ZD6474 inhibits tumor growth and intraperitoneal dissemination in a highly metastatic orthotopic gastric cancer model
ZD6474 inhibits tumor growth and intraperitoneal dissemination in a highly metastatic orthotopic gastric cancer model
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DOI：
10.1002/ijc.21340
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发表时间：
2006-01-15
影响因子：
6.4
通讯作者：
Nishio, K
中科院分区：
文献类型：
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作者：
Arao, T;Yanagihara, K;Nishio, K
血管生成抑制剂已被用于治疗一些癌症，但这些药物对胃癌的治疗潜力尚不清楚。为了研究它们的治疗潜力，我们用未分化的胃癌细胞系58As1建立了高转移原位模型，观察了选择性靶向血管内皮生长因子受体-2(VEGFR-2；KDR)酪氨酸激酶和表皮生长因子受体(EGFR)酪氨酸激酶的药物ZD6474的作用。ZD6474(100 mg/kg/天，口服，2周)显著抑制肿瘤生长(与对照组相比P<；0.05)，并减少肿瘤向腹膜腔的扩散(与对照组相比P<；0.05)。此外，为了确定在临床环境中反映ZD6474治疗效果的可能的肿瘤生物标志物，我们在体内检测了ZD6474治疗的植入性胃肿瘤的基因表达谱。共鉴定出28个候选基因，包括IGFBP-3、ADM、ANGPTL4、PLOD2、DSIP1、NDRG1、ENO2、HIG2和BNIP3L，它们是已知的低氧诱导基因。这些基因和基因产物可能是监测ZD6474治疗效果的有用生物标志物。ZD6474还通过移植另一种未分化的胃癌细胞系44As3提高了小鼠的存活率。综上所述，我们的结果提示ZD6474可能具有抗胃癌，特别是腹膜转移的未分化胃癌的临床活性。我们还通过基因表达谱确定了可能用于监测ZD6474药效作用的生物标志物。(C)2005年Wiley-Liss。Inc.
Angiogenesis inhibitors have been used to treat some cancers, but the therapeutic potential of these agents for gastric cancer has remained unclear. To investigate their therapeutic potential, we examined the effect of ZD6474, an agent that selectively targets vascular endothelial growth factor receptor-2 (VEGFR-2; KDR) tyrosine kinase and epidermal growth factor receptor (EGFR) tyrosine kinase, in a highly metastatic orthotopic model using an undifferentiated gastric cancer cell line, 58As1. ZD6474 (100 mg/kg/day, p.o., 2 weeks) significantly inhibited tumor growth (p < 0.05 vs. control) and reduced tumor dissemination into the peritoneal cavity (p < 0.05 vs. control). In addition, to identify putative tumor biomarkers that would reflect the effects of ZD6474 treatment in clinical settings, we examined the gene expression profiles of implanted gastric tumors treated with ZD6474 in vivo. Twenty-eight candidate genes were identified, including IGFBP-3, ADM, ANGPTL4, PLOD2, DSIP1, NDRG1, ENO2, HIG2 and BNIP3L, which are known to be hypoxia-inducible genes. These genes and gene products may be useful biomarkers for monitoring the effects of ZD6474 treatment. ZD6474 also improved the survival of mice with implanted another undifferentiated gastric cancer cell line, 44As3. In conclusion, our results suggest that ZD6474 may have clinical activity against gastric cancer, particularly undifferentiated gastric cancer with peritoneal dissemination. We also identified putative biomarkers for monitoring the pharmacodynamic effects of ZD6474 by gene expression profiling. (c) 2005 Wiley-Liss. Inc.