Effects of nonselective cyclooxygenase inhibition with low-dose ibuprofen on tumor growth, angiogenesis, metastasis, and survival in a mouse model of colorectal cancer.
OBJECTIVE
To determine whether the nonselective and relatively inexpensive nonsteroidal anti-inflammatory drug ibuprofen would be effective in inhibiting colorectal cancer and might improve mortality in a mouse model.


METHODS
The effects of ibuprofen on tumor growth inhibition and animal survival have been examined in both mouse and human colorectal cancer tumor models. Angiogenesis was measured by in vitro endothelial cell tube formation and immunohistochemistry.


RESULTS
Ibuprofen significantly inhibited cell proliferation in mouse (MC-26) and human (HT-29) colorectal cancer cell lines. In vitro angiogenesis assays also indicated that ibuprofen decreased both cell proliferation and tube formation. The administration of chow containing 1,360 ppm ibuprofen, which achieved an average plasma concentration of ibuprofen lower than the peak level achieved in humans at therapeutic doses, inhibited tumor growth by 40% to 82%. Fewer liver metastases were found in the ibuprofen group compared with the control group. In combination therapy with the standard antineoplastic agents, 5-fluorouracil, or irinotecan (CPT-11), tumor volumes in the groups with ibuprofen +/- CPT-11 or 5-fluorouracil were smaller than in the control group. Ibuprofen was similar to the cyclooxygenase-2 selective inhibitor rofecoxib in its ability to suppress tumor growth and improve overall survival.


CONCLUSIONS
Ibuprofen, in part by modulating tumor angiogenesis, decreases both tumor growth and metastatic potential in mice. The ibuprofen doses were in the low range of therapeutic human plasma concentrations. Ibuprofen potentiates the antitumor properties of CPT-11 and improves survival of mice without increasing gastrointestinal toxicity.
Yao
Min
M
Section of Gastroenterology, Boston University School of Medicine and Boston Medical Center, 650 Albany Street, Boston, MA 02118, USA.
Zhou
Wei
W
Sangha
Simren
S
Albert
Andrew
A
Chang
Albert J
AJ
Liu
Thomas C
TC
Wolfe
M Michael
MM
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D015153:Blotting, Western; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005472:Fluorouracil / Q000008:administration & dosage; D019073:HT29 Cells; D006801:Humans; D007052:Ibuprofen / Q000008:administration & dosage / Q000494:pharmacology*; D000077146:Irinotecan; D007783:Lactones / Q000008:administration & dosage / Q000494:pharmacology; D008113:Liver Neoplasms / Q000517:prevention & control / Q000556:secondary; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000517:prevention & control*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D013450:Sulfones / Q000008:administration & dosage / Q000494:pharmacology; D016019:Survival Analysis; D023041:Xenograft Model Antitumor Assays
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007783:Lactones; D008565:Membrane Proteins; D013450:Sulfones; C116926:rofecoxib; D000077146:Irinotecan; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; D015232:Dinoprostone; D005472:Fluorouracil; D007052:Ibuprofen; D002166:Camptothecin