Sunitinib malate is active against human urothelial carcinoma and enhances the activity of cisplatin in a preclinical model

Guru Sonpavde, Weiguo Jian, Hao Liu, Meng Fen Wu, Steven S. Shen, Seth P. Lerner

Research output: Contribution to journalArticle

74 Citations (Scopus)

Abstract

Purpose: 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)-α and β, 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. Design: 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.

Original languageEnglish (US)
Pages (from-to)391-399
Number of pages9
JournalUrologic Oncology: Seminars and Original Investigations
Volume27
Issue number4
DOIs
StatePublished - Jul 1 2009
Externally publishedYes

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Cisplatin
Carcinoma
Heterografts
Cell Line
Neoplasms
Vascular Endothelial Growth Factor Receptor-3
Vascular Endothelial Growth Factor Receptor-1
sunitinib
Platelet-Derived Growth Factor Receptors
Therapeutics
Caspase 3
Vascular Endothelial Growth Factor A
Phosphotransferases
Immunohistochemistry
Apoptosis

Keywords

  • Cisplatin
  • Sunitinib malate
  • Urothelial carcinoma

ASJC Scopus subject areas

  • Oncology
  • Urology

Cite this

Sunitinib malate is active against human urothelial carcinoma and enhances the activity of cisplatin in a preclinical model. / Sonpavde, Guru; Jian, Weiguo; Liu, Hao; Wu, Meng Fen; Shen, Steven S.; Lerner, Seth P.

In: Urologic Oncology: Seminars and Original Investigations, Vol. 27, No. 4, 01.07.2009, p. 391-399.

Research output: Contribution to journalArticle

Sonpavde, Guru ; Jian, Weiguo ; Liu, Hao ; Wu, Meng Fen ; Shen, Steven S. ; Lerner, Seth P. / Sunitinib malate is active against human urothelial carcinoma and enhances the activity of cisplatin in a preclinical model. In: Urologic Oncology: Seminars and Original Investigations. 2009 ; Vol. 27, No. 4. pp. 391-399.
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AU - Jian, Weiguo

AU - Liu, Hao

AU - Wu, Meng Fen

AU - Shen, Steven S.

AU - Lerner, Seth P.

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N2 - Purpose: 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)-α and β, 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. Design: 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.

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