Axitinib (AG-013736), an oral specific VEGFR TKI, shows potential therapeutic utility against cholangiocarcinoma

Hiroyuki Takahashi, Hidenori Ojima, Hiroko Shimizu, Junji Furuse, Hiroyuki Furukawa, Tatsuhiro Shibata

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Objective: Cholangiocarcinoma is a refractory cancer whose incidence has been increasing worldwide in recent years. Neoangiogenesis plays an important role in the growth of various solid cancers, including cholangiocarcinoma. Vascular endothelial growth factor plays an important role in tumor-induced angiogenesis and its expression is associated with the progression and prognosis of cholangiocarcinoma. This study examined whether axitinib (AG-013736, INLYTA®), a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2 and 3, could be a potentially useful therapeutic agent for cholangiocarcinoma. Methods: We performed expression profiling of angiogenesis-related molecules in eight cholangiocarcinoma cell lines and found that three of them showed high vascular endothelial growth factor expression. Among them, we examined the in vivo anti-tumor effect of axitinib on NCC-BD1 (a gemcitabine-sensitive extra-hepatic cholangiocarcinoma cell line) and TKKK (a gemcitabine-resistant intra-hepatic cholangiocarcinoma cell line) using subcutaneous xenograft models. Results: Oral administration of axitinib significantly inhibited the growth of TKKK xenografts at a dose of 6 mg kg-1 day-1 (P,0.05), and the growth of NCC-BD1 xenografts at 30 mg kg-1 day-1 (P,0.05). Treated tumors showed a significant decrease of microvessel density and the tumor cell proliferation index and a mild but significant increase of the apoptotic index in comparison with untreated tumors. Conclusions: Our results suggest that axitinib should be a promising therapy for vascular endothelial growth factor-expressing cholangiocarcinoma, irrespective of tumor origin and gemcitabine sensitivity.

Original languageEnglish
Article numberhyu045
Pages (from-to)570-578
Number of pages9
JournalJapanese Journal of Clinical Oncology
Volume44
Issue number6
DOIs
Publication statusPublished - 2014
Externally publishedYes

Fingerprint

Cholangiocarcinoma
gemcitabine
Neoplasms
Heterografts
Vascular Endothelial Growth Factor A
Therapeutics
Cell Line
Hepatocytes
Growth
Vascular Endothelial Growth Factor Receptor-3
Vascular Endothelial Growth Factor Receptor-1
Vascular Endothelial Growth Factor Receptor-2
axitinib
Microvessels
Oral Administration
Cell Proliferation
Incidence

Keywords

  • Axitinib
  • Cholangiocarcinoma
  • VEGFR-TKI
  • Xenograft model

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Radiology Nuclear Medicine and imaging

Cite this

Axitinib (AG-013736), an oral specific VEGFR TKI, shows potential therapeutic utility against cholangiocarcinoma. / Takahashi, Hiroyuki; Ojima, Hidenori; Shimizu, Hiroko; Furuse, Junji; Furukawa, Hiroyuki; Shibata, Tatsuhiro.

In: Japanese Journal of Clinical Oncology, Vol. 44, No. 6, hyu045, 2014, p. 570-578.

Research output: Contribution to journalArticle

Takahashi, Hiroyuki ; Ojima, Hidenori ; Shimizu, Hiroko ; Furuse, Junji ; Furukawa, Hiroyuki ; Shibata, Tatsuhiro. / Axitinib (AG-013736), an oral specific VEGFR TKI, shows potential therapeutic utility against cholangiocarcinoma. In: Japanese Journal of Clinical Oncology. 2014 ; Vol. 44, No. 6. pp. 570-578.
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AU - Furuse, Junji

AU - Furukawa, Hiroyuki

AU - Shibata, Tatsuhiro

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AB - Objective: Cholangiocarcinoma is a refractory cancer whose incidence has been increasing worldwide in recent years. Neoangiogenesis plays an important role in the growth of various solid cancers, including cholangiocarcinoma. Vascular endothelial growth factor plays an important role in tumor-induced angiogenesis and its expression is associated with the progression and prognosis of cholangiocarcinoma. This study examined whether axitinib (AG-013736, INLYTA®), a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2 and 3, could be a potentially useful therapeutic agent for cholangiocarcinoma. Methods: We performed expression profiling of angiogenesis-related molecules in eight cholangiocarcinoma cell lines and found that three of them showed high vascular endothelial growth factor expression. Among them, we examined the in vivo anti-tumor effect of axitinib on NCC-BD1 (a gemcitabine-sensitive extra-hepatic cholangiocarcinoma cell line) and TKKK (a gemcitabine-resistant intra-hepatic cholangiocarcinoma cell line) using subcutaneous xenograft models. Results: Oral administration of axitinib significantly inhibited the growth of TKKK xenografts at a dose of 6 mg kg-1 day-1 (P,0.05), and the growth of NCC-BD1 xenografts at 30 mg kg-1 day-1 (P,0.05). Treated tumors showed a significant decrease of microvessel density and the tumor cell proliferation index and a mild but significant increase of the apoptotic index in comparison with untreated tumors. Conclusions: Our results suggest that axitinib should be a promising therapy for vascular endothelial growth factor-expressing cholangiocarcinoma, irrespective of tumor origin and gemcitabine sensitivity.

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