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


METHODS
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 was 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.
Yang
S
S
State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, 510060, PR China.
Wu
J
J
Zuo
Y
Y
Tan
L
L
Jia
H
H
Yan
H
H
Zhu
X
X
Zeng
M
M
Ma
J
J
Huang
W
W
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002277:Carcinoma; D017024:Chemotherapy, Adjuvant; D006801:Humans; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use
D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C452423:vandetanib