Streptococcal preparation OK-432 enhances the antitumor activity of CPT-11 by increasing Th1-cytokine production in mice

Background: The streptococcal preparation OK-432 is an immunomodulator widely used for cancer therapy in Japan. The purpose of this study was to evaluate the efficacy of the combined treatment of OK-432 and CPT-11. Materials and Methods: In C57BL/6 mice inoculated with B16 melanoma, the antitumor mechanism of this combined therapy was investigated through an analysis of cytokine production by the splenocytes. Results: SN-38, the active metabolite of CPT-11, exerted dose-dependent inhibition of interferon (IFN)-γ production induced by OK-432 in mouse splenocytes. In contrast, the optimum concentration of SN-38 increased interleukin (IL)-6 and IL-12 production by OK-432-activated splenocytes. In tumor-bearing mice, CPT-11 inhibited tumor growth and OK-432 had an additive antitumor effect with CPT-11. Investigation of cytokine production showed that CPT-11 treatment principally inhibited IL-12 and IFN-γ production, which was improved by the combined administration with OK-432. Conclusion: These results indicate that CPT-11 inhibits type-1 T helper (Th1) cells despite its potential to stimulate macrophages and that OK-432 enhances the antitumor activity of CPT-11 by increasing Th 1-cytokine production.