International Journal of Radiation Oncology*Biology*Physics
Biology ContributionTargeted Therapy Against VEGFR and EGFR With ZD6474 Enhances the Therapeutic Efficacy of Irradiation in an Orthotopic Model of Human Non–Small-Cell Lung Cancer
Introduction
Lung cancer is a major health problem worldwide and is the leading cause of cancer-related death for men and women (1). In the United States alone, more than 213,000 cases of lung cancer will be diagnosed, with approximately 160,000 deaths annually 1, 2. Non–small-cell lung cancer (NSCLC) accounts for 75–80% of lung cancer, and patients typically present with advanced disease (3). Currently, treatment options for a patient with locally advanced lung cancer include chemotherapy, radiotherapy, and/or surgery (4). Unfortunately, recent studies showed that conventional therapies may have reached a therapeutic plateau, illustrated by the 5-year survival rate for patients with NSCLC, which remains at 15% (1). Thus, the current therapeutic challenge is to optimize available nonsurgical strategies by incorporating new agents into current therapeutic regimens. Targeting the tumor vasculature with antiangiogenic agents in combination with radiotherapy is one promising approach (5).
Several studies showed that angiogenesis and the expression of vascular endothelial growth factor (VEGF) and other proangiogenic factors and their receptors correlated with less favorable clinical outcome for patients with lung cancer 6, 7, yet clinical trials of agents that target these pathways alone were disappointing. Preclinical studies suggested that monotherapy with antiangiogenic agents will not be sufficient for the treatment of patients with advanced cancer 8, 9 given that tumors typically progress before they respond to therapy and microscopic residual disease persists even after prolonged therapy with these agents. Clinically, bevacizumab, a humanized antibody against VEGF, has shown considerable promise and improved survival for patients with colorectal, breast, or lung cancer when used in combination with chemotherapy 10, 11, 12, 13. We hypothesized that targeting both the tumor and its vasculature by using VEGF and epidermal growth factor (EGF) receptor (VEFGR, EGFR) blockade would improve lung cancer treatment, particularly when combined with radiation therapy. To test this hypothesis, we evaluated the feasibility of combining ZD6474, a potent orally available inhibitor of VEGFR2 and, to a lesser degree, EGFR tyrosine kinase activity 14, 15, 16, 17, 18, 19, with radiation therapy in an orthotopic nude mouse model of human NSCLC that closely mimics the patterns of tumor growth observed in the clinic.
Section snippets
Cell proliferation assay
The NCI-H441 human lung adenocarcinoma cell line (American Type Culture Collection, Manassas, VA) was used for all studies and was maintained in Eagle's modified essential medium supplemented with 10% fetal bovine serum, sodium pyruvate, nonessential amino acids, l-glutamine, vitamin solution, and penicillin-streptomycin (Flow Laboratories, Rockville, MD) at 37°C in 5% carbon dioxide and 95% air. Cell proliferation was approximated by the 3-(4,5-dimethylthiazol-2yl)-2.5-diphenyl-tetrazolium
ZD6474 inhibits H441 lung adenocarcinoma cell proliferation after radiation
The MTT assay was used to characterize the effects of radiation and/or ZD6474 on H441 lung adenocarcinoma cell proliferation. ZD6474 alone inhibited cell proliferation in a dose-dependent fashion, whereas a single 4-Gy dose of radiation had no discernable effect. Within 72 hours of irradiation, proliferation of the lung cancer cells treated with radiation, measured by using MTT absorbance, was not different from that of nonirradiated cells because of rapid tumor cell repopulation. When ZD6474
Discussion
Recent clinical studies of patients with lung cancer showed that conventional therapies may have reached a therapeutic plateau, illustrated by the 5-year survival rate of 14% for patients with locally advanced NSCLC (1). Concurrent or sequential chemoradiotherapy is the current standard of care for patients with locally advanced lung cancer, but has only modestly improved survival for patients with lung cancer 23, 24, and the majority of patients with locally advanced Stage III NSCLC have
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2016, Translational OncologyCitation Excerpt :The mice were 7 weeks old and weighed 20-25 g when the experiments started. An orthotopic A549 xenograft model was developed in nude mice as follows [12,13]: A549 cells were harvested and suspended (4 × 107 cells/ml) in PBS (−) and mixed with the same volume of 10% Matrigel. BALB/cAjcl-nu/nu mice were anesthetized by intraabdominal injection of ketamine (2 mg/mouse) and xylazine (0.2 mg/mouse), and a small skin incision, approximately 2 cm on the left chest wall, was made.
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Supported in part by National Institutes of Health grant CA-06294, MD Anderson Physician Scientist Awards (M.S.O., R.S.H.), Department of Defense grant DAMD 17-02-1-0706, and an AstraZeneca research grant.
Conflict of interest: none.