ZD6474, an Inhibitor of Vascular Endothelial Growth Factor Receptor Tyrosine Kinase, Inhibits Growth of Experimental Lung Metastasis and Production of Malignant Pleural Effusions in a Non-Small Cell Lung Cancer Model

Abstract

ZD6474 is a novel, orally active inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase, with some additional activity against epidermal growth factor receptor (EGFR) tyrosine kinase. The purpose of this study was to determine the potential of ZD6474 in the control of established experimental lung metastasis and pleural effusions produced by human non-small cell lung cancer (NSCLC) cells. PC14PE6 (adenocarcinoma) and H226 (squamous cell carcinoma) cells express high levels of EGFR and only PC14PE6 cells overexpress VEGF. Neither ZD6474 nor the EGFR tyrosine kinase inhibitor gefitinib inhibit proliferation of PC14PE6 or H226 cells in vitro. Both PC14PE6 and H226 cells inoculated intravenously into nude mice induced multiple lung nodules after 5-7 weeks. In addition, PC14PE6 cells produced bloody pleural effusions. Daily oral treatment with ZD6474 did not reduce the number of lung nodules produced by PC14PE6 or H226 cells, but did reduce the lung weight and the size of lung nodules. ZD6474 also inhibited the production of pleural effusions by PC14PE6 cells. Histological analyses of lung lesions revealed that ZD6474 treatment inhibited activation of VEGFR-2 and reduced tumor vascularization and tumor cell proliferation. Therapeutic effects of ZD6474 were considered likely to be due to inhibition of VEGFR-2 tyrosine kinase because gefitinib was inactive in this model. These results indicate that ZD6474, an inhibitor of VEGFR-2, may be useful in controlling the growth of established lung metastasis and pleural effusions by NSCLC.

E7080 Suppresses Hematogenous Multiple Organ Metastases of Lung Cancer Cells with Nonmutated Epidermal Growth Factor Receptor

“…The concentrations of E7080 required to inhibit endothelial proliferation was lower, as was the dose needed to show antimetastatic effects (10 vs. 50 mg/kg; refs. 25,37,38). Furthermore, we found that E7080 prolonged survival in mice bearing multiple organ metastases of SBC-5 cells those with pleural effusion caused by PC14PE6 cells, clearly indicating that E7080 is a highly active inhibitor of angiogenesis of lung cancers with nonmutant EGFR.…”

“…However, lung lesions produced by SBC-5 cells were smaller than 2 mm in diameter and had few endothelial cells and lymph endothelial cells. In sharp contrast, PC14PE6 cells, which produce high amounts of VEGF, give rise to highly angiogenic and lymphangiogenic lung lesions greater than 2 mm in diameter (9,25). E7080 decreased the number of endothelial cells, lymph endothelial cells, and proliferating cells in PC14PE6 lung lesions, but it did not in SBC-5 lung lesions with few endothelial cells and lymph endothelial cells (Supplementary Figs.…”

Effects of Vandetanib on Lung Adenocarcinoma Cells Harboring Epidermal Growth Factor Receptor T790M Mutation In vivo

“…For the EGFR sequence, DNA was extracted from each cell line using a QIAamp DNA Mini kit (Qiagen) and the exons encoding the intracellular domain (exons [18][19][20][21][22] were amplified by PCR. Primer sequences and amplification conditions have been described previously (3).…”

“…A combination of bevacizumab with erlotinib seemed to have clinical benefit in the treatment of nonsquamous NSCLC (19). Vandetanib (ZACTIMA) is an orally available multitarget TKI inhibiting VEGFR-2, with additional inhibition of EGFR and rearranged during transfection (RET) receptor signaling (20)(21)(22). Vandetanib has shown promising results in phase II clinical trials in patients with pretreated NSCLC (23)(24)(25).…”

Intraperitoneal VEGF Inhibition Using Bevacizumab: A Potential Approach for the Symptomatic Treatment of Malignant Ascites?

“…Antibody treatment, to a lesser degree, also inhibited tumor growth [59,60,95,96] and prolonged the survival of mice inoculated with tumor cells [59]. Comparable preclinical efficacy was seen with tyrosine kinase inhibitors targeting VEGF receptors [97,98] or with a soluble VEGF decoy receptor inhibiting VEGF [67,99], and after i.p. infusion of a VEGF antisense oligonucleotide [100], but not with conventional chemotherapy applied i.p.…”