Combination therapy of human pancreatic cancer implanted in nude mice by oral fluoropyrimidine anticancer agent (S-1) with interferon-alpha.
OBJECTIVE
We evaluated the antitumor and antiangiogenic activities of human natural interferon-alpha (IFN-alpha) 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-alpha 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-alpha and S-1 (8, 10, 12 mg/kg six times a week).


RESULTS
Administration of IFN-alpha 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-alpha 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-alpha and S-1 exert its effects, we have utilized cDNA microarray including 124 known genes to determine the gene expression profile altered by IFN-alpha and S-1 treatment. We found a total of seven genes which showed a twofold change after IFN-alpha 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-alpha in combination with S-1 may provide a novel and effective approach to the treatment of human pancreatic cancer.
Miyake
Kotaro
K
Department of Digestive and Pediatric Surgery, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan.
Tsuchida
Kunihiro
K
Sugino
Hiromu
H
Imura
Satoru
S
Morine
Yuji
Y
Fujii
Masahiko
M
Shimada
Mitsuo
M
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D016898:Interferon-alpha / Q000008:administration & dosage; D020782:Matrix Metalloproteinases / Q000096:biosynthesis; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis; D016019:Survival Analysis; D005641:Tegafur / Q000008:administration & dosage; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
D020533:Angiogenesis Inhibitors; D000903:Antibiotics, Antineoplastic; D018076:DNA, Complementary; D016898:Interferon-alpha; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D018809:Proliferating Cell Nuclear Antigen; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D005641:Tegafur; D042943:Dihydrouracil Dehydrogenase (NADP); D020782:Matrix Metalloproteinases