zd-6126 and Lung-Neoplasms

With recent Food and Drug Administration approval of the anti-vascular endothelial growth factor (VEGF) antibody for the treatment of colon cancer, it may be possible to achieve similar progress in the treatment of locally advanced lung cancer. Antiangiogenic therapies in the clinic are a reality, and it is important to demonstrate that they can be used safely with conventional modalities, including radiation therapy (RT). Strategies under scrutiny in preclinical and clinical studies include the use of endogenous inhibitors of angiogenesis, use of agents that target VEGF and VEGF receptor signaling, targeting endothelial-related integrins during angiogenesis, and targeting the preexisting immature vessels growing within tumors (ie, vascular targeting). Regardless of the approach, it is necessary to address whether angiogenesis is a consistent phenomenon within the lung parenchyma around a cancer and a relevant target and whether inhibiting angiogenesis will improve current lung cancer therapies without increasing toxicity. Vascular-targeting agents (VTAs) are an interesting class of agents that have the potential to enhance RT, but their clinical promise has yet to be realized. In preclinical models, these agents selectively destroy the tumor vasculature, initiating a rapid centralized necrosis within established tumors. Characteristically, after treatment with VTAs, a rim of viable tumor cells remains at the periphery of the tumor, which remains well perfused and should therefore be relatively sensitive to radiation-induced cytotoxicity. This review will focus on VTAs in the treatment of lung cancer and includes a discussion of combination studies with RT in the laboratory and some of the hurdles in the clinical application of these agents.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Combined Modality Therapy; Humans; Lung Neoplasms; Neovascularization, Pathologic; Organophosphorus Compounds; Vascular Endothelial Growth Factors; Xanthones

ZD6126 is a vascular-disrupting agent that affects the endothelial tubulin cytoskeleton causing selective occlusion of tumor vasculature and extensive tumor cell necrosis. The present study evaluated the antitumor and antivascular activities of ZD6126 in the clinically relevant murine renal cell carcinoma (RENCA) model and also evaluated biological response to therapy using color Doppler imaging as biomarker. Mice were implanted with RENCA tumor cells (day 0) and established tumors were treated with ZD6126 (100 mg/kg i.p.) or vehicle with repeated intermittent doses on day 10, 14 and 18. ZD6126 treatment led to a significant reduction in tumor size and was associated with extensive tumor necrosis and a reduction in tumor blood flow versus controls. MVD increased with intermittent treatment (day 10, 14 and 18). In an additional study, animals were treated at day 19 and quantitative three-dimensional microvascular corrosion casting was performed to enable detailed assessment of the tumor vascular architecture. Corrosion casting showed that tumor vessel architecture is affected by treatment, whereas pre-existing vessels in control tissues are practically not affected. Inter-vessel and inter-branch distances as well as vessel diameters are influenced by treatment. In conclusion, ZD6126 showed potent antitumor efficacy in the RENCA model and our data suggest that decrease in tumor blood flow may be a useful surrogate marker of treatment effect.

Topics: Adenocarcinoma; Animals; Apoptosis; Blotting, Western; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Female; Immunoenzyme Techniques; Kidney Neoplasms; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Neovascularization, Pathologic; Organophosphorus Compounds

Endostatin is an anti-angiogenic agent that blocks endothelial cell proliferation, tumor growth, and metastasis. Several lines of direct evidence show that gliomas express high levels of endostatin. However, the anti-angiogenic activity and cellular mechanisms of endostatin from tumor cells have not been completely elucidated. In this study, we established C6 glioblastoma (GBM) xenografts in nude mice by subcutaneously injecting glioma cell lines, C6-null cells, and stable transfected-C6 cells overexpressing mock vector (C6-mock) and endostatin (C6-endo). We found that overexpression of endostatin in C6-endo cells significantly suppressed the expression of VEGF in tumor cells in vivo as well as in vitro. Furthermore, the tumor growth derived from C6-endo cells was inhibited. Our data demonstrate that endostatin could play a direct role in inhibiting tumor cells, and suggest that enhancing endostatin expression in gliomas could be an effective treatment strategy.

Topics: Adenocarcinoma; Angiogenesis Inhibitors; Animals; Apoptosis; Blotting, Western; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Down-Regulation; Endostatins; Gene Expression; Genetic Vectors; Glioblastoma; Immunoenzyme Techniques; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Organophosphorus Compounds; Rats; Vascular Endothelial Growth Factors

Targeting the tumor vasculature may offer an alternative or complementary therapeutic approach to targeting growth factor signaling in lung cancer. The aim of these studies was to evaluate the antitumor effects in vivo of the combination of ZD6126, a tumor-selective vascular-targeting agent; ZD1839 (gefitinib, Iressa), an epidermal growth factor receptor tyrosine kinase inhibitor; and ionizing radiation in the treatment of non-small cell lung cancer xenograft model.. Athymic nude mice with established flank A549 human non-small cell lung cancer xenograft model xenografts were treated with fractionated radiation therapy, ZD6126, ZD1839, or combinations of each treatment. ZD6126 (150 mg/kg) was given i.p. the day after each course of radiation. Animals treated with ZD1839 received 100 mg/kg per dose per animal, 5 or 7 days/wk for 2 weeks. Immunohistochemistry was done to evaluate the effects on tumor growth using an anti-Ki67 monoclonal antibody. Effects on tumor-induced vascularization were quantified using an anti-factor VIII-related antigen monoclonal antibody.. ZD6126 attenuated the growth of human A549 flank xenografts compared with untreated animals. Marked antitumor effects were observed when animals were treated with a combination of ZD6126 and fractionated radiation therapy with protracted tumor regression. ZD6126 + ZD1839 resulted in a greater tumor growth delay than either agent alone. Similar additive effects were seen with ZD1839 + fractionated radiation. Finally, the addition of ZD6126 to ZD1839 and radiation therapy seemed to further improve tumor growth control, with a significant tumor growth delay compared with animals treated with single agent or with double combinations. Immunohistochemistry showed that ZD1839 induced a marked reduction in A549 tumor cell proliferation. Both ZD1839 and ZD6126 treatment substantially reduced tumor-induced angiogenesis. ZD6126 caused marked vessel destruction through loss of endothelial cells and thrombosis, substantially increasing the level of necrosis seen when combined with radiation therapy. The combination of radiation therapy, ZD6126, and ZD1839 induced the greatest effects on tumor growth and angiogenesis.. This first report shows that a selective vascular-targeting agent (ZD6126) + an anti-epidermal growth factor receptor agent (ZD1839) and radiation have additive in vivo effects in a human cancer model. Targeting the tumor vasculature offers an excellent strategy to enhance radiation cytotoxicity. Polytargeted therapy with agents that interfere with both growth factor and angiogenic signaling warrants further investigation.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Endothelium, Vascular; Enzyme Inhibitors; Epidermal Growth Factor; ErbB Receptors; Female; Gefitinib; Immunohistochemistry; Ki-67 Antigen; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Necrosis; Neoplasm Transplantation; Neovascularization, Pathologic; Organophosphorus Compounds; Protein Kinase Inhibitors; Quinazolines; Signal Transduction; Time Factors

Topics: Disease Progression; Endothelial Growth Factors; Humans; Intercellular Signaling Peptides and Proteins; Lung Neoplasms; Lymphokines; Neovascularization, Pathologic; Organophosphorus Compounds; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

ZD6126 (ANG453) is a novel vascular targeting agent that selectively disrupts the cytoskeleton of endothelial cells in tumor. In mouse s.c. xenograft models, ZD6126 was found to induce selective occlusion of tumor blood vessels, cessation of tumor blood flow, and death of tumor cells because of the starvation of oxygen and nutrition. Here, we investigated whether ZD6126 inhibited the metastatic formation of human non-small cell lung cancer cells. PC14PE6 (adenocarcinoma) and H226 (squamous cell carcinoma) cells were injected into the tail vein of nude mice, and lung metastases were estimated. ZD6126 treatment involved either a single dose on 24 h before killing or daily doses from day 14 until the end of the experiment. Single treatment with i.p. injection of 200 mg/kg ZD6126 caused bleeding and necrotic changes in the tumor by 24 h. Histological analysis revealed that apoptotic tumor cells were markedly increased in the ZD6126-treated group. Moreover, ZD6126 induced the apoptosis of CD31-positive vascular endothelial cells in tumors but not in the normal lung parenchyma. When mice were treated daily with 100 mg/kg ZD6126 from day 14 until the end of the experiment, the lung weight was significantly less in the ZD6126-treated group than that of the control group, despite no difference in the number of metastatic nodules. These data suggest that ZD6126 could demonstrate its antitumor activity against both already established and early phase of lung cancer metastasis by causing the selective apoptosis of tumor endothelial cells and destruction of the tumor vasculature.

Topics: Adenocarcinoma; Angiogenesis Inhibitors; Animals; Apoptosis; Cell Division; Endothelium, Vascular; Growth Inhibitors; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neovascularization, Pathologic; Organophosphorus Compounds