A review of the anti-tumor effect of the combined administration of a cyclooxygenase-2 selective inhibitor and a non-specific immunostimulant protein-bound polysaccharide on an advanced colon cancer model using colon cancer cell lines

Abstract

The anti-tumor effect of a cyclooxygenase (COX)-2 selective inhibitor or a non-specific immunostimulant (PSK) alone, as well as the anti-tumor effect of their combined administration were examined on a hepatic metastasis model of colon cancer using a colon 26 cell line (CT26) and its highly metastatic variant. Anti-tumor effects were assessed by the number of hepatic metastases. Serum MMP-9, TGF-β and IL-6 were also measured. In a preliminary experiment, cells (5×10(5)) of a mouse colon cancer 26 cell line (CT26) and its highly metastatic variant were implanted below the splenic capsule in BALB/c and CDF1 mice. The number of hepatic metastatic CT26 cell lesions in the CDF1 mice of the non-spleen-removed group at 2 weeks was found to be optimum for the experiments. Although no significant difference was found, etodolac treatment showed the highest inhibitory effect on the number of hepatic metastases at a concentration of 30 mg/kg. In contrast, intraperitoneal administration of 50 mg/kg PSK showed an inhibitory effect on hepatic metastases, but a significant difference was not observed. PSK (p=0.002) or the combined use of etodolac and PSK (p=0.001) exhibited a significant inhibition of the number of hepatic metastases. In addition, MMP-9 was significantly inhibited by the single use of etodolac or PSK, and was inhibited with an additive effect by the combined use of etodolac and PSK. IL-6 and TGF-β were significantly inhibited following the combined use of etodolac and PSK. In conclusion, etodolac did not exhibit any significant hepatic metastasis inhibitory effect, whereas it significantly reduced the MMP-9 level. PSK reduced both the number of hepatic metastases and MMP-9. Combined use of etodolac and PSK did not show any additive effect in the inhibition of the number of hepatic metastases, whereas it inhibited MMP-9, TGF-β and IL-6, suggesting the benefit of a combined effect.