Alferez Denis, Wilkinson Robert W, Watkins Jim, Poulsom Richard, Mandir Nikki, Wedge Stephen R, Pyrah Ian T, Smith Neil R, Jackson Lynsay, Ryan Anderson J, Goodlad Robert A
Cancer Research UK, Histopathology Unit, London Research Institute, London, UK.
Mol Cancer Ther. 2008 Mar;7(3):590-8. doi: 10.1158/1535-7163.MCT-07-0433.
Both the epidermal growth factor (EGF) and the vascular endothelial growth factor (VEGF) pathways are associated with intestinal cancer, and therapeutic approaches targeting either EGF receptor (EGFR) or VEGF receptor (VEGFR) signaling have recently been approved for patients with advanced colorectal cancer. The Apc(Min/+) mouse is a well-characterized in vivo model of intestinal tumorigenesis, and animals with this genetic mutation develop macroscopically detectable adenomas from approximately 6 weeks of age. Previous work in the Apc(Min/+) mouse has shown that therapeutic approaches targeting either VEGFR or EGFR signaling affect predominantly the size or number of adenomas, respectively. In this study, we have assessed the effect of inhibiting both these key pathways simultaneously using ZD6474 (Vandetanib, ZACTIMA), a selective inhibitor of VEGFR and EGFR tyrosine kinases. To assess the effects of ZD6474 on early- and later-stage disease, treatment was initiated in 6- and 10-week-old Apc(Min/+) mice for 28 days. ZD6474 markedly reduced both the number and the size of polyps when administered at either an early or a later stage of polyp development. This reduction in both adenoma number and size resulted in a total reduction in tumor burden in the small intestine of nearly 75% in both studies (P < 0.01). The current data build on the concept that EGFR-dependent tumor cell proliferation and VEGF/VEGFR2-dependent angiogenesis and survival are distinct key mechanisms in polyp development. Pharmacologic inhibition of both signaling pathways has significant antitumor effects at both early and late stages of polyp development. Therefore, targeting both VEGFR- and EGFR-dependent signaling may be a beneficial strategy in early intestinal cancer.
表皮生长因子（EGF）和血管内皮生长因子（VEGF）通路均与肠癌相关，针对表皮生长因子受体（EGFR）或血管内皮生长因子受体（VEGFR）信号传导的治疗方法最近已被批准用于晚期结直肠癌患者。Apc(Min/+)小鼠是一种特征明确的肠道肿瘤发生体内模型，具有这种基因突变的动物从大约6周龄开始会发展出肉眼可检测到的腺瘤。先前在Apc(Min/+)小鼠中的研究表明，针对VEGFR或EGFR信号传导的治疗方法分别主要影响腺瘤的大小或数量。在本研究中，我们评估了使用ZD6474（凡德他尼，ZACTIMA）同时抑制这两个关键通路的效果，ZD6474是一种VEGFR和EGFR酪氨酸激酶的选择性抑制剂。为了评估ZD6474对早期和晚期疾病的影响，在6周龄和10周龄的Apc(Min/+)小鼠中开始治疗，持续28天。在息肉发育的早期或晚期给予ZD6474时，息肉的数量和大小均显著减少。在两项研究中，腺瘤数量和大小的减少均导致小肠肿瘤负担总共降低了近75%（P < 0.01）。目前的数据基于这样的概念，即EGFR依赖性肿瘤细胞增殖以及VEGF/VEGFR2依赖性血管生成和存活是息肉发育中不同的关键机制。对这两种信号通路的药物抑制在息肉发育的早期和晚期均具有显著的抗肿瘤作用。因此，靶向VEGFR和EGFR依赖性信号传导可能是早期肠癌的一种有益策略。
