Antitumor effect of sunitinib against skeletal metastatic renal cell carcinoma through inhibition of osteoclast function

We investigated the inhibitory effect of sunitinib, a newly approved multitargeted tyrosine kinase inhibitor, against the progression of renal cell cancer (RCC) bone metastases in vivo. In vitro cell proliferation was determined using the MTS assay. To investigate the inhibitory effects of sunitinib...

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Bibliographic Details
Published in:International journal of cancer 2012-02, Vol.130 (3), p.677-684
Main Authors: Maita, Shinya, Yuasa, Takeshi, Tsuchiya, Norihiko, Mitobe, Yoko, Narita, Shintaro, Horikawa, Yohei, Hatake, Kiyohiko, Fukui, Iwao, Kimura, Shinya, Maekawa, Taira, Habuchi, Tomonori
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
Animals
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Biological and medical sciences
bone metastases
Bone Neoplasms - drug therapy
Bone Neoplasms - secondary
Cancer
Carcinoma, Renal Cell - pathology
Cell Proliferation - drug effects
Collagen Type I - blood
Collagen Type I - urine
Disease Models, Animal
Diseases of the osteoarticular system
Female
Humans
in vivo imaging system
Indoles - pharmacology
Indoles - therapeutic use
Kidney Neoplasms - pathology
Macrophage Colony-Stimulating Factor - blood
Male
Medical research
Medical sciences
Mice
Mice, Inbred BALB C
Mice, Nude
Middle Aged
Osteoclasts - drug effects
Peptides - blood
Peptides - urine
Pyrroles - pharmacology
Pyrroles - therapeutic use
renal cell carcinoma
sunitinib
Tumors
Tumors of striated muscle and skeleton
Vascular Endothelial Growth Factor A - blood
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Summary:We investigated the inhibitory effect of sunitinib, a newly approved multitargeted tyrosine kinase inhibitor, against the progression of renal cell cancer (RCC) bone metastases in vivo. In vitro cell proliferation was determined using the MTS assay. To investigate the inhibitory effects of sunitinib in vivo, we established luciferase‐labeled ACHNLuc cells derived from papillary RCC. Mice in which ACHNLuc cells had been transplanted into the left ventricle to establish bone metastases were treated orally with 40 mg/kg/day sunitinib or vehicle control for 3 weeks. Growth of the cancer cells was monitored using an in vivo imaging system. In addition, 16 patients with metastatic RCC were treated with sunitinib, and serum and urine levels of amino‐terminal telopeptide (NTx) were measured as markers of bone resorption. Sunitinib did not inhibit the growth of RCC cells in vitro at clinically or experimentally achievable serum levels (100 nM–1 μM). To investigate the inhibitory effect of sunitinib in vivo, we established luciferase‐labeled human RCC cells (ACHNLuc). Sunitinib prevented the growth of ACHNLuc RCC cells in the bone metastatic mouse model. The number of osteoclasts in sunitinib‐treated mice was significantly less than that in control mice. Serum and urine levels of NTx in patients with metastatic RCC declined significantly during the first 4 weeks of sunitinib treatment (p = 0.027). Sunitinib is a potent anticancer agent for RCC bone metastases, at least for papillary RCC.
ISSN:0020-7136
1097-0215
DOI:10.1002/ijc.26034