Addition of receptor tyrosine kinase inhibitor to radiation increases tumour control in an orthotopic murine model of breast cancer metastasis in bone

The receptor tyrosine kinase inhibitor, SU11248, was added to localised radiation to evaluate the response of bone metastases and to define the basic mechanism of radiosensitisation. Treatment with SU11248 and radiation was assessed in vitro using cultured 4T1 breast cancer cells and in vivo using an orthotopic 4T1 murine mammary tumour model of breast cancer bone metastasis. Cultured 4T1 cells treated with SU11248 (1 μM) and radiation (10 Gy) showed an almost 7.5-fold increase in caspase-mediated apoptosis after 24 h of incubation, compared to either treatment alone. Mice treated with SU11248 (40 mg/kg/daily) and radiation (15 Gy/single-dose) had a relatively greater reduction in tumour growth, bone osteolysis, osteoclast maturation and microvessel density. Combined modality treatment resulted in improvements in behavioural pain assessment scores and normalisation of neurochemical changes in the spinal cord receiving primary afferent innervation from tumour-bearing femora. Our study demonstrates that SU11248 enhances the radiation control of metastatic breast tumours in bone and tumour-induced pain.