In this study, the effects of combination
therapy consisting of X-ray irradiation and
Z-100 on the survival time of C57BL/6 mice inoculated with B16F10
melanoma were investigated. Survival time was significantly prolonged in B16F10
melanoma-bearing mice treated with the X-ray irradiation (5 Gy) and
Z-100 (10 mg/kg s.c.) combination
therapy compared with mice irradiated with X-rays alone. The weight of primary
tumors and number of metastatic colonies were also significantly suppressed by the combination
therapy compared with that in the X-ray irradiation group. These results indicated that
Z-100 could enhance the anti-
tumor effects of
radiotherapy against B16F10
melanoma. On the other hand, the survival time of CD4 knockout mice bearing the same
tumors was not prolonged by the combination
therapy compared with mice irradiated with X-rays alone, suggesting that CD4+ cells are partly involved in augmentation of the anti-
tumor effect of
radiotherapy by
Z-100. In addition, type 1
cytokine (IL-2, IFN-gamma) production was significantly increased and type 2
cytokine (IL-4, IL-10) production was significantly suppressed in the
tumor-bearing mice treated with the combination
therapy compared with the X-ray irradiation group. Moreover,
interleukin-12 production by CD11c+ cells was also significantly increased in mice treated with the combination
therapy compared with the X-ray irradiation group. These results indicate that
Z-100 augmented the anti-
tumor effects of X-ray irradiation. Moreover, we demonstrated that the effects of
Z-100 were expressed at least in part, by the improvement of the T cell responses from type 2-dominant to type 1-dominant via up-regulation of
IL-12 production.