Combination therapy of human pancreatic cancer implanted in nude mice by oral fluoropyrimidine anticancer agent (S-1) with interferon-alpha

Purpose: We evaluated the antitumor and antiangiogenic activities of human natural interferon-alpha (IFN-α) alone or in combination with S-1 against human pancreatic cancer cells. Methods: Three days after the subcutaneous (s.c.) implantation of tumor cells, mice (n = 12) were received s.c. injection with IFN-α alone (10,000 U six times a week), oral administration with S-1 alone (8 mg/kg six times a week), or both with IFN-α and S-1 (8, 10, 12 mg/kg six times a week). Results: Administration of IFN-α in combination with S-1 significantly decreased progressive growth and angiogenesis of human pancreatic cancer cells. The combination therapy produced more significant inhibition in expression of the representative proangiogenic molecules, vascular endothelial growth factor and basic fibroblast growth factor than individual treatment either IFN-α or S-1 alone did. These treatments also decreased the staining of proliferating cell nuclear antigen, induced apoptosis and decreased microvessel density. In order to better understand the precise molecular mechanisms by which IFN-α and S-1 exert its effects, we have utilized cDNA microarray including 124 known genes to determine the gene expression profile altered by IFN-α and S-1 treatment. We found a total of seven genes which showed a twofold change after IFN-α and S-1 treatment in addition to VEGF, bFGF, CD31, MMP-2, MMP-7 and MMP-9. Among these genes, we found down-regulation of six genes and up-regulation of one gene, which are related to angiogenesis, tumor cell invasion and metastasis. Conclusions: These data suggest that administration of IFN-α in combination with S-1 may provide a novel and effective approach to the treatment of human pancreatic cancer.