewing sarcoma.
OBJECTIVE
Mammalian target of rapamycin suppression by rapamycin inhibits tumor growth and neovascularization via cyclooxygenase-2 (COX-2) downregulation with no effect on lung metastases. We hypothesize that combining a selective COX-2 antagonist (celecoxib) with rapamycin would decrease lung metastases.


METHODS
Ewing sarcoma cells (SK-NEP-1) were surgically implanted into the left kidney of athymic mice (n = 40). The mice were divided into 4 treatment groups (control, rapamycin only, celecoxib only, and combination) and then killed at 6 weeks. Primary tumors were weighed. Vasculature was examined using lectin angiography and immunohistochemistry, and lung metastases were examined using H&E and CD99 immunostaining. Tumor weight and lung metastases were analyzed.


RESULTS
Mean primary tumor weights were significantly reduced in the rapamycin-treated groups but not in the celecoxib-only group. Lectin angiography and endothelial markers immunostaining showed markedly decreased vascularity in the rapamycin-treated groups but not in the celecoxib-only group. Celecoxib-treated groups showed significantly fewer mice with lung metastases than non-celecoxib-treated groups.


CONCLUSIONS
Celecoxib prevents lung metastasis in a murine model of Ewing sarcoma with no effect on tumor size or neovascularization. Cyclooxygenase-2 may represent a future potential target for metastatic disease prevention.
Division of Pediatric Surgery, Steven and Alexandra Cohen Children's Medical Center of New York, North Shore-Long Island Jewish Health System, New Hyde Park, NY 11040, USA.
Amir S
AS
Gendy
Aaron
A
Lipskar
Richard D
RD
Glick
Bettie M
BM
Steinberg
Morris
M
Edelman
Samuel Z
SZ
Soffer
D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000068579:Celecoxib; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D004359:Drug Therapy, Combination; D005260:Female; D008175:Lung Neoplasms / Q000473:pathology / Q000517:prevention & control* / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000517:prevention & control; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D012512:Sarcoma, Ewing / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D020123:Sirolimus / Q000627:therapeutic use; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*
D020533:Angiogenesis Inhibitors; D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D051546:Cyclooxygenase 2; D000068579:Celecoxib; D020123:Sirolimus