Preclinical evaluation of sunitinib as single agent or in combination with chemotherapy in nasopharyngeal carcinoma.
OBJECTIVE
Sunitinib is a multi-target receptor tyrosine kinase (RTK) inhibitor against vascular endothelial growth factor receptors, platelet-derived growth factor receptors (PDGFR), c-kit and RET. Several of these RTKs are known to be involved in the progression of nasopharyngeal carcinoma (NPC). Here, we evaluated the preclinical activities of sunitinib in NPC.


METHODS
We determined the basal level of total and phosphorylated PDGFR, c-kit and RET by immunoblotting in a panel of five NPC cell lines. The effect of sunitinib on NPC cell proliferation was evaluated by MTT assay. We further studied the effect of sunitinib on NPC cell cycle progression and apoptosis. We investigated the in vitro and in vivo activities of sunitinib as single agent and in combination with cisplatin or docetaxel in NPC cell lines and tumor xenografts.


RESULTS
Sunitinib exhibited dose-dependent growth inhibition in all NPC cell lines tested with IC(50) between 2-7.5 μM and maximum inhibition of over 97%. Sunitinib induced apoptosis and cell cycle arrest at G(0)/G(1) phase. In vitro, sunitinib moderately enhanced the growth inhibition of cisplatin or docetaxel. Single agent sunitinib demonstrated significant growth inhibition, reduced microvessel density and caused extensive tumor necrosis in a NPC xenograft model. However, concurrent administration of sunitinib and docetaxel induced severe toxicity in mice without enhanced antitumor effect.


CONCLUSIONS
Single agent sunitinib demonstrated potent in vitro and in vivo growth inhibition in NPC. When combined with chemotherapy, sequential instead of concurrent administration schedule should be further explored.
Hui
Edwin Pun
EP
Cancer Drug Testing Unit, Department of Clinical Oncology, State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Shatin, Hong Kong.
Lui
Vivian W Y
VW
Wong
Cesar S C
CS
Ma
Brigette B Y
BB
Lau
Cecilia P Y
CP
Cheung
Crystal S F
CS
Ho
Kakiu
K
Cheng
Suk-Hang
SH
Ng
Margaret H L
MH
Chan
Anthony T C
AT
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology*; D000077210:Sunitinib; D043823:Taxoids / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D043823:Taxoids; D000077143:Docetaxel; D002945:Cisplatin; D000077210:Sunitinib
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