zd-6126 and Glioblastoma

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

The effect of ZD6126 on tumor oxygen tension and tumor growth delay in combination with ionizing radiation was examined in the human U87 glioblastoma tumor model. Resistance to ZD6126 treatment was investigated with the nitric oxide synthase inhibitor, l-N(G)-nitroarginine methyl ester (hydrochloride; l-NAME/active form, l-NNA).. U87 human xenografts were grown in athymic nude mice. ZD6126 was given with or without l-NNA. Tumor oxygen tension was measured using the Oxford Oxylite (Oxford, England) fiberoptic probe system. Tumor volume was determined by direct measurement with calipers and calculated by the formula [(smallest diameter(2) x widest diameter)/2].. Multiple doses of ZD6126 treatment (three doses) had a significant effect on tumor growth delay, reducing the average daily tumor growth rate from 29% to 16%. When given 1 hour before radiation, ZD6126 caused an acute increase in hypoxia in U87 tumors, and reduced tumor growth delay compared with that of radiation alone. The combination of ZD6126 given after radiation, either as a single dose or in multiple doses, had greater or similar antitumor activity compared with radiation alone. Twenty-four hours after administration, a single dose of ZD6126 induced little (10 +/- 8%) necrosis in U87 xenografts. l-NNA, when given in combination with ZD6126, significantly enhanced the effectiveness of ZD6126 in inducing tumor necrosis.. Our observation that ZD6126-induced tumor hypoxia can decrease radiation response when ZD6126 is given prior to radiation indicates the importance of scheduling. Our findings suggest that the optimal therapeutic benefit of ZD6126 plus radiation in human glioblastoma may require multiple dosing in combination with a nitric oxide synthase inhibitor, to be scheduled following radiotherapy.

Topics: Angiogenesis Inhibitors; Animals; Blood Vessels; Brain Neoplasms; Combined Modality Therapy; Drug Therapy, Combination; Enzyme Inhibitors; Glioblastoma; Humans; Hypoxia; Mice; Mice, Nude; Necrosis; Neovascularization, Pathologic; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Organophosphorus Compounds; Oxygen; Radiation Tolerance; Radiation, Ionizing; Transplantation, Heterologous; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A