ABSTRACT WINNER: BASIC SCIENCE CATEGORY

Abstract

Background: The prognoses of patients with bone metastases, a common type of metastasis for renal cell carcinoma (RCC), is poor when treated with cytokines; average life expectancy is 8 to 16 months. Sunitinib is a newly approved, multitargeted, small-molecule tyrosine kinase inhibitor for the treatment of metastatic RCC (mRCC). In this study, we show that sunitinib has anticancer activity as well as inhibitory activity against osteolysis in an experimental mouse model of bone metastasis of RCC cells. Methods: In vitro cell proliferation was determined using the MTS assay. Mice, which had RCC cells transplanted into the left ventricle for the establishment of bone metastases, were treated orally with sunitinib (40 mg/kg/day) or placebo for 3 weeks. Growth of the cancer cells was monitored using an in vivo imaging system. In addition, a total of 16 patients with mRCC were treated with sunitinib; serum and urine levels of amino-terminal telopeptide (NTx) were measured as markers of bone resorption. Results: Sunitinib did not inhibit the growth of RCC cells in vitro at clinically or experimentally achievable serum levels (100 nM – 1 mM). To investigate the inhibitory effect of sunitinib in vivo, we established luciferase-labeled human RCC cells (ACHN Luc ). Metastatic bone lesions of ACHN Luc cells in the control group progressed during the 3 weeks. On the other hand, photon emissions were significantly suppressed in the sunitinib treatment group (P ,.001). The mean body weights of mice did not differ significantly between the 2 groups. The mean number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts in mice treated with sunitinib was significantly lower than that in mice treated with vehicle control (23.1+ 4.7 versus 33.2+ 7.9 osteoclasts/100 high-power fields, respectively; P ¼ .0137). In addition, serum and urine levels of NTx in patients with mRCC declined significantly during the first 4 weeks of sunitinib treatment (P ¼ .027). Conclusion: In an animal model, we demonstrated that oral administration of a clinically achievable dose of sunitinib prevented the growth of RCC bone metastases in vivo. Because RCC cell lines are resistant to clinically and preclinically achievable plasma concentrations of sunitinib in vitro, prevention of osteoclast activity and/or maturation are possible mechanisms of sunitinib mediated growth inhibition in metastatic bone lesions in vivo. Our study supports the use of sunitinib as an initial treatment for RCC patients with bone metastasis.