Cancer Research UK, Histopathology Unit, 44 Lincoln's Inn Fields, London, WC2A 3PX.
Int J Oncol. 2010 Oct;37(4):767-72. doi: 10.3892/ijo_00000726.
The Apc(MIN/+) mouse is a well-characterised model of intestinal tumourigenesis in which animals develop macroscopically detectable adenomas. However, most of the adenomas are formed in the small intestine and resolution of events in the colon, the most relevant site for human disease, is limited. Inducing colitis with dextran sodium sulphate (DSS) can selectively enhance the development of lesions in the colon. We demonstrated that a DSS pre-treatment is well tolerated and effective at inducing colon adenomas in an Apc(MIN/+) mouse model. We then investigated the effect of inhibiting vascular endothelial growth factor (VEGFR)- and epidermal growth factor receptor (EGFR)-dependent signalling pathways on the development of adenomas induced in DSS-pretreated (DSS/Apc(MIN/+)) or non-DSS-pretreated (Apc(MIN/+)) mice using vandetanib (ZD6474), a potent and selective inhibitor of VEGFR and EGFR tyrosine kinase activity. Eight-week old Apc(MIN/+) mice were given either drinking water or 1.8% DSS and then vandetanib (ZD6474) (50 mg/kg/day) or vehicle by oral gavage for 28 days and sacrificed 24 h after the last dose and assessed for adenoma formation in the intestines. DSS pre-treatment was well tolerated and significantly enhanced formation of adenomas in the colon of control Apc(MIN/+) mice. Vandetanib treatment significantly reduced adenoma formation in the small intestine by 68% (P=0.001) and the colon by 77% (from 13.8 to 3.1, P=0.01) of DSS-pretreated Apc(MIN/+) mice. In the Apc(MIN/+) group, vandetanib also reduced the mean number of adenomas in the small intestine by 76% (P<0.001) and in the colon by 60% (from 3.9 to 1.5, P=0.1). DSS-pre-treatment increased the resolution of the model, allowing us to confirm statistically significant effects of vandetanib on the development and growth of colon adenomas in the Apc(MIN/+) mouse. Moreover these preclinical data provide a rationale for studying the effects of vandetanib in early stages of intestinal cancer in the clinic.
Apc（MIN/+）小鼠是一种成熟的肠道肿瘤发生模型，该模型中小鼠可形成肉眼可见的腺瘤。然而，大多数腺瘤发生在小肠中，而人类疾病最相关的部位——结肠中的病变的分辨率是有限的。用葡聚糖硫酸钠（DSS）诱导结肠炎可选择性增强结肠病变的发展。我们证明，DSS 预处理在 Apc（MIN/+）小鼠模型中是耐受良好且有效的，可诱导结肠腺瘤的形成。然后，我们使用血管内皮生长因子（VEGFR）和表皮生长因子受体（EGFR）依赖性信号通路的有效抑制剂凡德他尼（ZD6474），来研究其对 DSS 预处理（DSS/Apc（MIN/+））或未用 DSS 预处理（Apc（MIN/+））的小鼠中诱导的腺瘤发展的影响。8 周龄 Apc（MIN/+）小鼠给予饮用水或 1.8% DSS，然后用口服灌胃给予凡德他尼（ZD6474）（50mg/kg/天）或载体，共 28 天，并在最后一次给药后 24 小时处死，评估肠道中腺瘤的形成。DSS 预处理耐受良好，可显著增强对照 Apc（MIN/+）小鼠结肠中的腺瘤形成。凡德他尼治疗可使 DSS 预处理的 Apc（MIN/+）小鼠的小肠和结肠中的腺瘤形成分别显著减少 68%（P=0.001）和 77%（从 13.8 减少至 3.1，P=0.01）。在 Apc（MIN/+）组中，凡德他尼还使小肠和结肠中的腺瘤数量分别减少 76%（P<0.001）和 60%（从 3.9 减少至 1.5，P=0.1）。DSS 预处理增加了模型的分辨率，使我们能够确认凡德他尼对 Apc（MIN/+）小鼠结肠腺瘤的发生和生长的统计学显著影响。此外，这些临床前数据为研究凡德他尼在临床早期肠道癌症中的作用提供了依据。
