Ciardiello F, Bianco R, Damiano V, Fontanini G, Caputo R, Pomatico G, De Placido S, Bianco A R, Mendelsohn J, Tortora G
Cattedra di Oncologia Medica, Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica, Facoltà di Medicina e Chirurgia, Università degli Studi di Napoli Federico II, Naples, Italy.
Clin Cancer Res. 2000 Sep;6(9):3739-47.
Angiogenesis plays a key role in tumor growth and metastasis. The transforming growth factor alpha (TGF-alpha)-epidermal growth factor receptor (EGFR) autocrine pathway controls in part the production of angiogenic factors such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in cancer cells. In this study, we have evaluated the antiangiogenic and antitumor activity of monoclonal antibody (MAb) C225, an anti-EGFR chimeric human-mouse MAb, alone and in combination with a human VEGF antisense (AS) 21-mer phosphorothioate oligonucleotide (VEGF-AS) in human GEO colon cancer cells. MAb C225 treatment determined a dose-dependent inhibition of VEGF, bFGF, and TGF-alpha production by GEO cells in vitro. Treatment with VEGF-AS caused a selective inhibition in VEGF expression by GEO cells in vitro. Treatment of immunodeficient mice bearing established, palpable GEO xenografts for 3 weeks with VEGF-AS or with MAb C225 determined a cytostatic reversible inhibition of tumor growth. In contrast, a prolonged inhibition of tumor growth was observed in all mice treated with the two agents, in combination with a significant improvement in mice survival compared with controls (P < .001), to MAb C225 (P < .001), or to VEGF-AS (P < .001) treated mice. All mice died within 4, 6, and 8 weeks after tumor cell injection in the control, VEGF-AS and MAb C225 groups, respectively. In contrast, 50% of mice treated with the combination of VEGF-AS and MAb C225 were alive at 13 weeks. Ten % of mice treated with VEGF-AS plus MAb C225 were alive at 20 weeks and had no histological evidence of GEO tumors. Immunohistochemical analysis of GEO tumor xenografts demonstrated a significant reduction of VEGF expression after treatment with VEGF-AS with a parallel reduction in microvessel count. MAb C225 treatment determined a reduction in the expression of VEGF, bFGF, and TGF-alpha with a reduction in microvessel count. Finally, a significant potentiation in inhibition of VEGF expression and little or no microvessels were observed in GEO tumors after the combined treatment with the two agents.
血管生成在肿瘤生长和转移中起关键作用。转化生长因子α（TGF-α）-表皮生长因子受体（EGFR）自分泌途径部分控制癌细胞中血管生成因子如血管内皮生长因子（VEGF）和碱性成纤维细胞生长因子（bFGF）的产生。在本研究中，我们评估了单克隆抗体（MAb）C225（一种抗EGFR嵌合人-鼠单克隆抗体）单独以及与人类VEGF反义（AS）21聚硫代磷酸酯寡核苷酸（VEGF-AS）联合应用于人GEO结肠癌细胞中的抗血管生成和抗肿瘤活性。MAb C225处理在体外确定了对GEO细胞产生VEGF、bFGF和TGF-α的剂量依赖性抑制。用VEGF-AS处理在体外导致GEO细胞对VEGF表达的选择性抑制。用VEGF-AS或MAb C225处理已建立可触及GEO异种移植瘤的免疫缺陷小鼠3周，确定了对肿瘤生长的细胞生长抑制性可逆抑制。相比之下，在用两种药物联合处理的所有小鼠中观察到肿瘤生长的长期抑制，与对照组（P <.001）、MAb C225处理组（P <.001）或VEGF-AS处理组（P <.001）相比，小鼠存活率有显著提高。在对照组、VEGF-AS组和MAb C225组中，分别在肿瘤细胞注射后4、6和8周内所有小鼠死亡。相比之下，用VEGF-AS和MAb C225联合处理的小鼠中有50%在13周时存活。用VEGF-AS加MAb C225处理的小鼠中有10%在20周时存活且没有GEO肿瘤的组织学证据。对GEO肿瘤异种移植瘤的免疫组织化学分析表明，用VEGF-AS处理后VEGF表达显著降低，同时微血管计数平行减少。MAb C225处理确定VEGF、bFGF和TGF-α的表达减少，微血管计数减少。最后，在用两种药物联合处理后的GEO肿瘤中观察到VEGF表达抑制的显著增强以及很少或没有微血管。
