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ZD6474, a Small Molecule Tyrosine Kinase Inhibitor, Potentiates the Anti-Tumor and Anti-Metastasis Effects of Radiation for Human Nasopharyngeal Carcinoma

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Purpose: To investigate the capacity for ZD6474, a small molecule tyrosine kinase inhibitor, to enhance antitumor and anti-metastasis effects of radiation on human nasopharyngeal carcinoma (NPC).

Experimental Design: NPC cell lines and xenograft models were evaluated following treatment with ZD6474 and radiation alone and in combination compared with untreated control mice.

Results: Treatment with ZD6474 enhanced the anti-proliferative effect of radiation on NPC cell lines as detected by cell proliferation and apoptosis assays. ZD6474 also induced a significant increase in the radiosensitivity of NPC cells, with radiation enhancement ratios (RERs) ranging from 1.2 to 1.6. Despite the cytotoxicity exhibited by NPC cells following radiotherapy, the invasion and migration of NPC cells were found to be unaffected. In contrast, treatment with ZD6474 strongly inhibited the invasion and migration of NPC cells. When the administration of radiation and ZD6474 was investigated in vitro, the ability of ZD6474 to inhibit activation of the pro-survival signaling pathways induced by radiation was demonstrated. In vivo, ZD6474 significantly enhanced the anti-metastasis effects of radiation, while treatment with radiation and ZD6474 was found to be well tolerated and resulted in a strong inhibition of tumor growth.

Conclusions: Our results suggest the combination of radiation and ZD6474 represents a promising strategy for the treatment of human NPC.
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Keywords: Anti-tumor; ZD6474; anti-metastasis; enhancement effect; epidermal growth factor receptor; nasopharyngeal carcinoma; radiation; vascular endothelial growth factor receptor-2

Document Type: Research Article

Publication date: 2010-09-01

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    As the discovery, identification, characterization and validation of novel human drug targets for anti-cancer drug discovery continues to grow; this journal has become essential reading for all pharmaceutical scientists involved in drug discovery and development.
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