Antiangiogenic and antitumor activity of anti-epidermal growth factor receptor C225 monoclonal antibody in combination with vascular endothelial growth factor antisense oligonucleotide in human GEO colon cancer cells

Angiogenesis plays a key role in tumor growth and metastasis, The transform ing growth factor alpha (TGF-alpha)epidermal growth factor receptor (EGFR) autocrine pathway controls in part the production of angiogenic factors suc h as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in cancer cells. In this study, we have evaluated the antiang iogenic and antitumor activity of monoclonal antibody (MAb) C225, an anti-E GFR chimeric human-mouse MAb, alone and in combination with a human VEGF an tisense (AS) 21-mer phosphorothioate oligonucleotide (VEGF-AS) in human GEO colon cancer cells. MAb C225 treatment determined a dose-dependent inhibit ion of VEGF, bFGF, and TGF-alpha production by GEO cells in vitro. Treatmen t with VEGF-AS caused a selective inhibition in VEGF expression by GEO cell s in vitro, Treatment of immunodeficient mice bearing established, palpable GEO xenografts for 3 weeks with VEGF-AS or with MAb C225 determined a cyto static reversible inhibition of tumor growth, In contrast, a prolonged inhi bition of tumor growth was observed in all mice treated with the two agents , in combination with a significant improvement in mice survival compared w ith 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 injec tion 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 ali ve at 13 weeks. Ten % of mice treated with VEGF-AS plus MAb, C225 were aliv e at 20 weeks and had no histological evidence of GEO tumors. Immunohistoch emical analysis of GEO tumor xenografts demonstrated a significant reductio n of VEGF expression after treatment with VEGF-AS with a parallel reduction in microvessel count. MAb C225 treatment determined a reduction in the exp ression of VEGF, bFGF, and TGF-alpha with a reduction in microvessel count. Finally, a significant potentiation in inhibition of VEGF expression and l ittle or no microvessels were observed in GEO tumors after the combined tre atment with the two agents.