McCarty Marya F, Wey Jane, Stoeltzing Oliver, Liu Wenbiao, Fan Fan, Bucana Corazon, Mansfield Paul F, Ryan Anderson J, Ellis Lee M
Department of Surgical Oncology, Unit 444, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009, USA.
Mol Cancer Ther. 2004 Sep;3(9):1041-8.
Vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) have been strongly implicated in the growth and metastasis of gastric cancer. The purpose of this study was to examine the effects of ZD6474, an inhibitor of inhibitor of VEGF receptor (VEGFR) tyrosine kinase with additional activity against EGF receptor (EGFR), on tumor growth and angiogenesis in an orthotopic model of gastric cancer. In vitro, ZD6474 inhibited human umbilical vascular endothelial cell and TMK-1 human gastric tumor cell proliferation in a dose-dependent fashion. EGF-mediated activation of EGFR and Erk-1/2 was decreased in tumor cells after ZD6474 treatment. In addition, VEGF-mediated activation of VEGFR2 and Erk-1/2 was decreased in human umbilical vascular endothelial cells. TMK-1 human gastric adenocarcinoma cells were injected into the gastric wall of nude mice. ZD6474 therapy was initiated on day 10. Mice (n = 14 per group) were treated p.o. with (a) 1% Tween 80 (control), (b) 50 mg/kg/d ZD6474, or (c) 100 mg/kg/d ZD6474. Mice were sacrificed on day 33. Tumors from each group were stained for markers of blood vessels, pericytes, proliferation, and apoptosis. ZD6474 at both 50 and 100 mg/kg/d led to marked inhibition of tumor growth (P < 0.05). ZD6474 reduced tumor cell proliferation by 48% in the 50 mg/kg/d group and 65% in the 100 mg/kg/d group (P < 0.03) and increased tumor cell apoptosis (P < 0.001) in vivo. ZD6474 led to a 69% decrease in microvessel density in the 50 mg/kg/d group (P < 0.001) and a 62% decrease in the 100 mg/kg/d group (P < 0.001). Although microvessel density was decreased by ZD6474, the remaining vessels showed a relatively higher percentage of pericyte coverage (3-fold increase; P < 0.001), perhaps reflecting selective loss of uncovered vessels in the ZD6474 group. In conclusion, therapies such as ZD6474 that target two distinct aspects of tumor growth, angiogenesis and tumor cell proliferation, warrant further investigation.
血管内皮生长因子（VEGF）和表皮生长因子（EGF）与胃癌的生长和转移密切相关。本研究旨在探讨ZD6474（一种VEGF受体（VEGFR）酪氨酸激酶抑制剂，对EGF受体（EGFR）也有额外活性）对胃癌原位模型中肿瘤生长和血管生成的影响。在体外，ZD6474以剂量依赖的方式抑制人脐血管内皮细胞和TMK-1人胃癌细胞的增殖。ZD6474处理后，肿瘤细胞中EGF介导的EGFR和Erk-1/2激活减少。此外，人脐血管内皮细胞中VEGF介导的VEGFR2和Erk-1/2激活也减少。将TMK-1人胃腺癌细胞注射到裸鼠胃壁中。在第10天开始ZD6474治疗。小鼠（每组n = 14）经口给予（a）1%吐温80（对照）、（b）50 mg/kg/d ZD6474或（c）100 mg/kg/d ZD6474。在第33天处死小鼠。对每组肿瘤进行血管、周细胞、增殖和凋亡标志物染色。50和100 mg/kg/d的ZD6474均导致肿瘤生长明显受到抑制（P < 0.05）。ZD6474在50 mg/kg/d组使肿瘤细胞增殖减少48%，在100 mg/kg/d组减少65%（P < 0.03），并在体内增加肿瘤细胞凋亡（P < 0.001）。ZD6474在50 mg/kg/d组使微血管密度降低69%（P < 0.001），在100 mg/kg/d组降低62%（P < 0.001）。尽管ZD6474降低了微血管密度，但剩余血管显示周细胞覆盖百分比相对较高（增加3倍；P < 0.001），这可能反映了ZD6474组中未被覆盖血管的选择性丢失。总之，像ZD6474这样针对肿瘤生长、血管生成和肿瘤细胞增殖两个不同方面的治疗方法值得进一步研究。
