In the present study, the anti-
tumor mechanism of
Z-100 was investigated with the use of pulmonary
metastasis of B16F10
melanoma. In B16F10 mice, Th1
cytokine production (IL-2, IFN-gamma) was suppressed in comparison with normal mice. On the other hand, Th2
cytokine production (IL-4, IL-10) was increased in the B16F10 mice. The administration of
Z-100 to B16F10 mice restored the balance of Th1/Th2 cell responses from the Th2 dominant state to the normal state.
Z-100 significantly suppressed the pulmonary
metastasis of B16F10
melanoma in a dose-dependent manner. These results suggest that
Z-100 restored the breakdown of Th1 cell responses, resulting in the suppression of pulmonary
metastasis of B16F10
melanoma. Moreover,
Z-100 decreased the
corticosterone levels, which is known to suppress the Th1 cell responses, in both serum specimens and splenic tissue, and the steroidogenic
CYP11A1 mRNA expression in CD4+ T cells. These results suggest that a suppression of pulmonary
metastasis and restoration of Thl/Th2 cell responses by
Z-100 may be due to the decrease in the
corticosterone levels and the steroidogenic
CYP11A1 mRNA expression of CD4+ T cells in B16F10 mice. Further, the role of Th1
cytokine, IFN-gamma, on these activities of
Z-100 was examined. The suppressive effects of
Z-100 on pulmonary
metastasis and restoration of Th1/Th2 cell responses were eliminated by the administration of anti-IFN-gamma mAb. Moreover, the suppressive effects of
Z-100 on
glucocorticoid-genesis were eliminated by the administration of anti-IFN-gamma-mAb. These results suggest that
Z-100 restores the balance of Th1/Th2 cell responses via the suppression of
glucocorticoid-genesis by Z-100-induced IFN-gamma. IFN-gamma acts as a key
cytokine in anti-
tumor activities of
Z-100.