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Effects of Nonselective Cyclooxygenase Inhibition with Low-Dose Ibuprofen on Tumor Growth, Angiogenesis, Metastasis, and Survival in a Mouse Model of Colorectal Cancer

Section of Gastroenterology, Boston University School of Medicine and Boston Medical Center, Boston, Massachusetts

Requests for reprints: M. Michael Wolfe, Boston Medical Center, Section of Gastroenterology, 650 Albany Street, Boston, MA 02118. Phone: 617-638-8330; Fax: 617-638-7785; E-mail: michael.wolfe{at}bmc.org.

Purpose: 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.

Experimental Design: 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.

Key Words: colorectal cancer • Cyclooxygenase • chemotherapy • Ibuprofen • angiogenesis

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