Sunitinib malate is active against human urothelial carcinoma and enhances the activity of cisplatin in a preclinical model.
OBJECTIVE
Sunitinib malate (Pfizer, Inc.) is a multitargeted kinase inhibitor that inhibits vascular endothelial growth factor (VEGF) receptor (R)-1, 2 and 3, platelet-derived growth factor receptors (PDGFR)-alpha and beta, Flt3, RET, and Kit. Angiogenesis and VEGF expression correlate with poor outcomes in human urothelial carcinoma. We designed a preclinical study to examine the efficacy of sunitinib alone and in combination with cisplatin against human urothelial carcinoma.


METHODS
The in vitro activities of sunitinib and cisplatin alone and in combination were determined against human urothelial carcinoma cell lines, TCC-SUP and 5637. Antitumor activities were also determined in vivo against murine subcutaneous 5637 xenografts. Immunohistochemistry (IHC) was performed to detect VEGFR2 and Kit, and modulation of proliferation, apoptosis, and angiogenesis.


RESULTS
Both cell lines expressed VEGFR2, but did not express Kit. Sunitinib displayed activity against both cell lines in vitro at low micromolar concentrations, which are not attainable in vivo, and was synergistic with cisplatin. Activity was observed for sunitinib at 20 and 40 mg/kg orally once daily for 4 weeks, which attains low nanomolar concentrations in vivo against murine 5637 xenografts. Sunitinib 20 mg/kg/d in combination with cisplatin 4 mg/kg/wk intraperitoneally induced tumor regression compared to no therapy (P < 0.0001) or cisplatin alone (P = 0.06). Cisplatin, sunitinib, and combination treated tumors displayed significantly reduced ki-67 expression compared with control untreated tumors, and the difference was also statistically significant for the combination compared with cisplatin. Cleaved caspase-3 expression was significantly higher for sunitinib single agent and combination therapy compared with untreated controls, and for combination therapy compared with cisplatin alone. CD31 expression was diminished for both single agents and combination therapy compared with untreated tumors.


CONCLUSIONS
Sunitinib is preclinically active against urothelial carcinoma, and enhances the activity of cisplatin probably by targeting the stroma.
Sonpavde
Guru
G
Texas Oncology, P.A. and U.S. Oncology Research, Houston, TX 77030, USA. gurus@bcm.tmc.edu
Jian
Weiguo
W
Liu
Hao
H
Wu
Meng-Fen
MF
Shen
Steven S
SS
Lerner
Seth P
SP
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis; D002277:Carcinoma / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use*; D004357:Drug Synergism; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D051379:Mice; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D011758:Pyrroles / Q000627:therapeutic use*; D000077210:Sunitinib; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy*; D019459:Urothelium / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D007211:Indoles; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D002945:Cisplatin; D000077210:Sunitinib