Antiangiogenic and antitumor activity of a novel vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor ZD6474 in a metastatic human pancreatic tumor model
Antiangiogenic and antitumor activity of a novel vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor ZD6474 in a metastatic human pancreatic tumor model
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DOI：
10.1097/cad.0b013e3280147d13
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发表时间：
2007-06-01
影响因子：
2.3
通讯作者：
Bruns, Christiane J.
中科院分区：
文献类型：
--
作者：
Conrad, Claudius;Ischenko, Ivan;Bruns, Christiane J.
ZD6474是一种新型的口服血管内皮生长因子受体激酶插入结构域受体/flk-1酪氨酸激酶活性抑制剂，对表皮生长因子受体-1酪氨酸激酶具有额外的活性。本研究的目的是评估ZD6474单独或联合吉西他滨在转移性胰腺癌原位模型中的应用。裸鼠（9 ~ 10只/组）原位注射1 × 10(6) L3.6pI人胰腺癌细胞。8天后，治疗开始仅使用载体，吉西他滨（100 mg/kg腹腔注射，每周两次），ZD6474 （50 mg/kg口服，每天一次）或两种治疗的组合。开始治疗后第24天处死动物。Western blotting分析不同人胰腺癌细胞和人脐静脉内皮细胞中血管内皮生长因子受体-2和表皮生长因子受体磷酸化水平以及AKT和细胞外信号调节激酶-1/2磷酸化水平。与对照组（1231 mg）相比，吉西他滨、ZD6474和联合组治疗肿瘤的平均重量分别减少到836、541和308 mg。与对照组和吉西他滨组的10/10和9/9相比，ZD6474单独治疗组和联合治疗组的淋巴结转移率均显著降低，分别有3/10和1/5的动物发生转移（P分别< 0.003和< 0.0003）。ZD6474组和联合治疗组微血管密度和细胞增殖均显著降低（P < 0.02）。用ZD6474治疗后，肿瘤样本的免疫组化结果显示，活化和磷酸化的表皮生长因子受体减少，而总表皮生长因子受体水平与对照肿瘤相当。Western blot分析发现，ZD6474通过抗血管内皮生长因子受体-2机制抑制肿瘤血管生成，通过抗表皮生长因子受体机制抑制癌细胞生长。与对照组或单独使用吉西他滨相比，ZD6474降低了原发性胰腺肿瘤的生长，减少了淋巴结和肝脏转移。在接受ZD6474和吉西他滨联合治疗的动物中，肿瘤生长进一步受到抑制。
ZD6474 is a novel, orally available inhibitor of vascular endothelial growth factor receptor kinase insert domain receptor/flk-1 tyrosine kinase activity with additional activity against the epidermal growth factor receptor-1 tyrosine kinase. The aim of this study was to evaluate ZD6474, alone and in combination with gemcitabine, in an orthotopic model of metastatic pancreatic cancer. Nude mice (nine to 10/group) were injected orthotopically with 1 x 10(6) L3.6pI human pancreatic cancer cells. Eight days later, treatment was initiated with vehicle only, gemcitabine (100 mg/kg intraperitoneal twice weekly), ZD6474 (50 mg/kg oral once daily) or a combination of the two treatments. Animals were killed on day 24 posttreatment initiation. The phosphorylation status level of vascular endothelial growth factor receptor-2 and epidermal growth factor receptor as well as the phosphorylation level of AKT and extracellular signal-regulated kinase-1/2 in different human pancreatic carcinoma cells and in human umbilical vein endothelial cells was analyzed by Western blotting. Compared with controls (1231 mg), the mean weight of treated tumors was reduced to 836, 541 and 308 mg in the gemcitabine, ZD6474 and combination groups, respectively. Lymph node metastasis was significantly reduced in both the ZD6474 alone and combined treatment groups, with 3/10 and 1/5 animals developing metastases, compared with 10/10 and 9/9 in the control and gemcitabine groups (P < 0.003 and < 0.0003, respectively). Microvessel density and cell proliferation were significantly reduced in the ZD6474 and combined treatment groups (P < 0.02). Immunohistochemistry of tumor samples following treatment with ZD6474 resulted in a reduction of the activated and phosphorylated epidermal growth factor receptor, whereas total epidermal growth factor receptor levels were comparable with control tumors. On the basis of Western blot analysis, ZD6474 provides inhibition of tumor angiogenesis through an anti-vascular endothelial growth factor receptor-2 mechanism and inhibition of cancer cell growth through an anti-epidermal growth factor receptor mechanism. ZD6474 decreased primary pancreatic tumor growth and reduced lymph node and liver metastases compared with controls or gemcitabine alone. Tumor growth was inhibited further in animals receiving ZD6474 and gemcitabine in combination.