Toll-like receptor 4 signaling : Enhancement of therapeutic effect of anti-cancer drugs and radiation in oral Cancer

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Of 67 oral cancer patients who received OK-432,UFT in combination with radiation therapy (RT), complete remission (CR) was observed in 38 cases (56.7%), partial response in 29 cases (43.3%). Response rate was 100%. Of 14 patients received RT+UFT without OK-432,CR was observed only in 2 cases (14,3%). Therapeutic effect of this protocol was almost completely dependent on the expression of Toll-like receptor (TLR) 4 and MD-2 genes on peripheral blood mononuclear cells derived from the patients. We have isolated an active component from the OK-432, a lipoteichoic acid-related molecule designated OK-PSA. OK-PSA induced the maturation of human dendritic cells (DCs), and OK-PSA-treated DCs stimulated allogeneic T cells to produce IFN-γ, and to induce allo-antigen specific cytotoxic T cells. These activities of OK-PSA were also dependent on the gene expression of TLR4 and MD-2. Next, we encapsulated OK-PSA with poly (lactide-co-glycolide) micro-particles, and designated PLG-OK-PSA. In tumor-bearing mice, PLG-OK-PSA augmented the anti-cancer effect of RT and UFT far better than OK-PSA as well as OK-432,and CR was observed in most of the animals bearing tumors. Th1-type cytokines and nitric oxide were detected in the sera derived from the mice administered PLG-OK-PSA. The increased cytotoxic activities of the lymphocytes were also observed. These effects of OK-432,OK-PSA as well as PLG-OK-PSA were not observed in TLR4-mutant and in TLR4-deficient mice. It was greatly suggested that RT+UFT+OK-432 therapy is effective for the regulation of oral cancer, that TLR4 signaling is involved in anti-cancer effect of this therapy, and that PLG-OK-PSA may be useful tool for treating human cancer.