Combination therapy of human pancreatic cancer implanted in nude mice by oral fluoropyrimidine anticancer agent (S-1) with interferon-alpha
Combination therapy of human pancreatic cancer implanted in nude mice by oral fluoropyrimidine anticancer agent (S-1) with interferon-alpha
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DOI：
10.1007/s00280-006-0250-5
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发表时间：
2007-01-01
影响因子：
3
通讯作者：
Shimada, Mitsuo
中科院分区：
文献类型：
--
作者：
Miyake, Kotaro;Tsuchida, Kunihiro;Shimada, Mitsuo
目的：我们评价了人天然干扰素-α（IFN-α）单独或与S-1联合对人胰腺癌细胞的抗肿瘤和抗血管生成活性。方法：皮下（s.c.）移植肿瘤细胞后，小鼠（n = 12）接受s.c.注射单独的IFN-α（10，000 U，每周六次）、口服单独的S-1（8 mg/kg，每周六次）或同时口服IFN-α和S-1（8、10、1.2mg/kg，每周六次）。结果如下：IFN-α与S-I联合给药显著降低了人胰腺癌细胞的进行性生长和血管生成。联合治疗比单独IFN-α或S-I单独治疗对代表性促血管生成分子、血管内皮生长因子和碱性成纤维细胞生长因子的表达产生更显著的抑制。这些处理还减少了增殖细胞核抗原的染色，诱导凋亡和降低微血管密度。为了更好地理解IFN-α和S-1发挥其作用的精确分子机制，我们利用包括124个已知基因的cDNA微阵列来确定IFN-α和S-1处理改变的基因表达谱。我们发现，除了VEGF、bFGF、CD 31、MMP-2、MMP-7和MMP-9之外，在IFN-α和S-I处理后，总共有7个基因显示出两倍的变化。在这些基因中，我们发现有6个基因表达下调，1个基因表达上调，这些基因与血管生成、肿瘤细胞侵袭和转移有关。结论：这些数据表明IFN-α与S-1联合给药。可能为人类胰腺癌的治疗提供一种新的有效途径。
Purpose: 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, 1.2 mg/kg six times a week). Results: Administration of IFN-alpha in combination with S-I 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-I 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-I 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.