Etodolac inhibits interleukin-6 production and improves survival combined with chemotherapy in a colon 26 cachexia model

It has been suggested that inflammatory components, including interleukin (IL)-6 and transforming growth factor (TGF)-β, play an important role in the formation of cancer cachexia. Cyclooxygenase (COX)-2 has been reported to suppress tumor progression and to inhibit production of these inflammatory mediators, and, thus, may not only be effective in preventing cachexia, but also beneficial for survival. Etodolac, one of the selective COX-2 inhibitors, was administered to mice bearing cachexigenic clones of colon 26, together with either one of two doses (5 and 10 mg/kg/day) of 5-fluorouracil. Serum concentrations of IL-6 were measured in each treatment group. In the groups treated with 5-fluorouracil alone, survival and tumor growth were significantly improved with 10 mg/kg/day. In the group with etodolac alone, survival improved, however, tumor growth was enhanced. Combination of 5-fluorouracil (5 mg/kg/day) and etodolac improved survival, and the enhancement of tumor growth seen in the etodolac only group, disappeared. By combining 5-fluorouracil (10 mg/kg/day) with etodolac, positive effects on survival and tumor growth were obtained. Serum concentrations of IL-6 were elevated in tumor-bearing mice and were significantly suppressed by treatment with etodolac. In the group with combined treatment, the suppressive effect on IL-6 was synergistic. Our findings suggest that the potential use of COX-2 inhibitors in combination with chemotherapy might be therapeutically advantageous especially in patients with terminal stages of cancer.