epidermal-growth-factor and vatalanib

Advances in the medical treatment of colorectal cancer patients have resulted in considerable improvements through the introduction of new cytotoxic drugs. The significant progress in molecular and tumour biology has produced a great number of targeted, tumour-specific, monoclonal antibodies that are now in various stages of clinical development. Two of these antibodies, cetuximab (Erbitux) und bevacizumab (Avastin), directed against the epidermal growth factor receptor (EGFR) and the vascular epithelial growth factor (VEGF), respectively, have recently been approved for use in metastatic colorectal cancer. The combination of well-known and newly developed cytotoxic agents with monoclonal antibodies makes the medical treatment of colorectal cancer patients considerably more complex, but also provides additional therapeutic strategies for patients in advanced stages of disease.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Bevacizumab; Camptothecin; Cetuximab; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Drug Therapy, Combination; Epidermal Growth Factor; ErbB Receptors; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoplasm Metastasis; Panitumumab; Phthalazines; Pyridines; Randomized Controlled Trials as Topic; Vascular Endothelial Growth Factor A; Vitamin B Complex

Receptor tyrosine kinases of the ErbB family play important roles in the control of tumor growth. Vascular endothelial growth factor (VEGF) stimulates endothelial cell proliferation, enhances vascular permeability, and plays an important role in tumor vascularization. We evaluated the effects of selective VEGF receptor (VEGFR; PTK787/ZK222584) and ErbB (PKI166 and ZD1839) inhibitors on tumor growth and angiogenesis and asked whether additional therapeutic benefit was conferred by combination treatment.. The antitumor activity of each inhibitor alone or in combination was assessed in human cancer models in immunocompromised mice. ErbB receptor expression and activation of downstream signaling pathway was evaluated in both tumor and endothelial cells.. Both ErbB inhibitors significantly enhanced the antitumor activity of PTK787/ZK222584. In vitro, ErbB1 inhibition blocked VEGF release by tumor cells and proliferation of both tumor and endothelial cells. In an in vitro angiogenesis assay, epidermal growth factor (EGF) stimulated the release of VEGF by smooth muscle cells resulting in increased angiogenesis, a response blocked by administration of PTK787/ZK222584. Under basal condition, both ZD1839 and PTK787/ZK222584 blocked sprouting, likely via inhibition of an autocrine ErbB1 loop and VEGFR signaling, respectively, in endothelial cells. In conditions of limiting VEGF, EGF plays an important role in endothelial cell proliferation, survival, and sprouting.. We have shown that activation of ErbB1 triggers a plethora of effects, including direct effects on tumor and endothelial cells and indirect effects mediated via induction of VEGF release. Simultaneous blockade of ErbB1 and VEGFR pathways results in a cooperative antitumor effect, indicating that this combination may represent a valid therapeutic strategy.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Apoptosis; Cell Line; Cell Line, Tumor; Coculture Techniques; Drug Synergism; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor; ErbB Receptors; Fluorescent Antibody Technique; Gefitinib; Humans; Immunoblotting; In Situ Nick-End Labeling; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Neoplasms, Experimental; Phthalazines; Platelet Endothelial Cell Adhesion Molecule-1; Protein Kinase Inhibitors; Pyridines; Quinazolines; Transplantation, Heterologous; Vascular Endothelial Growth Factor A