Perrotte P, Matsumoto T, Inoue K, Kuniyasu H, Eve B Y, Hicklin D J, Radinsky R, Dinney C P
Department of Urology, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Clin Cancer Res. 1999 Feb;5(2):257-65.
Epidermal growth factor receptor (EGFR) regulates the growth and progression of human transitional cell carcinoma (TCC) of the bladder. We have shown that therapy targeting EGFR inhibited the growth of human TCC established orthotopically in nude mice. The purpose of this study was to evaluate whether EGFR-directed therapy affects angiogenesis associated with the growth and metastasis of human TCC. We determined the cytostatic effect and the effect on production of angiogenic factors after in vitro treatment of the human TCC cell line 253J B-V with MAb C225, a chimerized monoclonal anti-EGFR antibody. The 253J B-V cells were implanted orthotopically into athymic nude mice, and established tumors (4 weeks) were treated with i.p. MAb C225. Expression of the angiogenic factors vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), and basic fibroblast growth factor (bFGF) was evaluated by immunohistochemistry and in situ mRNA hybridization analyses and correlated with microvessel density evaluated after immunohistochemical staining with anti-CD31. In vitro treatment with MAb C225 inhibited mRNA and protein production of VEGF, IL-8, and bFGF by 253J B-V cells in a dose-dependent manner. MAb C225 therapy of nude mice with established TCCs growing orthotopically resulted in inhibition of growth and metastasis compared with controls (P <0.0005). VEGF, IL-8, and bFGF expression was significantly lower in treated tumors than in controls. The down-regulation of these angiogenic factors preceded the involution of blood vessels. These studies indicate that therapy with anti-EGFR MAb C225 has a significant antitumor effect mediated, in part, by inhibition of angiogenesis.
表皮生长因子受体（EGFR）调节人膀胱移行细胞癌（TCC）的生长和进展。我们已经表明，靶向EGFR的治疗可抑制在裸鼠体内原位建立的人TCC的生长。本研究的目的是评估EGFR导向治疗是否影响与人TCC的生长和转移相关的血管生成。我们用嵌合单克隆抗EGFR抗体MAb C225对人TCC细胞系253J B-V进行体外处理后，测定其细胞生长抑制作用以及对血管生成因子产生的影响。将253J B-V细胞原位植入无胸腺裸鼠体内，对形成的肿瘤（4周）腹腔注射MAb C225进行治疗。通过免疫组织化学和原位mRNA杂交分析评估血管生成因子血管内皮生长因子（VEGF）、白细胞介素-8（IL-8）和碱性成纤维细胞生长因子（bFGF）的表达，并与抗CD31免疫组织化学染色后评估的微血管密度相关联。体外使用MAb C225处理以剂量依赖方式抑制253J B-V细胞中VEGF、IL-8和bFGF的mRNA和蛋白质产生。与对照组相比，对原位生长有TCC的裸鼠进行MAb C225治疗可抑制生长和转移（P<0.0005）。治疗后的肿瘤中VEGF、IL-8和bFGF表达明显低于对照组。这些血管生成因子的下调先于血管退化。这些研究表明，抗EGFR单克隆抗体MAb C225治疗具有显著的抗肿瘤作用，部分是通过抑制血管生成介导的。
