The aim of the study was to investigate inhibitory effects of the
receptor tyrosine kinase (RTK) inhibitor
SU11248 against CSF-1R and osteoclast (OC) formation. We developed an in vivo model of
breast cancer metastasis to evaluate efficacy of
SU11248 against
tumor growth and
tumor-induced
osteolysis in bone. The in vitro effects of
SU11248 on CSF-1R phosphorylation, OC formation and function were evaluated. Effects on 435/HAL-Luc
tumor growth in bone were monitored by in vivo bioluminescence imaging (BLI), and inhibition of
osteolysis was evaluated by measurement of serum
pyridinoline (PYD) concentration and histology. Phosphorylation of the receptor for
M-CSF (CSF-1R) expressed by NIH3T3 cells was inhibited by
SU11248 with an IC50 of 50-100 nM, consistent with CSF-1R belonging to the class III split
kinase domain RTK family. The early
M-CSF-dependent phase of in vitro murine OC development and function were inhibited by
SU11248 at 10-100 nM. In vivo inhibition of
osteolysis was confirmed by significant lowering of serum PYD levels following
SU11248 treatment of
tumor-bearing mice (P = 0.047). Using BLI,
SU11248 treatment at 40 mg/kg/day for 21 days showed 64% inhibition of
tumor growth in bone (P = 0.006), and at 80 mg/kg/day showed 89% inhibition (P = 0.001). Collectively, these data suggest that
SU11248 may be an effective and tolerated
therapy to inhibit growth of
breast cancer bone
metastases, with the additional advantage of inhibiting
tumor-associated
osteolysis.